Infection Management for Geriatrics in Long-Term Care Facilities

INFEC TION MANAGEMENT F O R G E R I AT R I C S I N L O N G -T E R M C A R E FA C I L I T I E S EDITED THOMAS T. BY ...

Author: Thomas T. Yoshikawa | Joseph G. Ouslander

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INFEC TION MANAGEMENT F O R G E R I AT R I C S I N L O N G -T E R M C A R E FA C I L I T I E S

EDITED

THOMAS

T.

BY

YOSHIKAWA

Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center Los Angeles, California

JOSEPH

G.

OUSLANDER

Emory University School of Medicine Atlanta, Georgia

Marcel Dekker, Inc.

New York • Basel

TM

Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.

ISBN: 0-8247-0784-2 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: 41-61-261-8482; fax: 41-61-261-8896 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 © 2002 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 2 1 PRINTED IN THE UNITED STATES OF AMERICA

To our wives, Catherine Yoshikawa and Lynn Ouslander, for their love and support.

Preface

With the increasing growth of the aging population—especially those aged 85 years and older—over the next 40 years, there will be a parallel demand for longterm care. Such a demand is inevitable, given the changes, diseases, disabilities, and socioeconomic factors associated with growing old. When such age-related factors in an older person create a need for care, services, and support that cannot be met by family and other caregivers, the need arises for long-term care outside the home environment. Although there are different types and venues for longterm care, nursing homes (nursing facilities) remain the dominant sites for providing care for chronically and functionally disabled and cognitively impaired older persons. Thus, nursing homes serve as the prototype long-term care facility (LTCF) that manages chronically disabled elderly individuals. As more and more care is provided in LTCFs, inherent risks and problems arise when the population is very old, frail, and disabled. The population at risk resides in a closed institutional setting; the ratio of healthcare staff to residents may be suboptimal; and quick and easy access to diagnostic, therapeutic, and preventive interventions is limited. One of the most common risks (and complications) of long-term care is infection. Infection (or presence of a fever) is often the reason an LTCF resident is sent to an emergency department or transferred to an acute care facility. However, the clinical diagnosis of an infection in a frail, elderly LTCF resident may be quite difficult, given the atypical clinical manifestations of infection in the very old, limited availability of a clinician onsite in the LTCF to examine the resident, and lack of quick access to diagnostic laboratory and radiological tests. Moreover, once a presumptive diagnosis of infection is made, the decision for an appropriate therapeutic approach may be v

vi

Preface

complex. Issues of advanced directives and/or desires of the resident/family regarding the extent of diagnostic and therapeutic interventions must be considered. Can the resident be treated in the LTCF or is transfer to an acute care facility more appropriate? Does the LTCF have the resources and appropriately trained personnel to treat the resident within the LTCF? If treatment is initiated in the LTCF, what antibiotics and dosages should be used? In addition, other clinical infectious disease issues to be considered when caring for residents in an LTCF include the following: What are the most common infections in this setting? What is the role of an LTCF nurse in managing infections? What ethical factors need to be considered? What should be done when an outbreak of an infection occurs? Are there drug-resistant pathogens in this setting, and how should these be managed? Infection Management for Geriatrics in Long-Term Care Facilities addresses these and many other important questions and issues related to the diagnosis, treatment, prevention, and control of infections in elderly residents of LTCFs. The book was written by internationally and nationally recognized experts in the area of infections, geriatrics, and long-term care. The editors are clinicians who have a long record of patient care, education and training, and research in the fields of geriatrics, gerontology, and long-term care. They are editor-inchief and deputy editor, respectively, of the Journal of the American Geriatrics Society, the leading journal in the field of aging. The book is divided into three major sections. The first is devoted to the principles of aging, long-term care, and infection, with chapters discussing the demographics of long-term care; the differences between acute care and long-term care; epidemiology and special aspects of infections in long-term care; host resistance changes with aging; the interrelationship between aging, nutrition, and immunity; altered clinical manifestations of infections with aging; ethical considerations in managing infections in this setting; the role of nursing in managing infections in LTCFs; principles of infection control in an LTCF; identification and management of outbreaks in an LTCF; and a rational approach to using antibiotics in residents of LTCFs. The second section focuses on the most common and important infectious diseases problems encountered in LTCFs. These include urinary tract infection; influenza and other respiratory viruses; pneumonia and bronchitis; tuberculosis; selected skin infections, i.e., herpes zoster, cellulitis, and scabies; infectious diarrhea; viral hepatitis; and vaccination. The third and final section addresses the problem of emerging drug-resistant pathogens in LTCFs, with detailed information on pathogenetic and molecular mechanisms for antibiotic resistance; methicillin-resistant Staphylococcus aureus; glycopeptide (primarily vancomycin)-resistant enterococci; gram-negative bacteria; and selected fungi (e.g., Candida). An appendix is included with definitions of common infections in a long-term care setting and guidelines for the evaluation of fever and infections in long-term care facilities.

Preface

vii

The book is formatted for easy and quick access to key information; there are numerous figures and tables that summarize important data; and the most relevant and up-to-date references are provided. Clinicians will find this book informative, easy to read, and helpful in managing their LTCF residents with fever and infection. Infection Management for Geriatrics in Long-Term Care Facilities is an essential resource for all healthcare providers and administrators involved with the care of elderly residents in LTCFs. The editors would like to thank Ms. Patricia Thompson for retyping and preparing all the manuscripts in their final form. Thomas T. Yoshikawa Joseph G. Ouslander

Contents

Preface Contributors

v xiii

I.

Principles of Aging, Long-Term Care, and Infection

1.

Demographics and Economics of Long-Term Care A. Jefferson Lesesne and Joseph G. Ouslander

2.

Evaluation of Infections in Long-Term Care Facilities Versus Acute Care Hospitals Andrew D. Weinberg

15

3.

Epidemiology and Special Aspects of Infectious Diseases in Aging Thomas T. Yoshikawa

27

4.

Impact of Age and Chronic Illness-Related Immune Dysfunction on Risk of Infections Steven C. Castle

33

5.

Nutrition and Infection Kevin P. High

51

6.

Clinical Manifestations of Infections Dean C. Norman

71

7.

Ethical Issues of Infectious Disease Interventions Elizabeth L. Cobbs

79

1

ix

x

Contents

8.

Nursing Management of Infections Donna L. Barton and Janet D. Register

99

9.

Establishing an Infection Control Program Janet Nau Franck, Elizabeth Owens Schwab, and David W. Bentley

115

10.

Epidemiologic Investigation of Infectious Disease Outbreaks Chesley L. Richards, Jr., and William R. Jarvis

133

11.

An Approach to Antimicrobial Therapy Shobita Rajagopalan, Jay P. Rho, and Thomas T. Yoshikawa

155

II.

Special Infectious Disease Problems

12.

Urinary Tract Infection Lindsay E. Nicolle

173

13.

Influenza and Other Respiratory Viruses Ghinwa Dumyati and Ann R. Falsey

197

14.

Pneumonia and Bronchitis Joseph M. Mylotte

223

15.

Tuberculosis Shobita Rajagopalan

245

16.

Infected Pressure Ulcers Nigel Livesley and Anthony W. Chow

257

17.

Herpes Zoster, Cellulitis, and Scabies Kenneth Schmader and Jack Twersky

283

18.

Infectious Diarrhea Abbasi J. Akhtar

305

19.

Hepatitis Darrell W. Harrington and Peter V. Barrett

313

20.

Vaccinations Stefan Gravenstein

337

III. Emerging and Drug-Resistant Pathogens 21.

Pathogenesis and Molecular Mechanisms of Antibiotic Resistance Robert A. Bonomo

363

Contents

xi

22.

Methicillin-Resistant Staphylococcus aureus Larry J. Strausbaugh

383

23.

Vancomycin (Glycopeptide)-Resistant Enterococci Lona Mody, Shelly A. McNeil, and Suzanne F. Bradley

411

24.

Gram-Negative Bacteria Vinod K. Dhawan

429

25. Candida and Other Fungi Carol A. Kauffman and Sara A. Hedderwick Appendix A: Definitions of Common Infections in Long-Term Care Facilities Appendix B: Guide to Evaluating Fever and Infection in a Long-Term Care Setting Index

449

473 477 481

Contributors

Abbasi J. Akhtar, M.D., M.R.C.P. Department of Internal Medicine, Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California Peter V. Barrett, M.D. Department of Medicine, Harbor–UCLA Medical Center, Torrance, California Donna L. Barton, R.N., B.C., B.S.N., FACDONA/LTC Director of Nursing, Lake Eustis Care Center, Eustis, Florida David W. Bentley, M.D. Department of Internal Medicine, Saint Louis University School of Medicine, and Geriatric Research, Education, and Clinical Center, St. Louis VA Medical Center, St. Louis, Missouri Robert A. Bonomo, M.D. Department of Medicine, Case Western Reserve University, Cleveland, Ohio Suzanne F. Bradley, M.D. Department of Internal Medicine, University of Michigan, and Divisions of Geriatric Medicine and Infectious Diseases, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan Steven C. Castle, M.D. Geriatric Research, Education, and Clinical Center, VA Greater Los Angeles Healthcare System, and UCLA School of Medicine, Los Angeles, California xiii

xiv

Contributors

Anthony W. Chow, M.D., F.R.C.P.(C), F.A.C.P. Department of Medicine, University of British Columbia, and Division of Infectious Diseases, Vancouver Hospital Health Sciences Centre, Vancouver, British Columbia, Canada Elizabeth L. Cobbs, M.D. Department of Geriatrics and Extended Care, Washington D.C. VA Medical Center, and George Washington University, Washington, D.C. Vinod K. Dhawan, M.D., F.A.C.P., F.R.C.P.(C) Department of Medicine, Charles R. Drew University of Medicine and Science, and UCLA School of Medicine, Los Angeles, California Ghinwa Dumyati, M.D. Infectious Disease Unit, University of Rochester School of Medicine, and Rochester General Hospital, Rochester, New York Ann R. Falsey, M.D. Infectious Disease Unit, University of Rochester School of Medicine, and Rochester General Hospital, Rochester, New York Janet Nau Franck, R.N., M.B.A., C.I.C. Consulting Professionals, Inc., St. Louis, Missouri Stefan Gravenstein, M.D., M.P.H. Department of Medicine, Glennan Center for Geriatrics and Gerontology, Eastern Virginia Medical School, Norfolk, Virginia Darrell W. Harrington, M.D. Department of Medicine, Harbor–UCLA Medical Center, Torrance, California Sara A. Hedderwick, M.R.C.P., D.T.M.&H Department of Infectious Diseases, Royal Victoria Hospital, Belfast, Northern Ireland Kevin P. High, M.D., M.Sc. Sections of Infectious Diseases and Hematology/Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina William R. Jarvis, M.D. Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Carol A. Kauffman, M.D. Department of Internal Medicine, University of Michigan, and Division of Infectious Diseases, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan A. Jefferson Lesesne, M.D. Geriatric Medicine and Gerontology, Emory University School of Medicine, Atlanta, Georgia

Contributors

xv

Nigel Livesley, M.D., F.R.C.P.(C) Department of Medicine, University of British Columbia, and Division of Infectious Diseases, Vancouver Hospital Health Sciences Centre, Vancouver, British Columbia, Canada Shelly A. McNeil, M.D., F.R.C.P.(C) Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada Lona Mody, M.D. Department of Internal Medicine, University of Michigan, and Division of Infectious Diseases, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan Joseph M. Mylotte, M.D. Department of Medicine, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York Lindsay E. Nicolle, M.D., F.R.C.P.(C) Department of Internal Medicine, Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada Dean C. Norman, M.D. Chief of Staff, VA Greater Los Angeles Healthcare System, and UCLA School of Medicine, Los Angeles, California Joseph G. Ouslander, M.D. Department of Medicine, Emory University School of Medicine, Atlanta, Georgia Shobita Rajagopalan, M.D. Department of Internal Medicine, Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California Janet D. Register, B.S., ICP, R.N., B.S.N. Department of Infection Control, Leesburg Regional Medical Center, Leesburg, Florida Jay P. Rho, Pharm.D. Department of Pharmaceutical Sciences, University of Southern California University Hospital, Los Angeles, California Chesley L. Richards, Jr., M.D. Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia Kenneth Schmader, M.D. Department of Medicine, Duke University Medical Center, and Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, North Carolina Elizabeth Owens Schwab, R.N., B.S.N., M.P.H. Center for Healthcare Quality, BJC Health System, St. Louis, Missouri

xvi

Contributors

Larry J. Strausbaugh, M.D. Division of Hospital and Specialty Medicine, Portland VA Medical Center, and Department of Internal Medicine, Oregon Health Sciences University School of Medicine, Portland, Oregon Jack Twersky, M.D. Department of Medicine, Duke University Medical Center, and Geriatric Research, Education, and Clinical Center, Durham VA Medical Center, Durham, North Carolina Andrew D. Weinberg, M.D., F.A.C.P. Department of Medicine, Emory University School of Medicine, Atlanta, Georgia Thomas T. Yoshikawa, M.D. Department of Internal Medicine, Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California

1 Demographics and Economics of Long-Term Care A. Jefferson Lesesne and Joseph G. Ouslander Emory University School of Medicine, Atlanta, Georgia

I. INTRODUCTION Long-term care has been defined as “a set of health, personal care, and social services delivered over a sustained period of time to persons who have lost or never acquired some degree of functional capacity” (1). Long-term care includes a broad range of services for chronically disabled individuals over an extended period. Venues for care are predominantly nursing homes (nursing facilities), assisted living facilities, senior housing, and personal dwellings without much, if any, coordination among these sites. The nursing facility remains the most common institutional setting for long-term care. In 1996 there were approximately 16,500 certified facilities with 1.8 million beds (2). This is nearly three times the number of acute care hospitals and twice the number of hospital beds. An aging society will create ever-increasing demands for services and costs associated with longterm care. This chapter will review the relevant demographic and economic factors affecting nursing facilities, with a brief discussion of the assisted living facility market.

II. DEMAND FOR NURSING FACILITY CARE Three main factors contribute to the demand for nursing home care: (1) the number of frail older adults with physical functional disabilities, mental health problems, or both that preclude independent living or community-based care; (2) the available social support system; (3) available, accessible and affordable commu1

2

Lesesne and Ouslander

Table 1 Factors Affecting the Need for Nursing Home Admission Characteristics of the individual Age, sex, race Marital status Living arrangements Degree of mobility Ability to perform basic and instrumental activities of daily living Urinary incontinence Behavior problems Mental status Memory impairment Mood disturbance Tendency for falls Clinical prognosis Income Payment eligibility Need for special services Characteristics of the support system Family capability Health and function of spouse (if married) Presence of responsible relative (usually adult child) Family structure of responsible relative Employment status of responsible relative Physician availability Amount of care currently received from family and others Community resources Formal community resources (See Table 2) Informal support systems Presence of long-term care institutions Characteristics of long-term care institutions Source: Kane RL, Ouslander JG, Abrass IB. Essentials of Clinical Geriatrics, 3rd ed. New York, McGraw-Hill, 1994.

nity-based long-term care resources (Table 1). 57% of people aged 65 and older report long-term care needs as measured by their need for assistance with activities of daily living (ADLs). Among those aged 85 and older, 21% resided in nursing facilities in 1995. In 1996, the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality) concluded in a consensus panel that moderate to severe dementia was prevalent in 2% of those aged 65 to 69, 4% of those aged 70 to 74, 8% of those aged 75 to 79, and 16% of those older than aged 85 (3). Another study concluded that 47% of people older than aged 85

Demographics and Economics

3

had some degree of dementia (4). Figure 1 depicts the projected increase in those with dementia over the next 50 years. The older, more cognitively impaired individual is more likely to need assistance with ADLs and, therefore, will need some form of long-term care. Much of the long-term care in the United States is carried out by family and friends, especially wives and daughters. A survey of informal caregivers indicated that nearly 75% are women, whereas 40% are spouses, and 35% are adult children (5). The average age of the informal caregiver is 60, with 70% of them not working outside the home. Two-thirds of those who work outside the home reported conflicts with work and caregiving. Approximately 20% of men and 50% of women aged 75 and older live alone. About one-third of those who live alone have no children. The older population now tends to have fewer children and are more geographically disbursed than previous generations (Fig. 2). The significance of informal caregiving is evident by the fact that 50% of older adults with long-term care needs and no family support reside in nursing facilities, compared with 7% of those with family caregivers (6). The geriatric population will see unprecedented growth with the aging of the baby boomer generation, and this growth will greatly increase the likelihood of needing long-term care (Fig. 3). The number of Americans aged 65 and older is expected to increase by approximately 60 to 90 million by 2040. The 85 and older population—those most likely to need long-term care—will increase by 8 to 20

Figure 1 Projected number of persons with dementia in the U.S. population. (Based on prevalence estimates and projections from the National Institute on Aging and U.S. Bureau of the Census.)

4

Lesesne and Ouslander

Figure 2 Frequency of seeing children among community-dwelling elderly who live alone. (Courtesy of Kane RL, Ouslander JG, Abrass IB. Essentials of Clinical Geriatrics, 2nd ed. New York, McGraw-Hill, 1989.)

Figure 3 Actual and projected growth of the U.S. geriatric population. (Courtesy of Kane RL, Ouslander JG, Abrass IB. Essentials of Clinical Geriatrics, 3rd ed. New York, McGraw-Hill, 1994.)

Demographics and Economics

5

Black Female White Female Black Male White Male

At Age

85

75

65 0

5

10 Years Remaining

15

20

Figure 4 Life expectancy in the geriatric population. (Courtesy of Kane RL, Ouslander JG, Abrass IB. Essentials of Clinical Geriatrics, 2nd ed. New York, McGraw-Hill, 1989.)

million people by this date (7). A portion of the increase is the result of increased life expectancy. Men aged 65 could expect to live 15 years in 1995; by 2030, they can expect to live 18 years (Fig. 4). Some estimates project the number of people aged 65 and older with functional limitations to be approximately 20 to 30 million by 2040. These demographic shifts will substantially increase the need for nursing facility care. Many community services are available to frail older adults. These services may delay or prevent nursing facility admission for some people (Table 2). They tend to be fragmented and, in many cases, are not reimbursable by most insurance or governmental funding sources. Additionally, there is poor integration of care in the acute and long-term care settings. The primary funding sources of Medicare and Medicaid have differing eligibility requirements and coverage rules that prevent integration. There is also a fear of financial loss on the part of commercial carriers, as there is no risk adjustment for chronically ill or disabled people. Social health maintenance organizations attempt to add community services and short-term nursing home care to a traditional health maintenance organization health plan. The Program for All-Inclusive Care for the Elderly (PACE) is designed for frail older adults, eligible for Medicaid, who are nursing home certifiable. PACE attempts to help these individuals age in the community. Many states are also developing their own initiatives to provide better community care and delay nursing home admission. The number of such programs is increasing, but many frail elders will reach a point at which institutional care is the most appropriate alternative. The growth in the number of assisted living facilities has had an impact on long-term care. There is no clear definition of what constitutes an assisted living

6

Lesesne and Ouslander

facility; however, these venues provide some level of long-term care for their residents. A national study of assisted living facilities recently estimated that there were approximately 11,500 facilities with 650,000 beds providing services to 560,000 residents (8). This survey included facilities with at least 11 beds, providing 24-hour oversight and serving at least two meals per day. The major difference is that this industry is composed of more real estate developers and hotel managers than healthcare providers. Nursing home usage rates vary by age, sex, and race (Fig. 5). There are more whites than blacks and more women than men in nursing facilities. Nearly 25% of white women reside in a nursing home by age 85. Interestingly the number aged 65 and older who stay overnight in a nursing home fell by 8% from 1985 to 1995

Table 2 Example of Formal Community Services Available Outside of Nursing Homes Housing Senior apartments Residential care facilities Assisted living Foster care Life care community Health promotion activities Wellness programs Exercise classes Family and patient education Nutrition consultation Meal programs Volunteer programs Outreach Screening clinics Mobile vans Discharge planning Case management Information and referral Meals-on-Wheels Transportation Emergency response system Respite care

Outpatient centers Geriatric clinics Psychosocial counseling Rehabilitation Adult day care Day hospital Home health Home health agencies Medicare-certified Private Visiting nurse association Hospice Homemaker Chore Home infusion therapies Durable medical equipment Acute inpatient units Geriatric Rehabilitation Psychiatric Alcohol/substance abuse

Source: Ouslander JG., Osterweil D, Morley J. Medical Care in the Nursing Home, 2nd ed. New York, McGraw-Hill, 1997.

Demographics and Economics

7

Figure 5 Percent of population aged 65 and older in nursing homes by age, sex, and race. (Based on 1985 data from the National Center for Health Statistics.)

(9). This decline may have resulted from a decline in disability rates of the elderly, increased use of home health services, and the growth in assisted living facilities. All of these tend to delay or prevent placement in a nursing facility.

III. ECONOMICS OF LONG-TERM CARE Financing for long-term care in the United States is primarily provided through private funding and governmental assistance programs, including Medicare and Medicaid. Private funding can include personal resources and may include a component of long-term care insurance. There are also “Medigap” insurance policies to cover the copayment required by Medicare. Long-term care costs as a percentage of personal health care expenditures have increased from 4% in 1960 to 11% in 1993 (3). Approximately $106 billion was spent on long-term care, including home care, in 1995. Medicare accounted for nearly 18% and Medicaid 38% (21% state Medicaid and 17% federal Medicaid) (Fig. 6). States are the major financiers of long-term care for older adults, whereas the federal government finances most acute care. Many Americans are unprepared for long-term care expenditures because they believe it is a Medicare benefit.

8

Lesesne and Ouslander

Figure 6 Expenditures on nursing home and home health care by source of funds, 1995. (From Health Care Financing Administration. Cited by National Academy on Aging, 1997.)

A. Medicare Medicare is a governmental insurance program that covers the cost of acute hospitalization for those aged 65 and older, as well as some disabled individuals younger than age 65 and those requiring renal dialysis or transplant. In addition, it covers outpatient services and post-acute hospital care for up to 100 days after a 3-day hospitalization. Currently there are approximately 39 million beneficiaries and in 1997, the annual budget was $215 billion dollars. Sixty-nine percent of Medicare expenditures goes to hospitals, with another 25% covering physician services. Less than 5% goes to nursing home care. Medicare expenditures for home health increased nearly 10 times from 1987 to 1995 (10). In response, Congress and the President enacted the 1997 Balanced Budget Act that greatly reduced these payments and initiated a significant effort to reduce fraud and abuse. Many states have developed strategies to help their Medicaid recipients maximize their Medicare home health benefits in an effort to conserve state Medicaid dollars. Medicare also limits its funding for long-term

Demographics and Economics

9

care by only covering post-acute or “subacute” skilled care. Medicare provides post-acute skilled care for 100 days after an acute hospitalization of 3 or more days. To qualify, the patient must require daily skilled nursing care or rehabilitation services for the condition that was treated in the hospital (Table 3). Funding for post-acute care from Medicare is transitioning to a prospective payment system (PPS) based on resident problems identified in the Minimum Data Set (MDS). Under the PPS model, a capitated reimbursement is made to the nursing home for care of particular medical problems after an acute hospitalization. The reimbursement is calculated based on the MDS and then translated into resource utilization groups or “RUGS,” similar to the Medicare diagnostic related group (DRG) payment system for acute hospitals. An important component is that all ancillary services (rehabilitation therapy, laboratory services, medications, etc.) are now bundled into one payment. This has profound implications for the relationship between nursing homes and physicians, because under PPS the nursing home bears the cost of physician-ordered laboratory tests, medications and therapies. B. Medicaid Medicaid is a federally sponsored, state-administered program to provide health insurance for the indigent. It covers both acute hospital care and outpatient services for those who qualify based on means testing. The long-term care compo-

Table 3 Admission Criteria to Subacute Units Intravenous antibiotics Physical therapy six to seven times/week Occupational therapy five times/week Weaning oxygen with blood gas measurements three times/week Tracheal suctioning at least two times/shift Respiratory therapy treatment three times/day or more frequently Capillary blood glucose monitoring two times/day with insulin coverage Injectable medications every 8 hours or two times/day Wound care (sterile) day Tube feeding Laboratory test monitoring every 2 to 3 days Renal dialysis with monitoring Bladder training Pain management (parenteral) Skilled nursing observation of congestive heart, liver, or renal failure Physician visits at least weekly

10

Lesesne and Ouslander

nent of Medicaid covers nursing home care on a means-tested basis. This program insures 41 million people (10% elderly) at an annual cost of $160 billion. Sixtynine percent of expenditures go to nursing homes, with 17% to hospitals and 3% to physician services. Each state administers the program differently, so there is substantial variability is terms of benefits covered. Virtually all nursing home care is paid for out-of-pocket or by Medicaid, which has led to a phenomenon known as “spend down” (Figs. 7 and 8). Individuals and families will deplete a person’s assets until they can pass the means test

Figure 7 Top: Sources of overall health care expenditures for the geriatric population. Bottom: Per capita health care expenditures by type of care and source for the geriatric population. Based on 1984 data. (Courtesy of Kane RL, Ouslander JG, Abrass IB, Essentials of Clinical Geriatrics, 2nd ed. New York, McGraw-Hill, 1989.)

Demographics and Economics

11

Figure 8 Proportions of Medicare, Medicaid, and out-of-pocket expenditures used for different types of care by the geriatric population. Based on data from the United States Special Committee on Aging, 1986. (From Ref. 1.)

12

Lesesne and Ouslander

for Medicaid funding for long-term care. Since nursing home care can cost as much as $40,000 to $60,000 per year, it does not take older adults very long to qualify for Medicaid. As a result, Medicaid has become, in effect, the payer of last resort for institutional long-term care. This has inspired many state Medicaid agencies to develop and work with programs that prevent or delay the need for institutional care. C. Private Funding Private long-term care insurance only covered 6% of nursing home and home-care costs in 1995 (6). The number of policies sold has recently seen a dramatic increase from 800,000 in 1987 to nearly 5 million in 1996. A wide range of coverage is available through these policies; however, most provide some type of home care component to avoid or delay nursing home coverage. Several states have promoted the purchase of long-term care insurance by providing a mechanism to protect assets from Medicaid eligibility requirements equal to the amount of longterm care coverage.

IV. EVOLVING CHANGES IN LONG-TERM CARE The long-term care industry has seen substantial growth of post-acute care in the United States over the last decade. As the population ages and hospital lengths of stay are shortened, more medically complex patients with greater nursing home care needs are being discharged from hospitals to nursing facilities. Often they are not functionally able or medically stable enough to return home. Subacute units in nursing facilities have become the place for residents to convalesce before their ultimate discharge. For these units to succeed, there needs to be adequate reimbursement, availability of skilled nurses, and quality medical care, as well as adequate ancillary services. Regulations to set standards for staffing ratios would most likely improve quality of care in nursing homes (11). Nursing homes would also benefit from a survey process that provides education and is outcomes based, rather than a punitive process to identify misconduct. Additionally, unfunded government mandates are difficult to implement, and they drain resources. Improved reimbursement will help ensure adequate staffing of nurses and therapists, as well as improve the availability of ancillary services. Improving nursing education and professional opportunities will also assist in attracting and retaining quality staff. This is true for physicians, nurse practitioners, and physician assistants. Innovative programs are essential to improving job satisfaction and quality of care provided by nursing aides, since they provide more than 90% of hands-on care in nursing homes.

Demographics and Economics

13

Reimbursements that are adjusted for risk and complexity will help provide quality care in the most appropriate setting. The RUGs system is a step in this direction. Outcome monitoring based on quality indicators will also provide the appropriate incentives for quality care in the nursing home (12). Integrated care systems composed of hospitals, primary care providers, long-term care facilities, and community-based partners will also improve quality and have financial implications. These systems must have shared visions, goals, and financial incentives to provide good care. They also implement care standards as well as develop much needed information systems. All of these features will reduce practice variability and medical errors, and improve the quality of care.

REFERENCES 1. 2. 3.

4.

5. 6. 7.

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9. 10. 11.

12.

Kane RA, Kane RL. Long-Term Care: Principles, Programs, and Policies. New York, Springer, 1987. American Association of Retired Persons: Across the States 1998. Profiles of LongTerm Care Systems, 3rd ed. Washington, DC, 1998. Stone RI. Long-Term Care for the Elderly with Disabilities: Current Policy, Emerging Trends, and Implications for the Twenty-First Century. Milbank Memorial Fund, 2000. Costa PT, Williams TF, Albert MS. Recognition and Initial Assessment of Alzheimer’s Disease and Related Dementias. Clinical Practice Guideline No. 19, AHCPR Publication No. 97–0702. Washington, DC, Agency for Health Care Policy and Research, 1996. The Assistant Secretary for Planning and Evaluation and the Administration on Aging: Informal Caregiving. Compassion in Action. Washington, DC, 1998. National Academy on Aging. Facts on Long-Term Care. Washington, DC, 1997. Available at http://geron.org/NAA/ltc.html U.S. Bureau of the Census. Population Projections of the United States by Age, Sex, Race, and Hispanic Origin: 1995 to 2050: Current Population Reports, P25–1130. Washington, DC, U.S. Government Printing Office, 1996. Hawes C, Rose M, Phillips CD, Iannacchione V. A National Study of Assisted Living for the Frail Elderly: Results of a National Telephone Survey of Facilities. Beachwood, Ohio, Menorah Park Center for the Aging, 1999. Bishop CE. Where are the missing elders? The decline in nursing home use, 1985 and 1995. Health Affairs 1999; 18(4):146–155. Kenney G, Rajan S, Soscia S. State spending for Medicare and Medicaid home care programs. Health Affairs 1998; 17(1):201–212. Wunderlich GS, Kohler PO (eds). Improving the Quality of Long-Term Care: A Report of the Institute of Medicine. Washington, DC, National Academy Press, 2001. National Academy of Sciences. Zimmerman DR, Karon SL, Arling G. Development and testing of nursing home quality indicators. Health Care Financing Rev 1995; 16:107–127.

2 Evaluation of Infections in Long-Term Care Facilities Versus Acute Care Hospitals Andrew D. Weinberg Emory University School of Medicine, Atlanta, Georgia

I. LONG-TERM CARE FACILITY VERSUS ACUTE CARE HOSPITAL In general, evaluation and management of acute care infections remains one of the greatest challenges to staff and healthcare practitioners in institutional long-term care facilities (LTCFs). The general goals and objectives, staffing patterns, available resources for diagnostic testing, and primary role of physicians and nursing staff are different between an acute care hospital and an LTCF, as indicated in Table 1. Thus, the approach to evaluating infections in LTCFs will also be different between an acute care hospital and an LTCF. The differences in the evaluation of infections in the hospital setting include the infrequent presence of physicians in the LTCFs, the inability to obtain timely and accurate laboratory and radiological data, and the limited nursing assessment that occurs at the LTCF, which is subsequently transmitted to the healthcare practitioner via telephone.

II. HOW INSTITUTIONAL LTCFS DIFFER IN INFECTION EVALUATION A. Staffing and Resources The majority of care in an LTCF is provided by licensed nursing staff (licensed practical nurses [LPNs] and registered nurses [RNs]). The staffing ratios in facil15

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Table 1 Differences Between Acute Care Facility and Long-Term Care Facility Parameter Patient population Setting Goals Length of stay Physician role Infection definition Resources for infection control Isolation capability

Acute care facility

Long-term care facility

Young and old High technology Acute disease treatment Days, weeks Primary Clinical tests Broad

Predominantly old Home-like Comfort, support Months, years Secondary, limited Clinical limited tests Variable and often limited

Broad

Limited to none

Adapted from: Yoshikawa TT, Norman DC: Infection control in long-term care. Clin Geriatr Med 1995;11:467–480.

ities may range from one licensed nurse per 20 residents to as high as one to 40 residents, depending on the shift. Certified nursing assistants (CNAs) provide the majority of hands-on care, including grooming, washing, ambulation, feeding, dressing, and overall supervision. The CNA staffing ratios may range from one CNA per 8 to 15 residents, again depending on the particular shift. In the majority of LTCFs, physicians are physically present in the facility for a limited number of hours per week and are only required by state or federal regulations to visit, on average, every 30 to 60 days after the first 90 days of residency in the facility. Thus, the vast majority of changes in a resident’s baseline condition and responses to acute medical illnesses are managed by telephone or fax transmissions from the RN to LPN to the primary or cross-covering physician of record, a nurse practitioner (NP), or a physician assistant (PA) (1–3). Often limited technical resources are available for the evaluation of infections in the LTCF setting, especially on evenings, nights, weekends, and holiday shifts. Practice guidelines for the evaluation of fever and infection in the long-term care setting have been recently published (4), but the majority of triage for an acute illness is done by telephone exchange with the nursing staff, often without the benefit of laboratory data at the time of the first contact. The availability of specialty consultations is virtually nonexistent onsite. Referrals to infectious disease specialists outside the nursing facility are difficult to arrange and involve significant nonreimbursable transportation costs. In general, staff and healthcare practitioners rely on the clinical history and symptoms and signs of illness rather than on advanced diagnostic testing. The CNAs are the first line of detection, as they interact closely with the residents and customarily can detect small changes in mental status or functional decline that could signal an underlying infection. The CNAs then report these observations to the licensed nurse on duty. The nurse is then expected to obtain vital signs and per-

Long-Term Care and Acute Care Facilities

17

form a nursing assessment so that this information, along with any recent, pertinent history, can be given to the practitioner when he or she is contacted. Infection remains one of the most common causes of death among LTCF residents and a frequent reason for transfer to the acute care setting and subsequent hospitalization (5–7). Those LTCF residents who are at greatest risk for developing clinical infections are more likely to require higher levels of nursing care, have significant functional disability, or have more indwelling catheters (3,8). Infections of the urinary tract, pulmonary system, and skin remain the most common sites of infection in the LTCF setting. B. Recognition of Infection Recognition of infection in this population may be hindered by the atypical presentation of these illnesses in cognitively impaired individuals who may not be able to effectively communicate to their caregivers when they feel ill (9,10). Certified nursing assistants or licensed nursing staff may be able to detect infections by subtle declines in cognitive or physical functioning or by the presence of new or increasing confusion. One of the universal indicators of infection is the presence of fever. However, it is now known that the basal body temperatures in the frail older adult may be lower than the well-established mean value of 37°C or 98.6°F (11). Thus, fever as a marker for infection in the LTCF resident is not the most sensitive of indicators. Also, “fever” can be defined somewhat differently from facility to facility, so it is important to be aware of the current definition used in each facility, especially when implementing evaluation and treatment protocols for infection. Additionally, temperatures may be obtained from different sites of measurement, including oral, rectal, axillary, or tympanic, and all are not necessarily equally as accurate (12). (See also Chapter 6, Clinical Manifestations of Infections.) The routine use of acetaminophen can mask the presence of fever, and its routine use should be discouraged until the source of fever is identified or the evaluation of an infection is in progress (13). Once the presence of a new fever is documented, the source of this temperature elevation should be sought. The particular areas to assess for potential sources of infection include the oropharynx, conjunctiva, skin (whole body evaluation), chest, heart, abdomen, perineum, perirectal area, and the central nervous system (14). Several groups have outlined general guidelines for the evaluation of suspected infections; however, these recommendations represent a consensus of opinion of individuals representing various longterm care organizations involved but have not been validated to date (15–17). Concurrent dehydration can also pose a risk to the outcome of infections in this population. In one study of 40 febrile LTCF residents (5), 24 (60%) had evidence of hypernatremia, increased blood urea nitrogen to serum creatinine ratio, or both. Studies have shown that not one specific physical finding was deemed to

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Weinberg

be of any particular value in diagnosing dehydration (5,18), and that laboratory data remain the most objective and easily attainable information on the state of hydration. C. The Initial Evaluation of Suspected Infection The initial assessment is usually completed by the nurse on duty in the facility after being notified of a change in status by the CNA. The nurse then reports the findings via telephone to the NP, PA, or attending physician (4). (See Appendix B for a summary of guidelines for evaluation of fever and infection in LTCF [4]) The NP, PA, or physician may then order additional laboratory or radiological tests, initiate treatment, or order the resident transferred to an acute care setting for further evaluation. Initial laboratory data obtained usually consists of a urinalysis with culture if an infection in the genitourinary tract is suspected, a chest X-ray if a pulmonary process is suspected, and a complete blood count with differential to determine the severity of the problem (Fig. 1). “Stat” laboratory and radiological tests are available, but several hours or even a full day may elapse until the results are relayed back to the ordering healthcare practitioner. If an epidemic is suspected in the facility (usually defined as 10% or more of the resident population ill at the same time), nursing staff should alert the director of nursing who, in turn, must notify the medical director. The infection control nurse should also be contacted so that ongoing monitoring can be carried out. Nursing staff should be briefed or inserviced (as time permits) on the relevant portions of the infection control policies for the facility that would pertain to this outbreak. Overall evaluation and treatment in the LTCF setting must take into consideration the resident’s wishes (or a legal guardian or next of kin if the resident is incompetent to make medical decisions), the cost of evaluation, and the effect of treatment on the quality of life given the wishes of the resident/family. Tests should be ordered if the results will cause the clinician to change or reassess the current treatment and improve overall management or the comfort of the resident. The need for specific laboratory tests should be based on the clinical presentation of each resident. Protocols to aid the staff in their approach to suspected infections should be developed and distributed, and inservice education should be provided to all three shifts. The ability to obtain adequate culture specimens may be problematic in the LTCF setting. The prevalence of asymptomatic bacteriuria may run as high as 50% of all noncatheterized female residents of LTCFs and does not usually require treatment with antibiotics (19). This may confound the interpretation of culture results. When such cultures are indicated, it is possible to collect adequate specimens in both men and women without catherization (4). Blood and sputum cultures are extremely difficult to obtain in the LTCF setting. Obtaining adequate

Long-Term Care and Acute Care Facilities

19

Suspected Infection Functional decline Change in mental status Fever Onset of viral, urinary tract, respiratory or diarrheal symptoms Evidence of unexplained discomfort (crying, moaning, agitation) Significant decrease in food/fluid intake Nurse/Certified nursing assistant obtains vital signs (Temperature, pulse, respiratory rate, and blood pressure) Perform nursing assessment Review chart and document all assessments Call practitioner to relay information and recent medical history Note any current advance directives Practitioner

assesses

stability

via

telephone

or

by

visit

Unstable Advance directive limits intervention

Unstable No advance directive

Stable

Call family Comfort measures

Call family Transfer to acute care facility

Call family Order laboratory or other tests Order treatment if clinically indicated

Follow-up with family

Follow-up with family

Follow-up with family

Document in chart rationale and goals

Document in chart rationale and goals for transfer

Document all medical orders and test results Adjust treatment as indicated

Establish Continuous Quality Improvement (CQI) process for ongoing review and analysis of cases when resident is transferred to an acute care facility

Figure 1 Recommended clinical evaluation for suspected infections in long-term care residents.

specimens for sputum cultures in the LTCF setting is made difficult by the technical difficulties associated with the procedure in frail, cognitively impaired residents and the lack of specific training on the part of the staff. Additionally, contracted laboratories rarely can provide this service to LTCFs. Blood cultures obtained within 24 hours of presentation have been associated with improved sur-

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vival in community-acquired pneumonias with sepsis (20), but there are no similar studies in the LTCF setting and thus are not generally recommended (4). Pulse oximetry can be useful in assessing arterial oxygen partial pressures and is relatively inexpensive and easy to use in the LTCF setting. It can be a predictor of impending respiratory failure requiring hospital admission (21). Assessment of the resident for impending respiratory failure can also be done at the bedside using a rate greater than 25 breaths per minute and confirmed by pulse oximetry indicating an oxygen saturation of less than 90%, as suggested in the recent modification of the Pneumonia Prognosis Index in nursing home residents (22). Because respiratory therapy services are generally not available in LTCFs, pulse oximetry measurements by nursing staff can be very helpful in treating residents suspected of having pneumonia. D. Subacute Care Infection Control There are few articles in the literature regarding infection control practices in subacute (postacute care; PAC) units (23), and there is no mention of PAC units as a special setting in either the position paper on infection prevention and control in LTCFs from the Association for Professionals in Infection Control and Epidemiology or the Society for Healthcare Epidemiology of America (24). Postacute Care units are a specified number of Medicare-certified beds within an LTCF designed to provide more advanced medical, nursing, and rehabilitative services to post-hospitalized older adults for a period not exceeding 100 days per calendar year under Medicare Part A. The ability to administer intravenous antibiotics is a commonly provided service (25). Many individual patients are admitted to PAC units for completion of antimicrobial therapy for already diagnosed and partially treated infections, such as chronic osteomyelitis or endocarditis. Some deconditioned patients in these units may develop pneumonia because of their overall poor medical condition or from aspiration (e.g., after a stroke). The subsequent antibiotic administration, which can be accomplished in most LTCFs with PAC units (25), will usually cover the majority of nosocomial infections one might expect to encounter. The LTCF facility medical director (or PAC unit medical director) can be involved in the screening of high-acuity patients with known infections before their acceptance into the unit (26). This allows the stability of the patient’s infection to be assessed, as well as anticipated equipment and medical needs (e.g., the presence of central lines, specialty mattresses, stage IV pressure ulcer management). There have been recent changes to reimbursement for subacute services in PAC units involving a prospective payment system (PPS); a fixed per diem reimbursement to the facility based on functional and medical needs is provided. This PPS payment is required to cover all nursing and ancillary services, including the

Long-Term Care and Acute Care Facilities

21

cost of X-rays, laboratory tests, medications, and intravenous administration of antibiotics performed in the facility. As the evaluation and treatment of complicated infections that develop after admission to a PAC unit will be borne by the facility under PPS, it has the potential to affect the assessment or treatment of acute infections in this setting.

III. WHEN TO TRANSFER LTCF RESIDENTS TO AN ACUTE CARE SETTING An ongoing issue is appropriate use of the emergency department (ED) as a resource for the evaluation of suspected infections in LTCF residents. Some studies have suggested that such transfers are overutilized and deem them inappropriate (27,28). The expense and inconvenience to the resident is considerable when such transfers are not properly used. The reasons for and frequency of transfers of LTCF residents to EDs for evaluation vary considerably by practice and location (Table 2) (27,29). The ability to adequately evaluate, monitor, and safely treat an LTCF resident is often the key question confronting the practitioner. Also, the inability to obtain necessary radiological or laboratory testing, the nursing assessment of the resident’s stability, and family recommendation will all affect the practitioner’s final decision on whether to transfer an individual. Most common bacterial pathogens seen in the LTCF setting can be treated with broad-spectrum oral antimicrobial therapy (30,31), but some practitioners, for a variety of reasons Table 2 Reasons to Transfer an LTCF Resident to an Emergency Department for Suspected Infection in Absence of Advance Directives • Abrupt change in vital signs or mental status associated with suspected infection • Inability to maintain adequate hydration and nutrition • In nurse’s judgment, the resident is not stable and practitioner not able to make onsite evaluation • Infections that are not responding to initiated treatment • Need for intravenous antibiotics or other necessary treatment that cannot be administered at the facility • Inability to obtain critical laboratory or radiological studies in the LTCF setting in a timely manner • Required infection control measures cannot be adequately implemented in the facility • Family concerns that adequate care is not being provided in the facility and requests transfer for more aggressive intervention LTCF Long-term care facility. A suggested algorithm for evaluation of a suspected infection in the LTCF is shown in Figure 1.

22

Weinberg

including potential legal liability, may routinely order the transfer of all “acutely” ill residents to the local ED for “evaluation.” The ideal solution for those frail LTCF residents whose benefit/risk ratio for transfer and potential hospitalization is low is to discuss these issues in advance with the individual or a legal representative and specify guidance to the practitioner in the form of an advance directive. However, use of advance directives before the onset of a crisis is relatively low. Advance directives requesting “comfort care only” or “do not hospitalize” may facilitate the management of the LTCF resident with a suspected infection. However, studies examining advance directives in regard to the evaluation of suspected infections do not exist. Antibiotic treatment appears to be provided less often to residents with urinary, respiratory, or skin infections who have advance directives specifying “comfort care only” (32). Developing and implementing protocols to ensure that LTCF nursing staff can obtain and communicate adequate baseline information and assessments of the resident is critical for the practitioner to proceed with an organized and logical evaluation of a potential infection. Because much, if not all, of the initial information is transferred from the facility to the practitioner by telephone, this step may be considered the critical ink in the flow of information. More complete protocols for effective communication between nurses and physicians regarding resident assessment have been published (33), and one is available by the American Medical Directors Association (34). Following the resident’s advance directives and consulting with the legal representative can certainly give the practitioner direction as to the desired degree of evaluation or intervention and whether transfer to an ED is appropriate. If transfer is not desired, then appropriate laboratory, radiological, or specimen collection can be ordered to complete the evaluation at the LTCF site. Follow-up on any ordered tests and the response to prescribed treatment must be an ongoing process between the facility and the practitioner. Any pending laboratory or radiological results or recent family decisions as to the desired intervention should be conveyed to the “on call” practitioner for the night or weekend to avoid confusion and unwanted or unnecessary interventions. Facilities should develop Continuous Quality Improvement projects to review the entire evaluation and transfer process of residents to monitor the efficacy of current policies and procedures. Information on transfers and hospital admissions should be collected to assess whether there are procedures that can be implemented or current policies modified to improve the efficiency of the system in use. The facility medical director should be involved in the development, implementation, and review of all protocols to assure efficiency of assessments and information control procedures in collaboration with the infection control nurse and director of nursing. Data should also be collected on antibiotic resistance patterns, if possible (35).

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23

IV. SUMMARY The evaluation and treatment of infections in LTCFs is significantly different from acute care hospitals in many ways, including the availability of onsite assessment by physicians, specialty consultants, and diagnostic technologies. Although the vast majority of the more common clinical infections and their manifestations can be diagnosed and treated in the LTCF setting, there are instances when the severity of the illness or the treatment required may necessitate transfer to an acute care facility. Keeping this in perspective, advance directives and family discussions should be used to avoid undesired hospital transfers or aggressive treatments whenever possible. The medical director should be extensively involved in the development, review, and implementation of all infection control and treatment protocols. REFERENCES 1. 2. 3. 4.

5.

6. 7.

8. 9. 10. 11.

12.

Evans JM, Chutka DS, Fleming KC, Tangalos EG, Vittone J, Heathman JH. Medical care of nursing home residents. Mayo Clin Proc 1995; 70:694–702. Ouslander JG, Osterweil D. Physician evaluation and management of nursing home residents. Ann Intern Med 1994; 121:584–592. Smith PW, Rusnak PG. Infection prevention and control in the long-term care facility. Infect Control Hosp Epidemiol 1997; 18:831–849. Bentley DW, Bradley S, High K, Schoenbaum S, Taler G, Yoshikawa TT. Practice guideline for the evaluation of fever and infection in long-term care facilities. J Am Geriatr Soc 2001; 49:210–222. Weinberg AD, Pals JK, Levesque PG, Beal LF, Cunningham TJ, Minaker KL. Dehydration and death during febrile episodes in the nursing home. J Am Geriatr Soc 1994; 42:968–971. Irvine PW, Van Buren N, Crossley K. Causes for hospitalization of nursing home residents: The role of infection. J Am Geriatr Soc 1984; 32:103–107. Weinberg AD, Engingro PF, Miller RL, Weinberg LL, Parker CL. Death in the nursing home: Senescence, infection and other causes. J Gerontolog Nurs 1989; 15(4): 12–16. Nicolle LE, Garibaldi RA. Infection control in long-term care facilities. Infect Control Hosp Epidemiol 1995; 16:348–353. Berman P, Hogan DB, Fox RA. The atypical presentation of infection in old age. Age Ageing 1987; 16:201–207. Samily AH. Clinical manifestations of disease in the elderly. Med Clin North Am 1983; 67:333–344. Castle SC, Norman DC, Yeh M, Miller D, Yoshikawa TT. Fever response in elderly nursing home residents. Are the older truly colder? J Am Geriatr Soc 1991; 39: 853–857. Darowski A, Najim Z, Weinberg JR. The febrile response to mild infections in elderly hospital residents. Age Ageing 1991; 20:193–198.

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13.

Weinberg AD, Pals JK, McClinchey-Berroth R. The source of fever and the effect of acetaminophen use on time to diagnosis in febrile long-term care residents. Nurs Home Med 1996; 4:340–347. Yoshikawa TT, Norman DC. Approach to fever and infection in the nursing home. J Am Geriatr Soc 1996; 44:74–82. Smith PW. Consensus Conference Participants. Consensus conference on nosocomial infections in long-term care facilities. Am J Infect Control 1987; 15:97–100. Zimmer JG, Bentley DW, Valenti WM, Watson NM. Systemic antibiotic use in nursing homes. A quality assessment. J Am Geriatr Soc 1986; 34:703–710. AMDA. Clinical Practice Guideline: Altered mental states (E. Tangalos, Chairman). Columbia, MD, American Medical Directors Association, 1998. Gross C, Lindquist RP, Wolley AC, Granieri R, Allard K, Webster B. Clinical indicators of dehydration severity in elderly patients. J Emerg Med 1992; 10:267–274. Nicolle LE. Urinary tract infections in long-term care facilities. Infect Control Hosp Epidemiol 1993; 14:220–225. Arbo MDJ, Snydman DR. Influence of blood culture results on antibiotic choice in treatment of bacteremia. Arch Intern Med 1994; 154:2641–2645. Bartlett JG, Mundy LM. Current concepts: Community-acquired pneumonia. N Engl J Med 1997; 336:243–250. Mylotte JM, Naughton B, Saludades C, Maszarovics Z. Validation and application of the pneumonia prognosis index to nursing home residents with pneumonia. J Am Geriatr Soc 1998; 46:1538–1544. Mylotte JM, Bentley DW. Infection control in subacute care. Clin Geriatr Med 2000; 16(4):805–816. Friedman C, Barnette M, Buck AS, Ham R, Harris JA, Hoffman P, Johnson D, Manian F, Nicolle L, Pearson ML, Perl TM, Solomon SL. Special communication: Requirements for infrastructure and essential activities of infection control and epidemiology in out-of-hospital settings: A Consensus Panel report. Am J Infect Control 1999; 27:418–430. Weinberg AD, Pals JK, Wei JY. The utilization of intravenous therapy programs in community long-term care nursing facilities. J Nutr Health Aging 1997; 1:161–166. Weinberg AD. The medical director’s role in screening high-acuity admissions to subacute units. Ann Long Term Care 2000; 8(2):72–78. Jones JS, Dwyer PR, White LJ, Firman R. Patient transfer from nursing home to emergency department. Outcomes and policy implications. Acad Emerg Med 1997; 4:908–915. Rubenstein LZ, Ouslander JG, Wieland D. Dynamics and clinical implications of the nursing home-hospital interface. Clin Geriatr Med 1988; 4:471–491. Teresi JA, Holmes D, Bloom HG, Monaco C, Rosen S. Factors differentiating transfers from long-term care facilities with high and low transfer rates. Gerontologist 1991; 31:795–806. Fried TR, Gillick MR, Lipsitz LA. Short-term functional outcomes of long-term care residents with pneumonia treated with and without hospital transfer. J Am Geriatr Soc 1997; 45:302–306. Thompson RS, Hall NK, Szpiech M, Reisenberg LA. Treatment and outcomes of pneumonia in the elderly. J Am Board Fam Pract 1997; 10:82–87.

14. 15. 16. 17. 18. 19. 20. 21. 22.

23. 24.

25. 26. 27.

28. 29.

30.

31.

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Mott PD, Barker WH. Treatment decisions for infections occurring in nursing home residents. J Am Geriatr Soc 1988; 36:820–824. 33. Ouslander JG, Osterweil D, Morley J. Medical Care in the Nursing Home, 2nd edition. New York, McGraw-Hill, 1997. 34. AMDA. Protocols for physician notification: Assessing patients and collecting data on nursing facility patients: A guide for nurses on effective communication with physicians. Columbia, MD, American Medical Directors Association, 2000:1–33. 35. Nicolle LE, Strausbaugh LJ, Garibaldi RA. Infections and antibiotic resistance in nursing homes. Clin Microbiol Rev 1996; 9:1–17.

3 Epidemiology and Special Aspects of Infectious Diseases in Aging Thomas T. Yoshikawa Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California

I. EPIDEMIOLOGY OF INFECTIOUS DISEASES A. Pre-Antibiotic Era Infectious diseases have assumed an important role in the evolution of the human race and the history of mankind. Survival of man during the prehistoric era depended on avoiding predators. Subsequently, the ushering in of civilization brought new threats for survival. Infectious diseases became the major cause of death and disability until the mid-20th century. Outbreaks such as smallpox, plague, cholera, typhoid fever, diphtheria, tuberculosis, and typhus fever have been responsible for the deaths of millions of people (1). As recently as 1918, an international epidemic of “Spanish flu” (strain of influenza virus) accounted for 21 million deaths in all parts of the world, including approximately 550,000 deaths in the United States (2). In addition, certain infections resulted in death and often caused severe disabilities, deformities, and functional incapacities, such as mumps, measles, scarlet fever, rheumatic fever, pertussis, poliomyelitis, and syphilis (1). Not surprisingly, childhood mortality was very high. It is for this reason that, up until the mid-1900s, life expectancy was relatively limited (approximately 47 years in the United States) (3). B. Germ Theory and Its Impact Until the acceptance of microbes as causes of infections, the fundamental doctrine that explained the cause or causes of diseases was the doctrine of humoral pathol27

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ogy, that is, man’s health and temperament were affected by four body fluids or humors: blood, phlegm, black bile, and yellow bile (4). In the early 1800s, the concept of contagions and contagiousness, that is, diseases could be communicable and transmitted to others, laid the foundation for the establishment of the age of bacteriology and germ theory of medicine. In the mid- to late-1800s, discoveries by Louis Pasteur (pasteurization; microorganisms were the cause of disease; vaccines for anthrax, rabies, and swine erysipelas), Joseph Lister (antisepsis), and Robert Koch (cause of tuberculosis; tuberculin skin test) led to the eventual acceptance of the microbial cause of infections, hence, the “germ theory” of medicine (4). The clinical impact of the germ theory was the development and implementation of antisepsis, antibiotics, vaccination, sanitation, and public health measures. These practices and processes reduced deaths and complications from infectious diseases in industrialized nations beginning in the latter half of the 20th century and resulted in the increase in life expectancy observed during the past 50 years in such nations, including the United States. However, in less developed parts of the world, infections continue to be the primary cause of mortality, accounting for one-third of all deaths worldwide. The World Health Organization estimates that 50,000 deaths occur each day in the world from infectious diseases (4). With the increase in life expectancy, the population of aging adults has grown rapidly, including those requiring long-term care (see Chapter 1.) Heart disease, cancer, and stroke have become the leading causes of death in both young and older adults (5). However, infections remain an important cause of morbidity and mortality in the elderly population, especially the very old and frail elderly (6). Currently, there is no evidence that aging is associated with greater vulnerability to all infectious diseases. The available data indicate that select infections are especially important in the elderly person because of their higher frequency (incidence, prevalence) and/or poor outcomes (higher morbidity, mortality, or both). These infections are listed in Table 1 (7).

Table 1 Important Infections in the Geriatric Population Urinary tract infection Respiratory tract infection (pneumonia and bronchitis) Tuberculosis Skin and soft tissue infections (e.g., infected pressure ulcer, herpes zoster) Intra-abdominal infections (diverticulitis, cholecystitis, appendicitis) Bacterial meningitis Infective endocarditis

Epidemiology of Infectious Diseases

29

In the very old and frail elderly, such as residents in long-term care facilities (LTCFs), the susceptibility to and mortality from infections greatly increase. Pneumonia, urinary tract infection, and skin/soft tissue infections, such as cellulitis and infected pressure ulcers, are the most common infections found in residents of LTCFs (8,9). Moreover, within a closed institutional setting and environment, other types of infections become prominent. These include a variety of infectious diarrheas (see Chapter 18), scabies (see Chapter 17), viral hepatitis (see Chapter 19), and infections caused by multidrug-resistant bacteria (see Chapters 22, 23, and 24).

II. SPECIAL ASPECTS OF INFECTIONS IN THE ELDERLY A. Clinical Manifestations Infection is now well known to be an important cause of morbidity and mortality in elderly persons. However, the clinical diagnosis of infectious disease in older patients is often difficult and overlooked. The clinical manifestations of infections in the frail elderly LTCF resident may be atypical or absent (see Chapter 6). Fever may not be detectable in older persons with serious infections (10). In frail LTCF residents, studies have shown that baseline body temperatures may be subnormal, and febrile responses to an infection may occur but go unrecognized because the “fever” fails to reach a predetermined criterion (e.g., 101°F [38°C]). In such cases, a change in body temperature of at least 2°F from baseline should be interpreted as a possible “febrile” response (11). It also has been proposed that the absolute criterion for fever be lowered in frail elderly persons, that is, 99°F (37.2°C) for oral temperature and 99.5°F (37.5°F) for rectal temperature (12). B. Increased Susceptibility to Infections The increased susceptibility of older people to select infections may be a multifactorial process. A “normal” process of aging is the phenomenon of immune dysregulation or dysfunction (see Chapter 4). It is most likely the interrelationships between age-related immune dysregulation and age-associated chronic diseases that affect immune processes that place the older, frail LTCF resident at high risk for infectious diseases (13). In addition, other factors such as nutrition (see Chapter 5) and chronic use of antibiotics (see Chapter 11) have an impact on the risk, severity, and types of infections found in the geriatric population. The risk or severity of an infection can be simply illustrated in an equation that includes innate microbial factors (virulence), quantity of exposure to microorganisms, and

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host resistance: virulence inoculum size Infection (risk/severity) ⬇ host resistance This relationship states that infection risk or severity is directly proportional to the virulence of the pathogen and quantity of organisms, and inversely proportional to the integrity of host resistance (14). Certainly, frail LTCF residents are being exposed more to highly virulent organisms by virtue of several pathogens having resistance to multiple antibiotics (e.g., methicillin-resistant Staphylococcus aureus [MRSA], vancomycin-resistant enterococci [VRE]). The quantity of microorganisms to which these residents are exposed can be enormous, especially when they experience aspiration pneumonia, intra-abdominal infections, and infected skin/soft tissues (e.g., pressure ulcers). In addition, the age-related changes in immune function and the immune dysregulation associated with underlying chronic diseases reduce the elderly LTCF resident’s resistance to infection. C. Antimicrobial Therapy Chapter 11 provides an in-depth discussion of the principles and approach to prescribing antibiotics for elderly patients with suspected or confirmed infections. Nevertheless, it is important to consider the age-related changes in pharmacokinetics and pharmacodynamics whenever any drug is prescribed to an elderly patient. Dose adjustments and the pharmacological properties of a drug must be carefully determined because of the age-associated alterations in volume of distribution, reductions in renal function, and potential sensitivity of select organs to certain drugs. Moreover, because the vast majority of older patients are taking some type of prescribed or over-the-counter medication, potential drug interactions as well as adverse side effects, must be carefully evaluated before and during administration of an antibiotic (e.g., divalent ion-containing antacids may affect the absorption of many quinolones). Adverse drug events occur more often in the elderly and increase with the number of drugs prescribed (15). It is imperative, therefore, that careful monitoring for adverse events in elderly patients or residents be performed regularly during administration of antibiotics or any other drug. Because elderly persons may not exhibit typical manifestations of drug side effects as described by the drug information packet, it is important to be aware that unexplained changes in cognitive function, behavior, or physical capacity may be attributable to medications. However, close monitoring is especially difficult in LTCFs because of the high level of disability and inability to communicate in many of the residents in these institutions, the limited number of visits made by physicians and other health providers, and lack of immediate availability of laboratory tests in such facilities. Given these limitations, prescribing antibiotics to

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LTCF residents will require careful thought, appropriate indications, and judicious selection.

REFERENCES 1. 2. 3.

4. 5.

6. 7. 8. 9.

10. 11.

12. 13. 14. 15.

Lyons AS, Petrucelli RJ. Medicine: An Illustrated History. New York, Harry N. Abrams, 1978. Crosby AW. Epidemic and Peace, 1918, Part IV. Wesport, CT, Greenwood Press, 1976. U.S. Department of Health and Human Services (DHHS), Public Health Service, National Center for Health Statistics: Health United States 1985. DHHS Publication No. (PHS) 86-1232. Hyattsville, MD, DHHS, 1986. Kupersmith C. Three Centuries for Infectious Disease. An Illustrated History of Research and Treatment. Greenwich, CT, Greenwich Press, 1998. National Center for Health Statistics. Leading causes of death and number of deaths according to age: United States, 1980 and 1993. In: Health United States, 1995. Department of Health and Human Services (DHHS) Publication No. (PHS) 96-1232. Hyattsville, MD, DHHS, 1996. Yoshikawa TT. Geriatric infectious diseases: An emerging problem. J Am Geriatr Soc 1983; 31:34–39. Yoshikawa TT: Important infections in elderly persons. West J Med 1981; 135: 441–445. Yoshikawa TT, Norman DC. Fever in the elderly. Clin Infect Dis 2000; 31:148–151. Bentley DW, Bradley S, High K, Schoenbaum S, Taler G, Yoshikawa TT. Practice guideline for evaluation of fever and infection in long-term care facilities. Clin Infect Dis 2000; 31:640–653. Norman DC. Fever in the elderly. Clin Infect Dis 2000; 31:148–151. Castle SC, Yeh M, Toledo S, Norman DC. Lowering the temperature criterion improves detection of infections in nursing home residents. Aging Immunol Infect Dis 1993; 4:67–76. Norman DC, Yoshikawa TT. Fever in the elderly. Infect Dis Clin North Am 1996; 10:93–99. Castle SC. Clinical relevance of age-related immune dysfunction. Clin Infect Dis 2000; 31:578–585. Yoshikawa TT, Norman DC. Aging and Clinical Practice: Infectious Diseases. Diagnosis and Treatment. New York, Igaku-Shoin, 1987. Wong FS, Rho JP. Drug dosing and life-threatening drug reactions in the critically ill patient. In: Yoshikawa TT, Norman DC (eds). Acute Emergencies and Critical Care of the Geriatric Patient. New York, Marcel Dekker, Inc., 2000:31–47.

4 Impact of Age and Chronic IllnessRelated Immune Dysfunction on Risk of Infections Steven C. Castle VA Greater Los Angeles Healthcare System, and UCLA School of Medicine, Los Angeles, California

I. INTRODUCTION The increased risk and severity of infections in the elderly population is well documented, and immunosenescence, the state of dysregulated immune function with aging, is felt to be a significant contributor to this increased risk. However, of more clinical relevance is the even higher risk of nosocomial infections in longterm care facilities (LTCFs). Surveillance of LTCF-acquired infections by the National Nosocomial Infections Surveillance system has reported a high incidence of 3.82 infections per 1000 resident-days of care, but with significant variability (1). Data vary widely depending on the type of facility, nature of the residents, definitions used for infections, and type of data analysis. Prevalence rates of infection range from 1.6% to 32.7%, and overall incidence rates range from 1.8 to 13.5 infections per 1000 resident-days of care, with equal variability for specific infections such as urinary tract infection or pneumonia. The questions that are raised from these data are: (1) What resident or facility factors contribute to this wide variability of incidence of infections? (2) Can anything be done to reduce the risk of infection by treatment of residents? (3) What impact could changes in infection control policy have on infection rate for a given facility? If the goal is to prevent serious infections in the elderly, it appears the field of geriatric immunology/infectious disease is faced with the tremendous challenge of studying a very diverse population of chronically ill individuals in addition to the study of the very healthy elderly. Grouping individuals by disease severity or 33

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by level of impairment of specific components of immunity may help to advance our ability to improve host defense in an at-risk population (2).

II. IMMUNOSENESCENCE: AGING CHANGES IN IMMUNITY EXCLUDING IMPACT OF DISEASE Immunosenescence is defined as the state of dysregulated immune function that contributes to the increased susceptibility of the elderly to infection and, possibly, to autoimmune disease and cancer (3). This perspective will focus on the relevance that age-related immune dysregulation has on susceptibility to infectious disease; however, there is growing interest in the pathogenetic role of a dysregulated immune system in common age-related illness such as atherosclerosis, Alzheimer’s dementia, diabetes mellitus, or osteoporosis. The immune system is arbitrarily divided into innate (natural) and adaptive (acquired) components, but recent advances in the field have focused attention on the interface between these two components. Extensive studies in inbred laboratory animals and in very healthy elderly humans have identified age-related changes in immunity, which have been essentially limited to phenotypic and functional changes in the T-cell component of adaptive immunity. In an attempt to standardize laboratory methods and isolate aging changes from external changes of disease and medications, studies over the past 15 years have included only the very healthy elderly. This has been accomplished by the exclusion of subjects with evidence of disease or use of medications, by applying rigorous criteria as defined by the SENIEUR Protocol (4). This concept of distinguishing nature (genetic) versus nurture (environment) has long been debated and tends to distinguish the subtle differences in the interests of gerontologists (the study of aging) and geriatricians (the care of the aged). The SENIEUR Protocol criteria exclude subjects with unhealthy lifestyle choices; any clinical information that suggests the presence of infection, inflammation, malignancy, or other immune disorders; and any laboratory data that suggest abnormal organ function as well as anyone on medications for treatment of a defined disease. These stringent criteria exclude 90% of subjects aged 65 or older, 25% of younger subjects, and virtually 100% of the population in LTCFs (5–7). It would appear the original intent of the SENIEUR protocol was to develop a reference population, but it has been applied to exclude subjects with significant external/environmental exposure, which limits our understanding of mechanisms of vulnerability to infections in the at-risk population with underlying chronic diseases. Hence, despite extensive studies on possible mechanisms for age-related changes in T-cell phenotype and function in a very healthy population, no compelling scientific evidence has shown that these changes have direct relevance to the common infections seen in the aged population (4–7).

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III. IMPACT OF CHRONIC ILLNESS ON INFECTIONS SEEN IN THE ELDERLY Despite 90% complete involution of the thymus by age 40, true opportunistic infections are NOT seen among elderly patients, even those with significant chronic disease. This suggests that there is likely compensation for the lost activity of the thymus gland. Infections that are a problem in this population are well known to the clinician, that is, primarily bacterial infections (pneumonia, urinary tract, and skin and soft tissue) and some viral infections (reactivation of herpes zoster, and significantly increased morbidity and mortality associated with influenza virus). In addition, changes in immunity create difficulty in detecting both active (primary and reactivation) and inactive tuberculosis. Response to vaccination, which requires intact cell-mediated immunity to drive the humoral response, is clearly diminished in many different elderly populations as well as in laboratory animals (3,5,6). A. Impact of Age and Chronic Illness on Influenza Age-related changes in immunity likely have the most clinical relevance towards an impaired response to influenza infection and/or immunization to influenza. An estimated 90% of the 10,000 to 40,000 excess deaths attributed to influenza annually in the United States occur in persons 65 years of age or older. The Centers for Disease Control and Prevention Report on prevention and control of influenza states that when the antigenic match between vaccine and circulating virus is close, infection is prevented in 70% to 90% of subjects younger than 65, compared with only 30% to 40% in those 65 years of age or older (8). A past review on antibody response to influenza found that 10 studies identified a decline in antibody response in an aged population, 16 reported no change, and four showed an increased response. This variability is related to both differences between populations and differences in defining a protective antibody response. Influenza vaccine efficacy in elderly persons is a complicated issue for a variety of reasons including the low attack rate and challenge in confirming actual influenza infection. There are also differences in defining an antibody response because older individuals often have higher prevaccination antibody levels compared with younger individuals who have had less exposure to infection and fewer vaccinations. Even if antibody responses were intact, they may not provide the same level of protection as in younger individuals. Thus, for example, in a study reporting on 72 vaccinated elderly who later were confirmed to have influenza infection, 60% of these individuals had antibody titers of 1:40 or higher, and 31% had titers of 1:640 or higher 4 weeks after vaccination (9,10) (see Chapter 20). Not only is vaccine response less in this population, but even when vaccine response appears adequate, protection from infection is lower than in younger adults, which is likely related to the quality of the antibody produced in neutralizing viral pathogenesis. Never-

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theless, despite the low efficacy in prevention of infections, it needs to be emphasized that vaccination in people aged 65 and older has been effective in reducing adverse events. In those 65 years of age or older, vaccination reduced the incidence of hospitalization or pneumonia 50% to 60%, and mortality was reduced by 80%. In a 3-year study on more than 75,000 community-dwelling elderly, there was a 46% (range of 39% to 54%) reduction in all-cause mortality associated with individuals who received influenza vaccination. Antibody response to vaccination (both magnitude and duration) is impaired in those aged 65 and older, but protective benefit to host defense likely occurs because cytotoxic T lymphocyte activity towards both killing efficiency of viral infected cell and duration of activity has been reported to be intact in older subjects (8,9,11,12). Underlying chronic illness dramatically increases the risk of influenza infection and impairs the response to vaccination. The presence of one or two chronic illnesses (such as emphysema, diabetes mellitus, or chronic renal insufficiency) is associated with a 40- to 150-fold increase in the basal incidence rate for influenza pneumonia (11). Whether chronic illnesses, medications, or other related external conditions directly contribute to further compromise of immune competence has not been elucidated. One study on vaccine response in nursing home residents demonstrated only 50% of residents had an adequate response, based upon a definition of a fourfold increase in antibody titers. Furthermore, the response to vaccination did not correlate with nutritional status or dehydroepiandosterone levels (13). Another study in a nursing home setting reported that only 36% of 137 vaccinated residents demonstrated a rise in antibody titer, and there was no correlation with age, body mass index, or functional status, as measured by the Barthel Index (14). B. Impact of Age and Chronic Illness on Pneumonia and Tuberculosis The risk and severity of pneumococcal pneumonia and tuberculosis increase with age. The incidence of pneumococcal infection is high in the first 2 years of life, then declines through adulthood, and finally increases dramatically in the geriatric population. Mortality is higher in elderly subjects and rises with advanced age, approaching 80% in those older than age 85. Rates of bacteremia and meningitis from the pneumococcal infection are higher in the elderly. In fact, unlike all other age groups, mortality from pneumococcal pneumonia has actually increased in those older than age 75 since the antibiotic era (1950 vs 1985). Efficacy of the pneumococcal vaccine in preventing infection has been difficult to demonstrate in randomized control trials but has been reported to be 50% to 80% effective in case series. Five years after vaccination, the efficacy remains about 70% for those younger than age 75, but only 53% in subjects 75 to 85, and only 22% effective in those older than age 85 (15,16) (see Chapter 20).

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The overall case rate for tuberculosis declined 26% in the United States between 1992 and 1997, with the highest number of cases reported in the 25 to 44 age group, which is a reflection of the human immunodeficiency virus (HIV) epidemic (see Chapter 15). Prior to this epidemic, tuberculosis case rates had an upward inflection point at age 75, due to both reactivation and primary cases of residents in institutional settings and community cases going undetected (11). The disease in the elderly remains largely distinct from tuberculosis in association with HIV infection, and the majority of the cases remain isoniazid sensitive. Differences in presentation between young and older persons with tuberculosis include more subtle presentation (less pronounced cough, night sweats or X-ray findings), and skin testing is difficult to interpret due to both a waning of delayed hypersensitivity (false negative for inactive and active disease), but a more pronounced booster effect (false positive for “conversion”). Mouse studies on tuberculosis show increased susceptibility with minor shifts in the host response. Briefly, it appears that in older animals there is a delayed recruitment of CD4 T cells, with less interferon gamma production. Hence, the infection tends to disseminate more and eventual containment is less. Adoptive transfer studies show that transfer of young T cells into old animals reverses many of these changes (17). C. Changes in Immunity in Subjects with Herpes Zoster Infection The incidence of herpes zoster dramatically increases in individuals older than age 75 (see Chapter 17). Younger individuals who develop active zoster infections have an increased association of immunosuppressive illness, but outbreaks are not associated with occult malignancy in older individuals. Factors that control or predict reactivation of latent infections are not known. Limited epidemiological studies have shown that blacks have less risk of developing zoster than whites, but measures of stress were not significantly associated with herpes zoster. Risk factors associated with the development of postherpetic neuralgia, such as the degree of immunological recall to the virus, have not been studied (18,19). No careful studies of immune changes in subjects who have had an outbreak of acute zoster or postherpetic neuralgia have been done; there are no studies to assess association of herpes zoster with subsequent development of bacterial, tubercular or influenza infection, or response to vaccination. D. Risk Factors for Colonization with Resistant Bacteria Colonization of resistant bacteria in residents of LTCFs, including methicillinresistant Staphylococcus aureus, vancomycin-resistant enterococci, aminoglycoside-resistant enterococci, and multidrug-resistant gram-negative bacilli varies significantly from facility to facility (see Chapters 21–24). Colonization may be

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more common in LTCFs than in acute care settings, whereas infection from these organisms is less common. Epidemiological markers of risk of colonization and infection are generally any marker of end-stage illness and frailty, including prior acute hospitalization, length of stay in an LTCF, poor functional status, recurrent urinary bladder catheterization, urinary incontinence, pressure ulcers, and gastrostomy tubes (20). Despite these markers of frailty, no studies have correlated colonization with resistant bacteria with specific changes in immunity, poor vaccine response, or risk of influenza or other bacterial infections. Hence, efforts toward prevention of colonization with resistant bacteria have included control/appropriate use of antibiotics and infection control measures of hand washing and appropriate isolation protocols.

IV. AGE-RELATED CHANGES IN COMPONENTS OF IMMUNE RESPONSE A. Innate and Acquired Immunity The immune response consists of two interactive components, an innate (natural) and an acquired (adaptive) response. Innate immunity is less studied but has cellular components, that is, macrophages, polymorphonuclear (PMN) cells, natural killer (NK) cells, and dendritic cells (DCs); and noncellular components, which involve recognition molecules, such as C-reactive protein, serum amyloid protein, mannose-binding protein and the complement cascade. The noncellular components bind carbohydrate structures that do not occur in eukaryotes to help differentiate invading pathogens from self, which are then eradicated by the cellular component (3). Adaptive or acquired immunity has unique characteristics: (1) there is a specific response to a given antigen; (2) interaction of cells is required to activate either a cellular (cytotoxicity) and/or humoral (antibody) response; (3) memory is present, which enables more rapid response upon subsequent rechallenge of the same antigen; and (4) both the cell-mediated and humoral functions are dependent on T cells. To initiate an adaptive immune response, T cells must be activated by functional antigen-presenting cells (APC). The degree of interaction of both T cells and APC can influence the subsequent type, quality, and quantity of immune response. Hence, it is at this key interface between innate and acquired immunity that regulation of turning on or off of a response occurs (3,11,21,23). Interaction between the different immune cell types that constitute these components of host defense is carried out by the relative mix of cytokines, hormone-like proteins that act locally in directing the characteristics of an inflammatory response, and the ability of effector cells to differentiate or respond to specific signals, both of which are likely affected by aging and chronic illness. In general, activation of acquired immunity that involves a cell-mediated immune re-

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sponse and is protective against most infectious agents is described as a T helper 1 (Th1) response and is associated with high levels of the cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-). In contrast, a T helper 2 (Th2) response, which is associated with allergic or parasitic infections but not associated with clearance of most bacterial or viral infections, is associated with high levels of IL10, IL-4, and IL-5 but low levels of IL-2 and IFN-. The relative concentrations of so-called proinflammatory cytokines, defined as those that upregulate a Th1 response (such as IL-12, IL-1, tumor necrosis factor alpha), or anti-inflammatory cytokines (important in turning off an inflammatory response such as IL-10, transforming growth factor beta, or IL-1 receptor antagonist) that are produced in local tissues, circulating APC including DCs, or by existing tissue macrophages, allow further refinement of the eventual outcome of an inflammatory response by influencing gene activation in effector immune cells (3,11,21–23). Mature DCs are required for efficient activation of influenza-specific cytotoxic (memory CD8) T cells (24). Hence, the differentiation of regulatory APC at the site of inflammation is important in determining the quality of the subsequent immune response, either due to the age-related changes in the cytokine mix at the site of inflammation or to cell-specific changes from aging or chronic disease. Examples of differentiation-dependent measures of the efficiency of the interaction include the ability of T-cell binding to APC, IFN- production, and the ability to generate influenza-specific cytotoxic T cells. Hence, adjuvants that may affect the ability of the DC to differentiate or mature should be considered to improve the suboptimal vaccine response seen in residents of LTCFs. B. Age-Related Changes in Acquired Immunity The overall impact of age on host immunity is thought to occur primarily along two mechanisms. The first is replicative senescence that may limit T-cell clonal expansion (the Hayflick phenomenon or loss of telomerase activity/telomere length, and may be more related to exposure to antigen than age). The second is developmental changes associated with involution of the thymus that precedes dysfunction of the T-cell component of adaptive immunity. Studies have shown a decrease in telomere length with age in T cells and B cells; recently, however, it was demonstrated that there was no significant change in telomerase activity upon stimulation of cells (25). This study may not have included individuals with repeated exposure to antigen (perhaps in individuals with chronic illness), but it suggests that age-specific changes are more due to developmental changes in T cells. Several recent reviews have summarized extensive studies on changes in T-cell function with aging (26–29). The age-related decline in T-cell function is preceded by involution of the thymus gland (cortex involutes much more than the medulla), with dramatic declines in thymic hormone levels, which has been described in both animals and humans. In addition, changes in bone marrow stem

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cells have also been described that are distinct from thymic changes. These changes are thought to result in a shift in the phenotype of circulating T cells, with a decrease in the number of naïve T cells (CD45RA CD4), and a relative accumulation of memory T cells (CD45RO CD4). In addition, the memory cells that remain include a spectrum of normal functioning and hypofunctioning T cells in comparison with younger adult controls. The decrease in functioning cells results in impaired proliferative capacity and IL-2 and IL-2 receptor expression. These changes can be traced to defective upstream postreceptor signaling at multiple steps, including the phosphorylation of mitogen-activated protein kinases (29). At the same time, there appears to be a propensity towards a shift to a Th2 anti-inflammatory response, as evidenced by an increase in IL-10 production (3,11,30). A wide spectrum of findings have been reported, but the healthier the population, the less impact on changes in T-cell function can be identified. Agerelated changes in T-cell cytokines other than IL-2 and IL-10 have demonstrated a much more varied response, especially IFN- and IL-4, which may relate as much to different species (mouse studies differ markedly from humans) and the type of stimulation. Finally, despite the rather universal changes in T-cell response with age, the relevance is unclear. In vitro support of antibody response of T cells has been shown to be impaired with age (9), but impaired proliferative response, even to specific antigen, was not able to predict impaired antibody response to influenza immunization (9). Studies on changes in CD8 cells are much less numerous and have described some age changes, with impaired binding to targets, but once bound, killing capacity appears intact with aging (11,23). Changes in B cells are much less clear but appear to have some similarities to T-cell age-related changes. B cells from older individuals show impaired activation and proliferation that also may be related to changes in costimulatory molecule expression (11,23). Both the primary and secondary antibody responses to vaccination have been impaired, with the degree of impairment being greater when T-cell involvement is required to drive the antibody response (usually related to the complexity of the antigen). The specificity and efficacy of antibodies produced in older individuals is lower than in younger populations (11,27). C. Interaction Between Innate and Acquired Immunity with Aging Age-specific changes in immunity have been largely limited to the T-cell compartment of acquired-immunity. Antigen-presenting cell function in healthy elderly is intact, but infection rates are increased in chronically ill elderly. Thus, it is surmised that the impact of chronic illness on host immunity may be manifested by impaired efficiency of interaction of innate and acquired immunity. Because the innate component of immunity is critical to both the number of immunocompetent units, as well as the magnitude of the immunological burst upon

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activation, it very well could be the target of chronic illness in reducing immune competence beyond normal age-related changes (2). Evidence, for the most part, has suggested innate immunity remains intact or is upregulated with aging. The frequently reported nonspecific increase of proinflammatory substances produced by the innate immune system and downregulation of specific immunity may reflect a compensatory event by either component, with causality unclear (2,11,17). In SENIEUR Protocol Healthy elderly, larger numbers of DCs were generated from circulating immune cells in comparison with younger adults, and DCs from elderly were effective in restoring proliferative capacity and in preventing the development of apoptosis (programmed cell death) in T cells grown to senescence (no longer able to proliferate) in culture (31,32). Likewise, antigen presentation capacity of circulating APCs has actually been shown to be higher in communitydwelling elderly in comparison with younger adult controls, and was associated with higher IL-12 and IL-10 levels (30). Preliminary studies in a nursing home population with chronic illness suggests a reversal in APC function, with impaired antigen presentation, impaired differentiation as manifested by reduced surface marker expression of major histocompatibility complex (MHC) class II and CD40 and no increased levels of the proinflammatory cytokine IL-12 (33, unpublished data). Hence, whether APC function, and DC in particular, is the specific target or the final common pathway of lost immune competence from chronic illness is unclear. The differentiation of DC has been identified as a key variable in the stimulation of effector T-cell function (IFN- production and cytotoxic T-cell function), and will be considered an important target for immunotherapeutic adjuvants to improve antigen delivery and boost immunity in general (24). The production and interaction of cytokines produced by cells of innate immunity are very complex. The timing and relative signal strength of these cytokines are crucial to the overall priming of the acquired immune response. Multiple studies suggest that there is a nonspecific increase in production of proinflammatory proteins in the aged population. Animal studies show exquisite sensitivity in the old animals to bacterial endotoxins, with significantly more endorgan inflammation (15). Low-level, nonspecific autoimmunity throughout different tissues may play a role in gradual loss of reserve capacity of a given organ system, a hallmark of aging, as well as a subsequent nonresponsiveness of immunity to infectious pathogens. Studies on age-related changes in proinflammatory cytokines show varied findings, most likely related to the very complex nature of response to cytokine networks, but most have shown an increase in stimulated production of IL-6, IL-8, and TNF-alpha, and a decrease in IL-1 (3,11,23,34). A recent review on IL-6 and aging describes 14 studies that report increases in IL-6 (34). Interleukin-6 itself has been shown to be inhibitory to TNF-mediated mycobacteriostatic activities in macrophages (35). Chronic illness likely contributes to further dysregulation of control of immune response. A recent study compared IL-2 and IL-6 levels in young and el-

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derly healthy and “almost healthy” populations by including individuals who did not meet the SENIEUR protocol because of a lack of regular exercise and the use of medications for conditions such as hypertension or osteoarthritis. The almost healthy group demonstrated lower levels of IL-2 and higher levels of IL-6 in both young and old age groups, with the most pronounced changes in the elderly almost healthy population (4). Table 1 summarizes the components of the immune system, the impact of age and chronic illness on immunity, and the interaction between innate and acquired immunity.

Table 1 Summary of Immunity, Aging, Chronic Diseases, and Their Interactions Innate immunity

Interface

Key elements

NK cells- Surveillance & infected cell killing PMN- Migration to sites of infection; phagocytosis, local inflammatory cells rescue PMNs; production of ROS for killing M/APC- Phagocytosis, killing of organisms, regulation of cytokines, wound healing

T cells- Provide long-term memory, direct lysis of infected cells, or rapidly amplify response production of proinflammatory cytokines (IL-2, IFN-). B cells- Production of antibodies to antigen; require help from T cells, stimulation of M/APC’s

Aging effects

NK cells- Incr cell number compensates for decr in efficiency; low count is associated with 3 incr mortality PMN- Tissue migration is intact in healthy elders M- Less efficient tumor lysis stimulation response to IFN-

Impact of chronic disease

NK- Little studied PMN- Tissue migration impaired in chronic bronchitis, brittle DM; very high oxidants produced in association with atherosclerosis M- Shown to be inhibitory to killing response to tuberculosis in lungs NK- Natural killer cells PMN- Neutrophil, polymorphonuclear cell M- Macrophage/monocyte APC- Antigen presenting cells GM-CSF- Granulocyte-macrophage colony-stimulating factor LPS- Lipopolysaccharide

NK- Produce proinflammatory cytokines IL-12 PMN- Cytokines from other cells (GM-CSF, IL-2, LPS) prevent PMNs from rapid cell death M- Antigen presentation requires Ms, and signals to T cells determine quality of immune response M-T cell: Many studies show impared response to PHA, likely due to decr in costimulatory molecule function; incr in IL-10 (antiinflammatory) occurs instead and is either a cause or consequence of incr nonspecific inflammation with aging Suggestion of more impairment of interaction with coexisting disease and little or enhanced response in very healthy/elderly IFN- Interferon-gamma IL- Interleukin Decr/incrDecrease/increase PHA- Phytohemagglutinin DM- Diabetes mellitus

Ag- Antigen Ab- Antibody ROS- Reactive oxygen species

Abbreviations

Acquired immunity

T cells- Memory cells accumulated are much slower to divide, and produce less IL-2, more IL-10. B cells- Produce more auto Ab (to self); levels of Ab remain stable, but specificity for antigen, pathogen decr Further impairment due to loss of stimulation of APC

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V. IMMUNE POTENTIATING EFFECTS OF MEDICATIONS AND DIETARY SUPPLEMENTS A. Modification of Immunity with Nutritional Treatments in Elderly with Nutritional Deficiencies Persons with protein energy undernutrition generally have associated micronutrient deficits. Specific nutrient deficiencies are also possible in individuals without gross undernutrition, but who may not have adequate resources in preparation of balanced meals. Elderly subjects who all met the SENIEUR Protocol but differed in having slightly low serum albumin values (3.0 to 3.5 g/dL) underwent a comparison of immune response. In comparison with those subjects with normal albumin values, the group with the lower albumin had significant decrease in proliferation to phytohemagglutinin, lower IL-2, and decrease in delayed-type hypersensitivity testing. However, there was less of a difference to antibody response to influenza vaccine (36,37). Micronutrient deficits are associated with alteration in immune parameters, especially deficits in zinc, selenium, folic acid, vitamin B-6, and vitamin E. The impact of zinc deficiency on immunity has been extensively studied, as zinc is a cofactor in many postreceptor activation steps that are essential to cell proliferation (see Chapter 5). Zinc deficiency has been found to be associated with impaired peripheral blood T-cell counts, impaired T-cell proliferation, decreased IL2 production, and diminished CD8 T-cell cytotoxicity. Zinc deficiency has been associated with progression of some disease that is thought to be due to a shift from a Th1 to a Th2 response, such as is found in leprosy, leishmania, schistosomiasis, and acquired immunodeficiency syndrome (38–40). In vitro models have reproduced this clinical observation, as zinc-deficient subjects have reduced production of IL-2 and IFN- but no change in Th2 cytokines of IL-4, IL-6, and IL10 (41). Of note, children with protein energy malnutrition have evidence of thymic atrophy and impaired T-cell differentiation, which is reversed by zinc supplementation and correlated with plasma zinc levels. In addition, it has been shown in several tissue culture conditions that zinc deficiency is associated with increased activation of apoptosis of both endothelial cells as well as T cells, which is reversed by zinc supplementation (42). Hence, the ability of local tissues and APCs in stimulating an appropriate immune response may be impaired in the presence of zinc deficiency due to induction of apoptosis of APCs and/or effector T cells upon activation and less support of a subsequent Th1 immune response. B. Effect on Immunity of Dietary Supplements in Elderly Without Known Nutrient Deficiency Other studies have investigated the immunopotentiation of dietary supplements, even if no deficiency is identified. One study has reported a significant increase in

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CD4DR cells in a randomized placebo design with zinc supplementation, but a decline in total CD3 and CD4 cells with vitamin A supplementation (43). Another study randomly assigned physiologic supplementation of vitamins (B6, A, C, E) and trace elements in 96 independently living elderly and evaluated changes in immune parameters and the incidence of infections over a 12-month period. In the intervention group, there were significant increases in percent CD3, CD4, and NK cells, with no change in CD8 or B cells. There was a significant increase in proliferative response of T cells to phytohemagglutinin with increases in IL-2 and IL-2 receptor expression, as well as NK activity. There was no significant change in the response to influenza vaccine (39). The supplemented group had less number of days of infection and less duration of use of antibiotics. Likewise, a study randomizing hemodialysis patients to 120 mg of zinc sulfate supplementation after each dialysis showed a significant increase in the serum zinc levels, as well as an increase in the percentage of B cells and the antibody response to influenza vaccination (44). Another group has reported an increase in delayed-type hypersensitivity testing at 12 months after supplementation with ascorbate, beta carotene, alpha tocopherol, folate, retinol, riboflavin, copper, and zinc. There was a significant increase in serum levels of all but retinol, riboflavin, copper, and zinc (38). Topical zinc has been associated with a boost in delayed-type hypersensitivity skin testing in elderly hospitalized patients (45). Finally, a recent randomized control trial comparing zinc acetate lozenges (a 12.8 mg zinc acetate lozenge every 2 to 3 hours while awake) with placebo in 50 ambulatory volunteers within 24 hours of developing cold symptoms showed a significant reduction in duration and severity of cold symptoms but did not demonstrate any change in proinflammatory cytokine levels while on treatment with zinc (46). Vitamin E, an antioxidant, has been found to be deficient in 50% of the population studies of healthy elderly in New Mexico (47–50). There is evidence that vitamin E inhibits the formation of prostaglandin E2 (PGE2). Prostaglandin E2 has been described to be elevated with age in humans and animal models and is associated with decreases in proliferative capacity and IL-2 production, and an increase in IL-10 production, all of which are thought to be associated with aging. Dose response improvements in immune function of old mice when given vitamin E supplementation, including delayed-type hypersensitivity, proliferative response and IL-2 with a decrease in PGE2 have been reported (51)). Similar results were obtained in healthy elderly humans supplemented with 800 IU of vitamin E for 30 days, with significant increases in delayed-type hypersensitivity and IL-2 and a trend toward increased proliferation of lymphocytes (48). Further studies on humans demonstrated that low doses of vitamin E (60 mg/day) were able to increase delayed-type hypersensitivity response, but higher doses were needed (200–800 mg/day) to demonstrate an increase in antibody response to several vaccines (hepatitis B, tetanus, and diphtheria) (48,49) and a 30% lower incidence in self-reported infections for a period of 235 days. In a murine influenza model, vitamin E sup-

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plementation showed significant reduction in lung influenza viral titers in old mice, with only modest improvement in young mice (50,51). However, epidemiological studies in elderly subjects have not found any correlation between immune parameters (lymphocyte response, delayed-type hypersensitivity, serum antibody levels) with vitamin E intake (52). In human studies, supplementation of vitamin E has not shown a shift from Th2 to Th1 cytokine profiles after supplementation, although delayed-type hypersensitivity has repeatedly been demonstrated to be boosted with vitamin E, especially in the lowest responders (53). The effect of supplementation of vitamins A, C and E on cell-mediated immunity in long-stay nursing home residents did demonstrate improved T-cell number, CD4/CD8 ratio, and T-cell proliferative response to phytohemagglutinin (54). Another study investigated the individual and combined effects of vitamin C (1 g) and E (400 mg alpha-tocopheryl acetate) on APC cytokines, proinflammatory cytokines, IL-1, IL-6 TNF-alpha, and PGE2 in response to lipopolysaccharide stimulation of peripheral blood mononuclear cells. The combination resulted in the higher increases in cytokines than either vitamin given alone and was also associated with a reduced PGE2 production (55). Other studies using 100 mg of alpha-tocopherol in 52 subjects aged 65 years and older did not demonstrate significant changes in antibody production or T-cell proliferative response (53,56). However, there may be subsets of elders who are more likely to benefit from vitamin E supplementation, especially low immune responders (53,55,57). C. Common Medications That May Have Significant Immunopotentiation In addition to obvious immunosuppressive medications, that is, corticosteroids, nonsteroidal anti-inflammatory agents (including cyclooxygenase type 2 inhibitors), and antineoplastic agents, there are several common medications that demonstrate some evidence of immune potentiation. Studies involving chronically ill individuals who are on multiple medications need to control for these medications in particular. The other approach would be to directly test if these medications have potential impact on boosting impaired immune competence in crossover designs. One class of agents that should be considered include beta adrenergic receptor antagonists (beta blockers) (58–60). Beta blockers have been shown to block the immunosuppressive effects of acute stress (58). One study on patients with dilated cardiomyopathy showed a decrease in the rate of anergy (from 70% down to 20%) with an increase in percentage of T cells and NK cells, and an increase in concanavalin A stimulation of IL-2 receptors, in comparison with those randomized to no beta blockers (61). Histamine has been found to affect immune response in a complex manner. Histamine antagonists, especially type 2 inhibitors, also modulate immune response and have been shown to boost proliferative response of T cells to IL-2, improve healing to herpes zoster, and

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boost delayed-type hypersensitivity response (62). Hormonal agents that appear to have an impact on immunity include sex hormones, growth hormone, and megestrol acetate (63–65). Estrogens are likely to have a complex effect, as women tend to have more autoimmune disorders and diminished skin testing responses (64). Growth hormone levels diminish with aging, whereas supplementation of growth hormone was found to reverse involution of the thymus and was associated with enhanced activation of immune systems, including a 50% increase in Tcell proliferative response and increases in IL2 receptor on T cells (65). Other confounding medical conditions that may alter immunity include stress and depression, as well as any primary disease that affects primary organ function, such as failure of the heart, kidney, or liver. These conditions make it difficult to identify causation of impaired host defense; however, they likely manifest by a limited number of impaired potential T cell-antigen presenting cell functions.

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Stevenson KB. Regional data set of infection rates for long-term care facilities: Description of a valuable benchmarking tool. Am J Infect Control 1999; 27:20–26. Castle SC, Uyemura K, Makinodan T. The SENIEUR Protocol after 16 years: A need for a paradigm shift? Mech Ageing Dev 2001; 122:127–140. Pawelec G. Immunosenescence: Impact in the young as well as the old? Mech Ageing Dev 1999; 108:1–7. Ligthart GJ, Corberand JX, Fournier C, Meinders AE, Knook DL, Hijmans W. Admission criteria for immunogerontological studies in man: The SENIEUR Protocol. Mech Ageing Dev 1984; 28:47–55. Mysliwski J, Bryl E, Foerster J, Mysliwski A. The upregulation of TNFa production is not a generalised phenomenon in the elderly between their sixth and seventh decades of life. Mech Ageing Dev 1999; 107:1–14. Wick G, Grubeck-Loebenstein B. The aging immune system: Primary and secondary alterations of immune reactivity in the elderly. Exp Gerontol 1997; 32:401–413. Rowe JW, Kahn RL. Successful Aging. New York, Pantheon, 1998. Fukuda F, Bridges CB, Brammer TL, Izurieta HS, Cox NJ. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999; 48:1–23. Bernstein E, Kaye D, Abrutyn E. Immune response to influenza vaccination in a large elderly population. Vaccine 1999; 17:82–94. Gravenstein S, Drinka PJ, Duthie EH, Miller BA, Brown CS, Hensley M, Circo R, Langer E, Ershler WB. Efficacy of an influenza hemagglutinin-diptheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak. J Am Geriatr Soc 1994; 42:245–251. Burns EA, Goodwin JS. Immunodeficiency of aging. Drugs Aging 1997; 11: 374–397. Mullooly JP, Bennett MD, Hornbrook MC, Barker WH, Williams WW, Patriarca PA,

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Rhodes PH. Influenza vaccination programs for elderly persons: Cost-effectiveness in a health maintenance organization. Ann Intern Med 1994; 121:947–952. Fulop T, Wagner JR, Khalil A, Weber J, Trottier L, Payette H. Relationship between response to influenza vaccination and the nutritional status in institutionalized elderly subjects. J Gerontol A Biol Sci Med Sci 1999; 54A:M59–M64. Potter JM, O’Donnel B, Carman WF, Roberts MA, Stott DJ. Serological response to influenza vaccination and nutritional and functional status of patients in geriatric medical long term care. Age Ageing 1999; 28:141–145. Butler JC, Spika JS, Nichol KL, Shapiro ED, Breinan RF. Effectiveness of pneumococcal vaccine. Lancet 1998; 351:1961–1962. Hedlund JU, Kalin ME, Ortqvist A, Henrichsen J. Antibody response to pneumococcal vaccine in middle-aged and elderly patients recently treated for pneumonia. Arch Intern Med 1994; 154:1961–1965. Orme I. Mechanisms underlying the increased susceptibility of aged mice to tuberculosis. Nutr Rev 1995; 53(S4):S35–S40. Schmader K. Postherpetic neuralgia in immunocompetent elderly people. Vaccine 1998; 16:1768–1770. Schmader K, George LK, Burchett BM, Pieper CF. Racial and psychosocial risk factors for herpes zoster in the elderly. J Infect Dis 1998; 178 Suppl 1:S67–S70. Kaufman CA, Hedderwick SA, Bradley SF. Antibiotic resistance: Issues in long-term care. Infect Med 1999; 16:122–128. Horan MA, Ashcroft GS. Ageing, defence mechanisms and the immune system. Age Ageing 1997; 26-S4:15–19. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392:245–252. Hirokawa K. In: Pathy MSJ (ed). Principles and Practice of Geriatric Medicine, 3rd edition. New York, John Wiley & Sons Ltd., 1998:35–47. Larsson M, Messmer D, Somersan S, Fonteneau JF, Donahoe SM, Lee M, Dunbar PR, Cerundolo V, Julkunen I, Nixon DF, Bhardwaj N. Requirement of mature dendritic cells for efficient activation of influenza A-specific memory CD8 T cells. J Immunol 2000; 165:1182–1190. Son NH, Murray S, Yanovski J, Hodes RJ, Weng N. Lineage-specific telomere shortening and unaltered capacity for telomerase expression in human T and B lymphocytes with age. J Immunol 2000; 165:1191–1196. Chakravarti B, Abraham GN. Review: Aging and T-cell-mediated immunity. Mech Ageing Dev 1999; 108:183–206. Hodes RJ, Fauci AS (eds). Report of Task Force on Immunology and Aging. National Institutes of Aging and Allergy and Infectious Disease. US Department of Health and Human Services, March 1996. Cossarizza A, Ortolani C, Monti D, Franceschi C. Cytometric analysis of immunosenescence. Cytometry 1997; 297–313. Miller RA. Cellular and biochemical changes in the aging mouse immune system. Nutr Rev 1995; 53:S8–S17. Castle S, Uyemura K, Crawford W, Wong W, Klaustermeyer WB, Makinodan T. Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12. Exp Gerontol 1999; 34:243–252.

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Meyandi SN, Beharka AA. Recent developments in vitamin E and immune response. Nutr Rev 1996; 56:S49–S58. Meyandi SN, Meyandi M, Blumberg JB, Leka LS, Siber G, Loszewski R, Thompson C, Pedrosa MC, Diamond RD, Stollar BD. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: A randomized controlled trial. JAMA 1997; 277:1380–1386. Han SN, Meydani SN. Vitamin E and infectious diseases in the aged. Proc Nutr Soc 1999; 58:697–705. Han SN, Meydani SN. Antioxidants, cytokines and influenza in aged mice and elderly humans. J Infect Dis 2000; 182 Suppl 1:S74–S80. Goodwin JS, Garry TJ. Relationship between megadoses of vitamin supplementation and immunological function in a healthy elderly population. J Clin Exper Immunol 1983; 51:647–653. Pallast EG, Shouten EG, de Waart FG, Fonk HC, Doekes G, von Blomberg BM, Kok FJ. Effect of 50- and 100-mg vitamin E supplements on cellular immune function in noninstitutionalized elderly persons. Am J Clin Nutr 1999; 69:1273–1281. Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: A randomized control trial. Age Ageing 1991; 20:169–174. Jeng KC, Yang CS, Siu WY, Tsai YS, Liao WJ, Juo JS. Supplementation with vitamins C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults. Am J Clin Nutr 1996; 64:960–965. De Waart FG, Portengen L, Doekes G, Verwaal CJ, Kok FJ. Effect of 3 months vitamin E supplementation on indices of the cellular and humoral immune response in elderly subjects. Br J Nutr 1997; 78:761–774. Beharka AA, Wu D, Han SN, Meydani SN. Macrophage prostaglandin production contributes to the age-associated decrease in T cell function which is reversed by the dietary antioxidant vitamin E. Mech Ageing Dev 1997; 93:59–77. Bachen EA, Manuck SB, Cohen S, Muldoon MF, Raible R, Herbert TB, Rabin BS. Adrenergic blockade ameliorates cellular immune responses to mental stress in humans. Psychosom Med 1995; 57:366–372. Hedberg A, Gerber JG, Nies AS, Wolfe BB, Molinoff PB. Effects of pindolol and propranolol on beta adrenergic receptors on human lymphocytes. J Pharmacol Exp Ther 1986; 239:117–123. Feldman RD, Hunningshake GW, McArdle WL. Beta-adrenergic-receptor-mediated suppression of interleukin-2 receptors in human lymphocytes. J Immunol 1987; 139:3355–3359. Maisel AS. Congestive heart failure/LVH: Beneficial effects of metoprolol treatment in congestive heart failure: Reversal of sympathetic-induced alterations in immune function. Circulation 1994; 90:1774–1780. Komlos L, Notmann J, Arieli J, Hart J, Levinsky H, Halbrecht I, Sendovsky U. In vitro cell-mediated reaction in herpes zoster patients treated with cimetidine. Asian Pacif J Allergy Immunol 1994; 12:51–58. Mantonvani G, Maccio A, Lai P, Massa E, Ghiani M, Santona MC. Cytokine in-

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5 Nutrition and Infection Kevin P. High Wake Forest University School of Medicine, Winston-Salem, North Carolina

I. INTRODUCTION Aging is associated with a decline in immune competence and an increased risk of infection (see Chapter 4). Nutritional factors have been shown to play a significant role in age-associated immune dysfunction (1–4), and the prevalence of malnutrition among older adults is greatest in residents of long-term care facilities (LTCFs) (5,6). Reversal of underlying nutritional deficits is an attractive and inexpensive option for reducing morbidity and mortality in elderly residents of LTCFs; however, there are few randomized, controlled trials of sufficient power to clearly define the utility of such interventions for clinical endpoints. Most frequently, surrogate markers of nutrition or immune function (i.e., reversal of previously documented vitamin deficiency, increases in serum albumin, vaccine responses, or delayed-type hypersensitivity reactions) have been the outcomes measured in clinical trials. With this limitation clearly stated, this chapter will review the prevalence, causes, methods of detection, and clinical relevance of malnutrition in residents of LTCFs, and provide evidence-based suggestions for practical interventions to boost immune response and reduce the risk of infection in this at-risk population.

II. PREVALENCE AND CAUSES OF MALNUTRITION IN OLDER RESIDENTS OF LTCFs Global malnutrition, a deficiency of protein and calories, is the most common form of malnutrition in older adults. Estimates of the prevalence of protein and 51

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caloric malnutrition is dependent on the variable used to define malnutrition. If one considers reduced daily intake to reflect malnutrition, the proportion of elderly adults who are malnourished ranges from 2% to 33% in both healthy, freeliving elderly adults and residents of LTCFs. However, using nutritional variables such as anthropometric measures or laboratory determinations (i.e., serum albumin, total lymphocyte count), the estimated incidence of global malnutrition in healthy older adults is 3% versus 15% to 66% in institutionalized populations (6). Residents of LTCFs are at greater risk for global malnutrition for two basic reasons: reduced nutritional intake and increased metabolic demands. Reduced intake in LTCF residents is rarely due to poverty, in contrast to poor nutritional intake in the community, because regulations require that meals meet specific nutritional standards. However, serving the meal does not guarantee that it will be consumed (Table 1). Obviously, many LTCF residents have significant disabilities that reduce their capacity to feed themselves or properly chew and swallow. Many residents may be depressed, have anorexia consequent to comorbid conditions or drugs, or other conditions that reduce the desire for food. Furthermore, the environment of LTCFs may not be conducive to caloric intake for some residents. Many elderly in the community maintain caloric intake through “grazing,” that is, eating small amounts throughout the day. Scheduled times for meals, a short duration of time to complete the meal, a lack of adequate staffing to feed all residents at meal time, and reduced preferences for “institutional” ways of preparing food all contribute to reduced caloric intake in residents of LTCFs (6,7). Finally, cog-

Table 1 Barriers to Voluntary Nutrient Consumption in Older Residents of Long-Term Care Facilities Physical conditions Disability (inability to feed oneself) Medications (see Table 6) Poor dentition/swallowing Gastrointestinal disorders (e.g., peptic ulcer disease, gastroesophageal reflux, constipation) Restrictive diets Cultural/psychosocial Food preferences (based on religious or cultural norms) Social isolation System barriers Inadequate staffing Lack of food between meals (inability of elderly to “graze”)

Cachexia/anorexia of underlying disease (e.g., cancer, infection) Increased metabolic demands (e.g., wound healing, renal disease) Metabolic disorders (poorly controlled diabetes mellitus, thyroid disease)

Bereavement Depression

Restrictive meal times

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Table 2 Common Nutritional Deficiencies in Older, Long-Term Care Facility Residents Nutrient

Prevalence

Comment

Protein/calories

17%–65%

Manifested by wasting, low BMI, low serum albumin, lymphopenia Deficiency more common if measured by dietary intake or corneal cytology than by serum levels Particularly important when LTCF residents placed on isoniazid for tuberculosis prophylaxis/therapy Atrophic gastritis is common in elderly Decreased sunlight exposure and dairy product intake Supplementation documented to improve some vaccine responses in older adults Zinc supplementation to speed wound healing probably only helpful in residents who are zinc deficient

Vitamin A

2%–20%

Vitamin B6 (pyridoxine)

28%–49%

Vitamin B12 Vitamin D

0%–20% 20%–48%

Vitamin E

5%–40%

Zinc

0%–21%

BMI, Body mass index; LTCF, Long-term care facility. Source: Refs. 1, 6.

nitively impaired patients may not perceive hunger and thirst in the same way, thus further limiting their internal drive to consume protein and calories. For many of these same reasons, specific nutritional deficiencies also are more common in residents of LTCFs (Table 2). Vitamins A, B6, B12, D, E, and the trace elements zinc and selenium are most often found to be deficient in residents of LTCFs, with prevalence estimates of 40% to 50% for some micronutrients. Specific risk factors for micronutrient deficiencies in elderly LTCF residents include reduced oral intake (vitamins A, B6, D, E, and zinc), increased metabolic requirements (e.g., zinc for wound healing), decreased exposure to sunlight (vitamin D), and a high prevalence of atrophic gastritis (vitamin B12). Like protein/calorie malnutrition, the prevalence of micronutrient deficiencies again varies widely with the techniques used to measure deficiency. For example, vitamin A, a fat-soluble vitamin that is stored in the liver, is essential for proper immune function and the integrity of skin and mucous membranes. A French study (8) showed that the prevalence of vitamin A deficiency in LTCF residents was 2%, 6%, 21%, or 55% depending on whether serum levels, corneal cytology, urinary excretion after a given oral load of vitamin A, or evaluation of oral intake, respectively, was used as the determinate of “deficiency.” Furthermore, there is significant debate as to what the “recommended” daily amount of vitamins or minerals should be in older

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adults (9). Recommended intakes have tended to focus on the average intake in large population studies rather than the optimal level of intake for the majority of the population. Obviously, these recommendations are usually handicapped by a lack of data as to what is optimal. Finally, recent data suggest that energy requirements predicted by frequently cited methods (such as the Harris-Benedict [H-B] equation) do not accurately reflect the metabolic needs of elderly subjects, overestimating metabolic needs in 20%, and underestimating metabolic need in 35% of LTCF residents (10). The accuracy of the H-B equation-predicted metabolic need is not improved by adding a commonly used “stress factor.” Thus, estimating metabolic or specific micronutrient needs in LTCF residents is difficult based on current techniques. Two excellent recent reviews (11,12) have examined the anorexia of aging, outlining the physiological and pathophysiological causes for reduced caloric intake in older adults. There are many instances in which undernutrition is a consequence of physiology, and thus cannot be modified by earlier recognition or intervention. Specific examples include incurable cancer, a competent patient’s refusal to eat or take supplements, endstage disease such as severe congestive heart failure, or chronic obstructive pulmonary disease. However, undernutrition is often the result of a reversible cause, if recognized (Table 3). Specifically addressing this problem in LTCFs, one study (7) identified 15 modifiable causes for undernutrition in LTCF residents (Table 4). Most of the suggested remedies could be set in place at minimal or no additional cost; others, like increasing or retraining

Table 3 Mnemonic for Identifying Causes of Weight Loss in Older Long-Term Care Facility Residents Medications Emotional problems (depression) Anorexia tardive (nervosa); alcoholism Late-life paranoia Swallowing disorders Oral factors No money (insufficient funds in Medicaid facilities for palatable, individualized diets and consultant dietitian) Wandering and other dementia-related behavior Hyperthyroidism, hyperparathyroidism, hypoadrenalism Enteric problems (malabsorption) Eating problems (inability to feed oneself) Low-salt, low-cholesterol diets Social problems (ethnic food preferences, isolation, “disgusting” food habits of other residents) Source: Ref. 12, with permission.

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Table 4 Reversible Causes of Malnutrition and Suggested Remedies Cause

Method of identification

Corrective action

Staff unawareness

Lack of documentation in chart by MD, RN, or RD

Staff education

Inappropriate use of restricted diets

Patient receiving a restricted diet no longer indicated Review of medications

Replace by ad lib diet

Use of drugs which impair desire or ability to eat Unmet need for eating assistance or self-help eating devices Suboptimal technique of eating assistance Suboptimal dining environment Prescription of maintenance instead of repletion dietary intakes (oral or enteral) Inadequate nutritional support during intercurrent illness Unrecognized febrile illness Unmet need for modified diet Inadequate management of tube-feeding complications Poor dental status Unmet need for dysphagia evaluation Suboptimal treatment of dysphagia

Observation and calorie count

Discontinue or replace offending drug Provide assistance or devices

Observation

Retrain the nursing aide

Observation

Improve the environment

1.5 RDA of calories and protein prescribed

Increase prescription to 1.5 RDA calories and protein

Weight and/or albumin decline during illness; inadequate nutrition support Daily temperatures reveals elevations Clinical review

Project MD will consult on each NHCU patient during intercurrent illness Identify and treat infections Prescribed indicated modified diet Correct management of complication

Prescribed tube-feeding volume not being administered or absorbed Oral examination Clinical signs suggest dysphagia; evaluation not requested Recommendations of speech pathology not being followed

Prompt dental care Consult speech pathology for swallowing evaluation Speech pathologist retrains ward staff

MD, Medical doctor; RN, Registered nurse; RD, Registered dietitian; RDA, Recommended daily allowance; NHCU, Nursing home care unit. Source: Ref. 7, with permission.

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staff, would require significant resources. However, as outlined in the following sections, there is potential for significantly better outcomes for LTCF residents if malnutrition is recognized. One important and often underrecognized cause of malnutrition in older LTCF residents deserves special focus: depression (and other psychiatric disorders). These disorders account for 22% to 32% of cases of significant weight loss in older LTCF residents (13,14) and community-dwelling elderly (15). Given the prevalence and frequently reversible nature of depression, it is incumbent upon all physicians and physician extenders who care for residents of LTCFs to have a heightened awareness of this disorder.

III. ASSESSMENT OF NUTRITIONAL STATUS AND CONSEQUENCES OF MALNUTRITION IN LTCF RESIDENTS Considerable research has been aimed at identifying at-risk or malnourished LTCF residents. Many identification methods include complex measures not available in most LTCFs. However, a review of the relevant literature suggests a number of indicators, readily available from common data sets, that correlate with more sophisticated measures of nutritional status to help identify those at risk. Recently, one study (16) confirmed that the weight and body mass index (BMI; weight divided by height in kg/m2) measures available in the Minimum Data Set (MDS) closely correlates with more sophisticated anthropometric measures and bioelectrical impedance analysis. In another study, BMI closely correlated with a widely used 30-point scale (Mini-Nutritional Assessment [MNA]) predictive of clinical outcomes in many studies of the elderly (Fig. 1) (17). In that Swedish study, malnutrition (an MNA 17) was present in 33% to 71% of LTCF residents depending on the type of facility. A BMI less than 24 kg/m2 correlated with an MNA score of less than 17, identifying the majority of malnourished elderly. Several studies have documented that a recent loss of more than 5% of body weight, a weight less than 90% ideal body weight for age/gender and complaints of anorexia by patients correlate with malnutrition (6,7,18). It may be obvious, but there is a strong correlation between physical impairment and risk for malnutrition. In a recent study (19), it was reported that malnutrition in elderly subjects (from the community or nursing home), as determined at the time of hospitalization, was much more likely in subjects dependent in at least one activity of daily living (ADL), and dependence for any one of the ADLs investigated (bathing, dressing, transfer, toileting, and eating) was independently predictive of malnourishment. Interestingly, of the comorbid conditions examined, congestive heart failure, dementia, chronic obstructive pulmonary disease, cancer, and diabetes mellitus, only diabetes mellitus was related to nutritional sta-

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Figure 1 Correlation of body mass index (BMI) with a 30-point comprehensive nutritional assessment, the Mini-nutritional Assessment (MNA). Reproduced from Ref. 17 with permission.

tus and was negatively associated with malnourishment. Several laboratory parameters also indicate a likelihood for malnutrition; low serum albumin (4.0 g/dL), total cholesterol (160 mg/dL), total lymphocyte count (1500/mm3), and hemoglobin (13 g/dL) all should raise the possibility of malnutrition in an LTCF resident (6,20,21). Nutritional factors are strongly predictive of subsequent hospitalization, disability, and mortality (6,7,18,21–23). One recent study specifically focusing on LTCF residents (23) evaluated 350 randomly selected residents and determined the value of 96 medical, functional, socioeconomic, and nutritional variables for predicting severe (life-threatening) complications. Only five of the 96 variables were predictive, of which three were nutritional (serum albumin, BMI, and amount of weight loss in the prior year), with the other two being renal function and functional status (ADLs). In a subsequent cohort of 110 residents, the authors found that these five variables could predict life-threatening events with a sensitivity of 88% and a specificity of 65% (23). The impact of any one indicator of malnutrition cannot predict with certainty which patients will live and which will die, nor are there specific data that reversing any one variable (e.g., serum albumin) will improve outcomes. However, the magnitude of the association for some nutritional variables with mortality is strong in elderly populations (reviewed in 20). For every decrease in serum

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albumin of 1.0 g/dL, mortality increases 10% to 22%. Furthermore, there is a fourfold risk of mortality when the total lymphocyte count is less than 1500/mm3, and a tenfold risk of mortality in subjects in whom the total cholesterol is less than 120 mg/dL, even after controlling for the presence of malignancy. Importantly, even well-nourished elderly residents of LTCFs often become malnourished during an acute hospitalization (24) and are more likely to become so than their community-dwelling counterparts (21). These elderly are much more likely to require discharge to a nursing or rehabilitation facility (relative risk [RR] 2.3; 95% confidence interval [1.1–4.6]), experience inhospital death (RR 8.0 [2.8–22.6] and death outside the hospital within 90 days (RR 2.9 [1.4–6.1]). Important and, at times, unavoidable interventions such as “NPO” (nothing per oral) orders without adequate replacement nutrition contribute heavily to the number of subjects malnourished during hospitalization.

IV. NUTRITIONAL INTERVENTIONS TO REDUCE INFECTION AND IMPROVE OUTCOMES IN LTCF RESIDENTS It is evident from the data outlined above that elderly LTCF residents are frequently malnourished, and poor nutritional status is associated with an increased risk of adverse outcomes; however, there are relatively few supplementation trials in LTCF residents (Tables 5 and 6). In most instances, the trials that have been published suffer from a lack of clinically relevant endpoints with regard to infection risk and have been significantly underpowered to detect such benefits. Most studies demonstrate increased caloric intake, increased weight, improved MNA scores, or higher serum levels of micronutrients. A few demonstrate trends toward reduced infection or improved vaccine responses, but frequently, other small studies contradict these findings. To the knowledge of the author, no trial of nutritional intervention in elderly LTCF residents has ever shown improved survival. A. Commercial Formulas/Protein-Energy Supplements Early data (reviewed in 7) suggested that commercially available nutritional supplements sometimes enhanced caloric intake and increased serum albumin and transferrin, but the effect on physical function or infection risk was not assessed. Several studies of oral supplementation of commercially available formulas have been performed in LTCF residents in the last 10 years (25–29), but unfortunately, still leave many questions unanswered. An early retrospective, case-control study (25) demonstrated that oral supplements are usually instituted for weight loss or poor appetite, and that oral supplementation resulted in weight gain back to baseline in the majority of residents. Serum albumin, lymphocyte counts, cholesterol,

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Table 5 Trials of Commercial Formula Supplements in Long-Term Care Facility Residents Total N (n on suppl)

Time/ study type

Johnson (25)

109(56)

Variable/C-C

Kayser-Jones (26)

40(29)

Variable/O

Turic (27)

58(28)

6 weeks/R,P

Lauque (28)

88(37)

2 months/ mixed*

Fiatarone Singh (29)

50(24)

10 weeks/R,P

Author (reference)

Comment Supplements started primarily due to weight loss (71%) and poor appetite (16%); weight regained, but no effect on infection or hospitalization rate; mortality higher in supplemented group (significantly more ill at baseline) Supplements rarely administered or consumed as ordered by the physician (overall mean percentage consumed 55% of that prescribed); supplements often prescribed without adequate evaluation of cause for weight loss; calorie intake of supplement offset by reduced meal caloric intake Compared commercial formula vs a snack three times a day; increased energy/protein/nutrient intake in formula group Good compliance, average energy intake increased 400 kcal/day; weight and mini nutritional assessment scores improved in supplemented residents vs control groups Several parameters (total caloric intake, serum folate/vitamin D) approached significance, but only serum transferrin was significantly improved by supplementation; meal caloric intake declined in supplemented group; no change in performance status vs control

* C-C, Case-control; O, Observational; R, Randomized; P, Placebo-controlled. This study used four groups, one well nourished that did not receive supplements (n 19), two groups of “at risk” subjects randomly assigned to supplement (n 19; provided one of four different supplement types) or no supplement (n 22), and a fourth group of malnourished elderly all provided a supplement (n 24).

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Table 6 Selected Micronutrient Supplementation Trials in Older, Long-Term Care Facility Residents Author (reference)

Total N (n on suppl)

Time/ trial type

Nutrient(s) Vitamins A,C,E Vitamin A

Penn (31)

30

1 month/R,P

Murphy (36)

109(53)

Van der Wielen (32)

33(15)

Single, high dose/R 12 weeks/R,P

Girodon (33)

81(61)

2 years/R,P,F

Zn selenium or Vitamins A, C, E or both

Fortes (35)

118(88)

3 months/R,P,F

Vitamin A, Zn, both or neither

Provinciali (37)

384(194)

2 months/R

Zn or Zn arginine

Girodon (34)

725(543)

2 years/R,P,F

Zn selenium or Vitamins A, C, E or both

kcal, thiamine, B6, B12, folate

Comment ⇑ T cells, CD4 cells, lymphocyte responses. No change in infection rate or antibiotic use Significantly increased weight, serum thiamine, vitamin B6, decreased serum homocysteine; no immunologic outcomes measured ⇑ serum selenium levels in Zn selenium group and BOTH group; ⇓ infectious episodes in the groups receiving Zn selenium, but not vitamins alone group ⇓ CD3 and CD4 in vitamin A group, ⇑ CD3, CD4, CD16 and CD56 lymphocytes Influenza vaccine administered in 3 years; no difference in % responders or mean antibody titer post-vaccination ⇑ serum micronutrient levels, but no effect on DTH responses; improved responses to influenza vaccine in Zn selenium groups, borderline reduction in respiratory infection in Zn selenium groups (P 0.06), no effect of vitamins alone

R, Randomized; P, Placebo-controlled; F, Factorial; DTH, Delayed-type hypersensitivity; ⇑, increased; ⇓ decreased.

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and hemoglobin tended to improve, but there were too few residents to allow purposeful conclusions. A trend toward higher mortality was apparent in the supplemented group (8/56 vs. 2/53; P 0.057), but these findings are subject to the significant bias of nonrandomized trials in which the intervention is often performed in a population that is more ill. In fact, in the indicated study, the supplemented group did have an older mean age and were more likely to have a history of stroke or pressure sores. There was no difference with regard to infection or hospitalization. However, a nonrandomized observational study (26) suggested that only slightly more than 50% of the volume of supplement ordered is actually consumed by LTCF residents, and that up to half of residents placed on oral supplements will continue to lose weight. Although not quantified, this study suggested that oral supplement use between meals “destroyed the residents’ appetites” in some cases, reducing the total caloric intake. This issue was also raised in a subsequent, randomized trial discussed below (29). Three recent randomized trials of commercial formula supplementation in older LTCF residents have been published. A study of 53 LTCF residents in four LTCFs in Ohio (27) compared an 8-oz serving of a commercially available supplement with a “snack” at 10 AM, 2 PM, and before bed, and assessed several nutritional variables at 3 and 6 weeks. Significantly greater intake of protein, many vitamins and trace elements, and caloric intake were documented, and the study found no decrease in the energy intake from meals alone. No clinical outcomes of health, infection, or functional status were measured in that study. In a second French study, 88 residents in an LTCF were assessed via the MNA (28). Those with a score of less than 17 (n 24) received supplementation. Those with a score of 24 or higher (n 19) received no supplementation. Those residents with scores of 17 to 23.5 (n 41) were considered nutritionally at risk and randomized in an unblinded fashion to receive oral supplements or not (no placebo provided). Twenty-two were randomized to no supplements. All of the 22 completed the observation period and were therefore included in the analysis. However, of the 19 randomized to receive supplements, six withdrew consent or were admitted to the hospital and were excluded from the analysis. The groups were evaluated at baseline and on day 60. Mean caloric (~25%; ~400 kcal) and protein (~30%; 25–30 g) intake improved in the supplemented groups and did not change in the groups that did not receive supplements. There were too few subjects to determine any differences in other outcomes measured between the randomized groups, even with regard to MNA score, and no information was provided regarding infection risk. The third study randomized and examined 50 LTCF residents in a placebo controlled, blinded trial of an oral liquid supplement and determined the impact of supplementation on caloric intake, serum measures of nutritional status, body composition, and health/physical status (29). There was no effect of supplemen-

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tation in any of the outcomes measured, even caloric intake. This was due to the fact that nonsupplemental calories (i.e., intake during meals) fell in the intervention group. Clearly there are issues of power in a study of only 25 subjects per arm, but these are the data available regarding oral supplementation in LTCF residents. In summary, protein-calorie supplements are frequently prescribed in LTCF residents, but compliance is often poor. Furthermore, such supplements inconsistently raise caloric intake due to reduced meal-time caloric intake by some residents. No impact on infection risk or survival has been demonstrated for these supplements in LTCF residents. B. Multivitamin/Mineral Supplements There have been many studies of micronutrient supplementation in elderly subjects. Most have been performed in free-living elderly rather than residents of LTCFs (reviewed in 1,30). In LTCF residents, there are four studies of multivitamin/mineral supplements (31–35), and a few studies of individual micronutrients (35–37) (Table 6). These studies have often shown contradictory results; however, some unifying principles can be gleaned from review of the interventions reported to date. Clearly, micronutrient supplements can enhance vitamin and mineral intake in LTCF residents and increase serum levels of many micronutrients. Furthermore, compliance with such supplementation is excellent and inexpensive. Trace elements, primarily zinc and selenium, may increase post-vaccine antibody titers, raise CD4 cell numbers, and reduce the risk of respiratory infection (33–35,37), whereas vitamin supplementation with vitamins A, C, E or -carotene has little or no effect in the studies outlined to date. One large, well-designed study of vitamin/mineral supplementation highlights the potential benefits and limitations of current data. This study (34) randomized 725 LTCF residents in 25 facilities in a factorial design to receive trace elements (zinc 20 mg selenium 100 mg), three vitamins (C 120 mg, E 15 mg, and -carotene 6 mg [ 1000 retinol equivalents]), both or neither for 2 years. Mortality was expectedly high in all four groups (~30%) and not different between groups. There was no effect on delayed-type hypersensitivity (DTH) responses, but a greater proportion of subjects in the trace element groups (vitamins trace elements or trace elements alone) had protective antibody titers after influenza vaccination (P 0.05). Surprisingly, vitamins alone appeared to have a negative effect on antibody titers (P 0.05). There was no effect on urogential tract infections, but a trend toward reduced incidence of respiratory tract infections (P 0.06) occurred in both trace element groups but not in those receiving vitamins alone. These data confirm the findings of a smaller, prior study by the same investigators (33), but in the earlier study, the reduction in respiratory infections in the Zn selenium groups reached statistical significance. The dose of vitamin E used in this and the previously mentioned study (33,34) was modest, 15

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mg/d. It should be noted that higher doses of vitamin E (200 or 800 mg/d) have been found to effectively enhance immune responses (DTH responses and T-cell dependent vaccine responses) in free-living elderly (38,39). Reportedly, a randomized trial of vitamin E supplementation in higher doses is underway in LTCF residents (40). Vitamin A (or -carotene, a vitamin A precursor) supplementation has been extensively studied. The rationale for vitamin A supplementation is strong because it is an essential nutrient for immune function and regeneration of epithelial surfaces in the gastrointestinal tract and respiratory tree, and vitamin A deficiency is relatively common in LTCF residents (8). However, no study has shown benefit from vitamin A supplementation in LTCF residents, and, somewhat surprisingly, some studies have found potential harm (33–36). Thus, based on current data, specific vitamin A supplementation should probably be avoided.

V. SPECIFIC SYNDROMES WHERE NUTRITIONAL SUPPLEMENTATION MAY BE OF BENEFIT A. Pneumonia There have been no specific studies of nutritional supplementation in LTCF residents with pneumonia. However, a recent randomized, single-blind study of a commercially available protein-calorie supplement for 1 month after hospitalization for community-acquired pneumonia in elderly subjects did include LTCF residents (41). The supplement improved nutritional status for a variety of variables measured but, most importantly, functional status was improved at a follow-up visit 3 months later when compared with the placebo group. The study was not powered to detect differences in rehospitalization or mortality and did not perform any measures of immune competence. Nevertheless, short-term (1 month) nutritional supplementation after an episode of community-acquired pneumonia may be of benefit in elderly LTCF residents. B. Pressure Ulcers Debate is considerable over whether nutritional supplementation can prevent or speed the healing of pressure ulcers (42,43). A recent multicenter trial (44) demonstrated a slightly reduced risk of pressure ulcers in a group receiving protein-calorie supplements, but several issues have been raised about this study (45). The caloric intake did not increase in supplemented subjects and the difference in incidence of pressure ulcers was relatively small: 41% in the supplemented group versus 47% in the control group. More widely accepted but based on no more convincing data is the practice of micronutrient (e.g., Zn) supplementation to assist in healing of pressure ul-

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cers. Most data suggest that if there is a benefit of vitamin/mineral supplementation for healing skin/soft tissue wounds, that it is likely limited to individuals deficient at baseline. Current recommendations are to provide adequate calories (30–35 kcal/kg) and protein (1–1.25 g/kg) to avoid negative nitrogen balance, and zinc at a dose of 220 mg/day (42). Vitamins A, C, and several B complex vitamins are necessary for wound healing, but there are no specific recommendations regarding dosing. C. Urinary Tract Infections One nutritional intervention has been reasonably well studied for the prevention of urinary tract infection (UTI) in elderly subjects: cranberry juice consumption (reviewed in 46). There has been only one study in LTCF residents (47); however, there has been one reasonably sized, randomized trial (48), another small crossover study that demonstrated benefit in the elderly (49), and a variety of studies in younger patients (46). However, there are valid criticisms against all these studies. In the randomized trial (48), the endpoint was reduction of bacteriuria with pyuria (15% in the 300 mL/d cranberry juice group vs. 28% in the control group), not symptomatic UTI. As outlined in Chapter 12, asymptomatic bacteriuria in the elderly does not require therapy. There was a trend toward reduced antibiotic use in the treatment group (1.7 vs. 3.2 antibiotics per 100 patient months) which, if confirmed in a larger study, would be of great value in and of itself. In the LTCF study (47), reported only in abstract form, both cranberry juice (220 mL/d) and capsules of cranberry juice extract were used, and the control group was historical. Five hundred thirty-eight LTCF residents were studied and UTIs reduced from 27/month in the historical control group to 20/month in the treatment group (P 0.01). There may be other benefits of cranberry juice (46). One possible cause for reducing antibiotic use could be a reduction by cranberry juice in malodorous urine, a common trigger for urinalysis and urine culture for institutionalized elderly. In addition, a small study of patients with urostomies who consumed 160 to 330 mL/d of cranberry juice experienced improvement in the skin surrounding the stoma. This could be of benefit in LTCF residents with incontinence and immobility who are at risk for skin breakdown, but no substantive trial testing this hypothesis has been performed.

VI. APPETITE STIMULANTS Appetite stimulants are poorly studied in LTCF residents, but a recent randomized, double-blind trial was reported that indicated megestrol acetate (MA) may be of some value (50). In that study, 800 mg/d of MA or placebo was provided for

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12 weeks to LTCF residents with weight loss or low body weight, and then the residents were followed up for an additional 13 weeks for subsequent health outcomes. At the conclusion of the 12-week supplementation period, there was no difference in weight, but appetite and sense of well-being were significantly better in the MA group. However, by the end of the 13-week follow-up period, the MA recipients were more likely to have gained 4 lb or more over their baseline. This approach appears to deserve further study.

VII.

DRUG-NUTRIENT INTERACTIONS

The elderly LTCF resident is likely to be receiving multiple prescription drugs. Increasingly, there is recognition that nutrient-drug interactions can cause serious adverse effects. In a recent study of residents in three LTCFs in New York (51), residents consumed approximately five drugs per patient and, on average, were at risk for 1.4 to 2.7 drug-nutrient interactions per month. With specific regard to infection, this is most likely to cause difficulty with antibiotic administration. Tetracyclines and fluoroquinolones may be poorly absorbed when antacids, multivalent cations (e.g., calcium), or tube feedings are provided. Certain antifungal compounds, particularly itraconazole, may be poorly absorbed with concomitant administration of antacids or hydrogen ion (H2) antagonists/proton pump inhibitors. More likely than nutrients influencing drug metabolism, drugs are likely to influence nutrient intake (Table 7). The most commonly prescribed drugs that are likely to induce anorexia and decrease nutrient intake are antibiotics, antidepressants, and other psychiatric drugs, digoxin, and anti-inflammatory agents. A critical part of nutritional care for elderly LTCF residents is frequent, thorough review of all medications with discontinuation of nonessential therapies.

VIII. CONCLUSIONS Residents of LTCFs are often at risk for malnutrition, and reversible causes of malnutrition are common. Most at-risk residents can be initially identified by information available in the MDS (weight and BMI) and initial screening laboratories (serum albumin, total lymphocyte count). More sophisticated assessments, such as the MNA, have been shown to be valid in LTCF residents. Once identified, data support the correction of underlying medical causes, particularly depression, and the use of nutritional supplements or appetite stimulants to increase caloric and protein intake in LTCF residents to reverse weight loss. However, the role of such supplements for preventing infection is less well defined by currently available data. Current data support the use of trace mineral supplements (20 mg/d Zn-sulfate and 100 g/d selenium sulfide) in most LTCF elderly, as the ex-

66 Table 7 Drugs that Cause Anorexia in Older Adults Anorectic agents Cardiovascular drugs Digoxin Amiodarone Procainamide Quinidine Spironolactone Gastrointestinal drugs Cimetidine Interferon Psychiatric drugs Phenothiazines Butyrphenones Lithium Amitriptyline Impramine Fluoxetine and other selective serotonin-reuptake inhibitors Anti-infective drugs Most antibiotics Metronidazole Griseofulvin Nutrient supplements Iron sulfate Potassium salts Vitamin D (in excess) Antineoplastics Cyclophosphamide and most others Antirheumatic drugs Nonsteroidal anti-inflammatory agents Colchicine Penicillamine Pulmonary drugs Theophylline Malabsorptive agents Laxatives Cholestyramine Methotrexate Colchicine Neomycin Ganglionic blockers Agents that increase metabolism Theophylline L-Thyroxine (in excess) Thyroid extract Triiodotyrosine (in excess) D-Pseudoephedrine Source: Ref. 11, with permission.

High

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pense and risk of adverse effects is small, and there appears to be a reduced risk of respiratory infection. Vitamin supplements have variable effects. Vitamin E at 200 mg/d improves immune responses in healthy elderly and may be of value in LTCF residents, but vitamin A supplementation should probably be avoided. Specific nutritional supplementation may be of value in certain infectious diseases such as recovery from community-acquired pneumonia (protein-calorie supplements) and prevention of UTIs (cranberry juice). Finally physicians should be aware of the potential for antibiotic-nutrient interactions and the effect of anorectic medications on nutrient intake. REFERENCES 1.

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Wright BA. Weight loss and weight gain in a nursing home: A prospective study. Geriatr Nurs 1993; 14:156–159. Wilson MG, Caswani S, Liu D, Morley JE, Miller DK. Prevalence and causes of undernutrition in medical outpatients. Am J Med 1998; 104:56–63. Blaum CS, O’Neill EF, Clements KM, Fries BE, Fiatarone MA. Validity of the minimum data set for assessing nutritional status in nursing home residents. Am J Clin Nutr 1997; 66:787–794. Saletti A, Lindgren EY, Johansson L, Cederholm T. Nutritional status according to mini nutritional assessment in an institutionalized elderly population in Sweden. Gerontology 2000; 46:139–145. Sullivan DH. Undernutrition in older adults. Ann Long-Term Care 2000; 8:41–46. Covinsky KE, Martin GE, Beyth RJ, Justice AC, Sehgal AR, Landefeld CS. The relationship between clinical assessments of nutritional status and adverse outcomes in older hospitalized medical patients. J Am Geriatr Soc 1999; 47:532–538. Omran ML, Morley JE. Assessment of protein energy malnutrition in older persons, part II: Laboratory evaluation. Nutrition 2000; 16:131–140. Kamel HK, Karcic E, Karcic A, Barghouthi H. Nutritional status of hospitalized elderly: Differences between nursing home patients and community-dwelling patients. Ann Long-Term Care 2000; 8:33–38. Volkert D, Kruse W, Oster P, Schlierf G. Malnutrition in geriatric patients: Diagnostic and prognostic significance of nutritional parameters. Ann Nutr Metab 1992; 36:97–112. Sullivan DH, Walls RC. The risk of life-threatening complications in a select population of geriatric patients: The impact of nutritional status. J Am Coll Nutr 1995; 14:29–36. Sullivan DH, Sun S, Walls RC. Protein-energy undernutrition among elderly hospitalized patients. A prospective study. JAMA 1999; 281:2013–2019. Johnson LE, Dooley PA, Gleick JB. Oral nutritional supplement use in elderly nursing home patients. J Am Geriatr Soc 1993; 41:947–952. Kayser-Jones J, Schell ES, Porter C, Barbaccia JC, Steinbach C, Bird WF, Redford M, Pengilly K. A prospective study of the use of liquid oral dietary supplements in nursing homes. J Am Geriatr Soc 1998; 46:1378–1386. Turic A, Gordon KL, Craig LD, Ataya DG, Voss AC. Nutrition supplementation enables elderly residents of long-term-care facilities to meet or exceed RDAs without displacing energy or nutrient intakes from meals. J Am Diet Assoc 1998; 98: 1457–1459. Lauque S, Arnaud-Battandier F, Mansourian R, Guigoz Y, Paintin M, Nourhashemi F, Vellas B. Protein-energy oral supplementation in malnourished nursing-home residents. A controlled trial. Age Ageing 2000; 29:51–56. Fiatarone Singh MA, Bernstein MA, Ryan AD, O’Neill EF, Clements KM, Evans WJ. The effect of oral nutritional supplements on habitual dietary quality and quantity in frail elders. J Nutr Health Aging 2000; 4:5–12. High KP. Micronutrient supplementation and immune function in the elderly. Clin Infect Dis 1999; 28:717–722. Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune

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Dignam R, Ahmen M, Denman S, Zayon RN, Wilks T, Shipman C, Wolfert R, Kleban M. The effect of cranberry juice on UTI rates in a long term care facility. J Am Geriatr Soc 1997; 45(Supplement):S53 (p. 169). Avorn J, Monane M, Gurwitz JH, Glynn RJ, Choodnovskiy I, Lipsitz LA. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994; 271:751–754. Haverkorn MJ, Mandigers J. Reduction of bacteriuria and pyuria using cranberry juice. JAMA 1994; 272:590. Yeh SS, Wu SY, Lee TP, Olson JS, Stevens MR, Dixon T, Porcelli RJ, Schuster MW. Improvement in quality-of-life measures and stimulation of weight gain after treatment with megestrol acetate oral suspension in geriatric cachexia: Results of a double-blind, placebo-controlled study. J Am Geriatr Soc 2000; 48:485–492. Lewis CW, Frongillo EA, Jr, Roe DA. Drug-nutrient interactions in three long-termcare facilities. J Am Diet Assoc 1995; 95:309–315.

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6 Clinical Manifestations of Infections Dean C. Norman VA Greater Los Angeles Healthcare System, and UCLA School of Medicine, Los Angeles, California

I. INTRODUCTION Infectious diseases are a leading cause of morbidity and mortality in the frail nursing home population and a leading cause of transfer of residents from a long-term care facility (LTCF) to an acute care facility. Higher morbidity and mortality rates in older patients in general result partly because of diminished physiological reserves and altered host defenses brought on by aging and comorbidities. This problem is magnified in residents of LTCFs because of debility caused by chronic disease. Elderly residents of long-term care institutions are typically taking multiple medications. This practice, coupled with age and morbidity-related changes in pharmacology of drugs, including antibiotics, increases the risk for adverse drug interactions in nursing home residents. Infected nursing home residents frequently are transferred to acute care hospitals. Unfortunately, hospitalization may be complicated by nosocomial infection and iatrogenic illness. Furthermore, once hospitalized, the elderly are more likely to undergo invasive procedures and to suffer complications. Vigorous prevention measures to control infectious diseases plus rapid diagnosis and timely initiation of appropriate empiric antimicrobial therapy will reduce the impact of infectious diseases in the long-term care population. However, atypical presentation and variability of diagnostic testing and other factors may delay diagnosis and therapy in a population that can least afford such delays. Fortunately, the differential diagnosis of important infectious diseases in the elderly is somewhat limited and dependent on the clinical setting and the patient’s functional status. Respiratory infections, including pneumonia, and urinary tract and soft tissue infections (acronym “PUS”), as well as gastrointestinal infections 71

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comprise the majority of acute infections in residents of long-term care institutions (1). The types of infections may be limited, but the microbial etiology of infections is more diverse in the elderly when compared with the younger population. In general, a variety of pathogens may account for a given infection. For example, pneumonia in the young is usually caused by relatively few pathogens, such as Streptococcus pneumoniae and Mycoplasma pneumoniae. Urinary tract infection in the young adult is usually caused by Escherichia coli. However, in the older adult a variety of pathogens may cause either of these common infections. A small but significant number of cases of community-acquired pneumonia in the elderly are caused by gram-negative bacilli, and a higher percentage of lower respiratory tract infections in nursing homes is caused by gram-negative bacilli and mixed flora (see Chapter 14). Similarly, urinary tract infection in the elderly in both the community and long-term care setting may be caused by any one of several species of gram-negative and gram-positive bacteria. Chronic indwelling bladder catheter-associated infections are typically polymicrobial. The diverse microbial etiology of urinary tract infections in residents of LTCFs requires obtaining urine cultures before initiation of antibiotic therapy for symptomatic urinary tract infection (see Chapter 12).

II. ATYPICAL PRESENTATIONS OF INFECTION Once an infection develops, the cornerstone of successful treatment is timely diagnosis and the rapid initiation of empiric antimicrobial therapy. Nonclassic presentations of acute illnesses occur often in the frail elderly, and acute infections are no exception. In the nursing home, infectious diseases provide unique diagnostic challenges because of atypical presentations—especially diminished fever responses (described in the next section), the frequent presence of cognitive impairment in nursing home residents, and the lack of availability of timely radiographs or laboratory data. The clinician caring for residents of LTCFs should be aware that virtually any acute change in functional status may herald the onset of a serious infectious disease. These manifestations include, but are not limited to lethargy, anorexia, falls, focal neurologic signs and delirium (Table 1). Changes in mental status from baseline are seen even when the infection does not involve the central nervous system. Common infections may present without classic symptoms. For example, pneumonia may be present without cough, purulent sputum, fever, or chest pain, and the only sign alerting the clinician may be tachypnea; meningitis may occur without a stiff neck; and symptomatic urinary tract infection may at times present solely as a decline in cognitive function without dysuria, urgency, or frequency. Moreover, the presentation of illness may not be in proportion to the severity of the underlying infection, a large percentage of

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Table 1 Nonspecific Presentations of Acute Infection in Nursing Home Patients Diagnostic clues • Anorexia • Any unexplained change in functional status from baseline • Change in baseline body temperature (a decrease may be caused by sepsis) • Decline in cognition • Failure to thrive • Focal neurologic signs (may be a clue to presence of meningitis, endocarditis) • Lethargy • Hypotension (may be a clue to presence of sepsis) • Tachypnea (may be initial finding in pneumonia, sepsis)

elderly women who present with symptoms and signs of pyelonephritis, which are indistinguishable from those of younger women, will be bacteremic, which is in contrast to younger women (2). Localizing peritoneal findings may be delayed in cases of severe intra-abdominal infection (3,4). This is especially problematic in LTCFs, where physicians are rarely present to perform physical examinations at the time of onset of symptoms.

III. FEVER A. Significance of Diminished Fever Response Studies of specific infections in older adults, including pneumonia (5,6), bacteremia (7,8), endocarditis (9,10), nosocomial febrile illness (11), meningitis (12), and intra-abdominal infection (13) confirm that fever, the hallmark of invasive microbial infection, may be blunted or absent in up to one-third of infected elderly patients (14–16). The absence of this cardinal sign of infection has implications beyond confounding clinical diagnosis. First, an absent or blunted fever response to infection is a poor prognostic sign, as demonstrated by a study of several hundred patients with bacteremia and fungemia (17). The results of this study confirmed that those patients responding to bacteremia or fungemia with a robust fever were more likely to survive. This classic study’s conclusion is now well established for many infectious diseases and applies to both young and older adults. Second, although the prognostic significance of the febrile response to infection is clear, it is less well established that fever is an essential adaptive mechanism that is an important host defense in humans. However, there is strong evidence that fever is an important host defense for a variety of other species (18). Cold-blooded animals such as certain types of lizards and fish seek warmer environments in order to raise body temperatures in response to infection. Laboratory experiments confirm that

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fever is an important host defense in these poikilothermic animals (19,20). In fact, enhanced resistance to infection appears to occur with increased body temperature (fever) in a variety of mammalian animal models (18). Therefore, based on these animal data, it can be considered that fever is potentially an important host defense in humans. The effect of fever on host defenses is independent of a direct effect of elevated body temperature on bacterial replication. The exceptions are that physiologically achievable temperature elevations may inhibit bacterial growth directly of Treponema pallidum, Neisseria gonorrhoeae, and certain strains of pneumococci. The mechanism by which fever augments host defenses and improves natural and cellular immune responses appears to be multifactorial; it minimally involves elevating certain monokine and cytokine production and enhancing cytokine activity. These cytokines include interleukins 1 and 6, tumor necrosis factor, alpha interferon, and others. These particular cytokines are also endogenous pyrogens and have many effects on cellular components of the immune response. One effect appears to be to facilitate adherence of leukocytes to endothelial cells and leukocyte migration to extravascular areas of infection. The mechanism by which a significant number of infected older adults fail to mount a febrile response is not known. Potential mechanism(s) have been proposed based on the current understanding of the pathogenesis of fever. The role of cytokines as endogenous mediators of fever has been recently reviewed (21,22). Bacterial products such as lipopolysaccharide (endotoxin) induce macrophages and other cells to produce cytokines that act as endogenous pyrogens. These pyrogens are produced either locally at the site of infection and enter the circulation or by macrophages adhering to endothelium in circumventricular organs of the brain. The pyrogens act on the anterior hypothalamus resulting in a biochemical cascade including the release of prostaglandin E2. This cascade raises the central nervous system “thermostat” (22). These changes result in shivering, vasoconstriction, and various behavioral responses, all of which elevate core body temperature, which then becomes the new baseline. When the infection is over, the thermostat is reset to the previous baseline; sweating and temperature-lowering behaviors occur, thus returning body temperature to normal. These pathways could be affected by aging, and thermoregulation in the elderly appears to be impaired to some degree. This is evidenced by the increased morbidity and mortality in older persons from heat stroke and hypothermia. A variety of endogenous pyrogens results in a lower fever response in older mice compared with younger mice (23–25). Other data in rats demonstrated that intracerebroventricular injection of interleukin 1 results in similar immediate fever responses between young and old animals. This suggests that blunted febrile responses observed in older mammals may result from an inability of peripheral endogenous mediators to reach the central nervous system rather than an unresponsiveness of the central nervous system (26). Other studies have demonstrated diminished production of endogenous pyrogens with age

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in various rodent models (27). Select rodent experiments have yielded evidence that changes in thermogenic brown fat may play a role in the blunted fever response of aging (28). Thus, reduced production and response to endogenous pyrogens may be important in the pathogenesis of the blunted febrile response to infection observed in the elderly. There is no evidence in humans that reducing a fever with antipyretic drugs increases the risk of morbidity and mortality if appropriate antimicrobial therapy is initiated. Fever in the elderly can result in discomfort, tachycardia, and other physiologic stresses that may be harmful, and these symptoms provide a rationale for antipyretic use (18). B. Baseline Temperatures and Definition of Fever in the Nursing Home The normal and febrile body temperature for older adults has been thoroughly reviewed recently (16). Baseline temperature and diurnal variation of temperature as measured by electronic thermometry was decreased in a nursing home population (29,30). Mean baseline morning rectal temperature was established to be 98.6 degrees Fahrenheit (F) (37 degrees centigrade [C]) in 22 residents in whom oral temperatures could not be easily obtained. The mean oral temperature of 85 additional residents was 97.4 degrees F (37.3 degrees C). Diurnal variation was only 0.6 degrees F (0.3 degrees C) for rectal temperatures and 0.4 degrees F (0.2 degrees C) for oral temperatures. In another study, 50 randomly selected nursing home residents had mean oral baseline temperature of 97.4 degrees F (36.3 degrees C) (29). A retrospective review found 69 infections in 26 of these residents, with the mean maximum temperature reaching 101.3 degrees F (38.5 degrees C). In nearly half these infections, the temperature did not reach 101 degrees F. Yet, a majority of these patients significantly increased their temperature over baseline by at least 2.4 degrees F (1.3 degrees C). Lowering the criterion for fever to 100 degrees F (37.8 degrees C) or higher raised the sensitivity to 70% for predicting infection with a specificity of 90%. These findings led to the recommendation by the Practice Guidelines Committee of the Infectious Diseases Society of America that a clinical evaluation be done for nursing home residents with a single oral temperature higher than 100 degrees F (37.8 degrees C) or persistent oral or rectal temperature higher than 99 degrees F (37.2 degrees C) or greater than 99.5 degrees F (37.5 degrees C), respectively. Two or more readings of more than 2 degrees F (1.1 degrees C) over baseline regardless of site of measurement should also stimulate an evaluation for infection (31). The chance of an infection is further increased if obvious symptoms and signs of infection exist or if there is any change in functional status accompanying the temperature changes (see Table 1). In some cases a significant decrease in temperature might also indicate a serious infection complicated by sepsis.

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C. Significance of Robust Fever Response and Fever of Unknown Origin (FUO) Infected elderly residents of LTCFs who mount a vigorous febrile response similar to younger adults, as defined by 101 degrees F orally (38.3 degrees C), can be expected to have a serious or life-threatening infection. This conclusion is extrapolated from a classic study of 1,200 ambulatory care patients (32) and two other confirmatory studies (33,34). In contrast to the young in whom these fevers were usually the result of benign viral infections, the elderly, especially the very old, usually suffered from a serious or life-threatening infection. Finally, infection is the leading etiology of FUO in the elderly, followed by connective tissue diseases such as temporal arteritis. A lesser number of cases are the result of malignancy (35–37). Many of these underlying conditions are treatable and, unless advanced directives preclude an extensive evaluation, an underlying cause for FUO in the older person should be sought.

IV. CONCLUSION The clinician must be familiar with all the manifestations of infections in the longterm care setting to minimize the impact of infectious diseases in this population. Preventive measures, rapid, aggressive diagnosis, and empiric therapy are essential to further reduce morbidity and mortality from infection. Fever, the hallmark of infection, may be absent or blunted in 20% to 30% of infections in the frail elderly. Alternatively, the presence of a vigorous fever in the older LTCF resident is more likely to be associated with a serious bacterial infection compared with a younger population, and requires a thorough and prompt evaluation.

REFERENCES 1.

2. 3. 4.

5.

Bradley SF. Infections and infection control in the long-term care setting. In: Yoshikawa TT, Norman DC (eds). Infectious Disease in the Aging. A Clinical Handbook. Totowa, Humana Press, 2001:245–256. Gleckman RA, Bradley PJ, Roth RM, Hibert DM. Bacteremic urosepsis: A phenomenon unique to elderly women. J Urol 1985; 133:174–175. Norman DC, Yoshikawa TT. Intraabdominal infection: Diagnosis and treatment in the elderly patient. Gerontology 1984; 30:327–338. Campbell BS, Wilson SE. Intraabdominal Infections. In: Yoshikawa TT, Norman DC (eds). Infectious Disease in the Aging. A Clinical Handbook. Totowa: Humana Press, 2001:91–98. Bentley DW. Bacterial pneumonia in the elderly: Clinical features, diagnosis, etiology and treatment. Gerontology 1984; 30:297–307.

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7. 8.

9. 10.

11.

12. 13. 14. 15. 16. 17.

18. 19. 20. 21. 22. 23. 24.

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Marrie TJ, Haldane EV, Faulkner RS, Durant H, Kwan C. Community-acquired pneumonia requiring hospitalization: Is it different in the elderly? J Am Geriatr Soc 1985; 33:671–680. Gleckman R, Hibert D: Afebrile bacteremia. A phenomenon in geriatric patients. JAMA 1982; 248:1478–1481. Finkelstein M, Petkun WM, Freedman ML, Antopol SC. Pneumococcal bacteremia in adults: Age-dependent differences in presentation and outcome. J Am Geriatr Soc 1983; 31:19–27. Terpenning MS, Buggy BO, Kauffman CA. Infective endocarditis: Clinical features in young and elderly patients. Am J Med 1987; 83:626–634. Werner GS, Schulz R, Fuchs JB, Andreas S, Prange H, Ruschewski W, Kreuzer H. Infective endocarditis in the elderly in the era of transesophageal echocardiography: Clinical features and prognosis compared with younger patients. Am J Med 1996; 100:90–97. Trivalle C, Chassagne P, Bouaniche M, Landrin I, Marie I, Kadri N, Menard JF, Lemeland JF, Doucet J, Bercoff E. Nosocomial febrile illness in the elderly: Frequency, causes, and risk factors. Arch Intern Med 1998; 158(14):1560–1565. Gorse GJ, Thrupp LD, Nudleman KL, Wyle FA, Hawkins B, Cesario TC. Bacterial meningitis in the elderly. Arch Intern Med 1984; 144:1603–1607. Potts FE, IV, Vukov LF: Utility of fever and leukocytosis in acute surgical abdomens in octogenarians and beyond. J Geront A Biol Sci Med Sci 1999; 54A(2):M55–M58. Yoshikawa TT, Norman DC: Fever in the elderly. Infect Med 1998; 15(10):704–706. Norman DC. Fever and aging. Infect Dis Clin Pract 1998; 7(8):387–390. Norman DC. Fever in the elderly. Clin Infect Dis 2000; 31:148–151. Weinstein MP, Murphy JR, Reller RB, Lichenstein KA. The clinical significance of positive blood cultures: A comprehensive analysis of 500 episodes of bacteremia and fungemia II: Clinical observations with special reference to factors influencing prognosis. Rev Infect Dis 1983; 5:54–70. Mackowiak, PA. Physiological rationale for suppression of fever. Clin Infect Dis 2000; 31(suppl 5):S185–S189. Kluger MJ, Ringler DM, Anver MR: Fever and survival. Science 1975; 188:166–168. Covert JB, Reynolds WM: Survival value of fever in fish. Nature 1977; 267:43–45. Netea MG, Kullberg BJ, Van der Meer JWM. Circulating cytokines as mediators of fever. Clin Infect Dis 2000; 31:S178–S184. Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis 1999; 179(suppl 2): S294–S304. Norman DC, Yamamura RH, Yoshikawa TT. Fever response in old and young mice after injection of interleukin. J Gerontol 1988; 43:M80–M85. Miller D, Yoshikawa TT, Castle SC, Norman DC. Effect of age in fever response to recombinant tumor necrosis factor alpha in a murine model. J Gerontol 1991; 46: M176–M179. Miller DJ, Yoshikawa TT, Norman DC. Effect of age on fever response to recombinant interleukin-6 in a murine model. J Gerontol A Biol Sci Med Sci 1995; 50A: M276–M279. Plata-Salamán CR, Peloso E, Satinoff E. Interleukin-1-induced fever in young and old Long-Evans rats. Am J Physiol 1998; 275:R1633–R1638.

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Bradley SF, Vibhagool A, Kunkel SL, Kauffman CA. Monokine secretion in aging and protein malnutrition. J Leukocyte Biol 1989; 45:510–514. Scarpace PJ, Bender BS, Burst SE. The febrile response of E. coli peritonitis in senescent rats. Gerontologist 1990; 30:215A. Castle SC, Norman DC, Yeh M, Miller D, Yoshikawa TT. Fever response in elderly nursing home residents: Are the older truly colder? J Am Geriatr Soc 1991; 39: 853–857. Castle SC, Yeh M, Toledo S, Yoshikawa TT, Norman DC. Lowering the temperature criterion improves detection of infections in nursing home residents. Aging Immunol Infect Dis 1993; 4:67–76. Bentley DV, Bradley S, High K, Schoenbaum S, Taler, G, Yoshikawa TT. Practice guideline for evaluation of fever and infection in long-term care facilities. Clin Infect Dis 2000; 31:640–653. Keating MJ III, Klimek JJ, Levine DS, Kiernan FJ. Effect of aging on the clinical significance of fever in ambulatory adult patients. J Am Geriat Soc 1984; 32:282–287. Wasserman M, Levinstein M, Keller E, Lee S, Yoshikawa TT. Utility of fever, white blood cells, and differential count in predicting bacterial infections in the elderly. J Am Geriat Soc 1989; 37:534–547. Schoeinfeld CN, Hansen KN, Hexter DA, Stearns DA, Kelen GD. Fever in geriatric emergency patients: Clinical features associated with serious illness. Ann Emerg Med 1995; 26(1):18–24. Esposito AL, Gleckman RA. Fever of unknown origin in the elderly. J Am Geriatr Soc 1978; 26:498–505. Berland B, Gleckman RA. Fever of unknown origin in the elderly: A sequential approach to diagnosis. Postgrad Med 1992; 92:197–210. Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993; 41:1187–1192.

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32. 33.

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35. 36. 37.

7 Ethical Issues of Infectious Disease Interventions Elizabeth L. Cobbs Washington D.C. VA Medical Center, and George Washington University, Washington, D.C.

I. INTRODUCTION Long-term care facilities (LTCFs) provide care to dependent persons with a variety of needs and expectations and, in a shifting medical marketplace, ethical issues are part of the daily routine. In the wake of shortened hospital stays, the use of nursing homes for subacute post-hospital stays has surged. Short-term residents may receive rehabilitation services or continuing medical treatment for serious illnesses such as osteomyelitis. Improvement in function and health is the usual goal, and discharge to the community is often expected. The other larger group of residents living in LTCFs is composed of frailer individuals who are likely to reside in the LTCF through the end of life. The nursing home is their home. Their expectations for medical care are varied, as are their abilities to make decisions and express treatment preferences. A subset of those residents are near the end of life. In addition to their medical complexity, LTCF residents are at increased risk for infectious diseases because of physiological changes associated with aging, the impact of chronic conditions, and the effects of institutional living (1). Infection has been cited as the most frequent cause of transfer to the hospital (2), and hospital transfer is a frequent response to the medically ill resident in the LTCF, although practice varies. To serve this diverse group of residents, the LTCF is expected to provide timely and appropriate medical care, while at the same time offering a comfortable, personalized residence. The dual task of meeting the medical needs of many residents and providing a homelike environment that delivers a pleasing quality of life for dependent frail persons creates the setting for a number of ethical dilem79

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mas faced by LTCF practitioners. “The ethical issues in any care system reflect the nature of the care provided, the setting in which the care takes place, the capabilities of the care recipients, the commitments of the care providers, and the social and financial arrangements that society has created to structure and reimburse activities of caring” (3).

II. THE PLACE OF ETHICS IN LTCFs Knowledge of medical ethics helps physicians and other practitioners to do the right thing in the long-term care environment, where competition between medical and humanistic agendas are typical. Several ethical themes are integral to life in LTCFs. A. Autonomy Autonomy refers to self-determination without overbearing external influence, a prized attribute in American society. Autonomy becomes a ubiquitous ethical concern in the LTCF because all those who live in this setting do so because their ability to function independently has been compromised. Serving the needs of dependent residents within a medical model requires a reworking of the definition of autonomy. Perception and experience of autonomy are influenced by many factors, including culture. The Milwaukee Hmong community, for example, perceives dementia not as a chronic disease that robs a person of autonomy but as a natural part of the life cycle. Individuals suffering from dementia are cared for in their sons’ homes and rarely display difficult behaviors such as combativeness and wandering (4). Autonomy in an LTCF is most often expressed through a pattern of living rather than through discrete decisions (3). B. Beneficience and Nonmaleficience Beneficience refers to doing good, and in the practice of medicine this translates to doing the right thing for the patient. Defining the “right thing” has undergone a shift in recent years with increased understanding of the needs of the growing population of older adults living with chronic conditions (causing both physical and mental deficits) and significant self-care needs. Weighing the burdens and benefits of possible interventions has become standard practice in making treatment decisions for LTCF residents, because of the risks associated with virtually all treatment options. Closely related to beneficience is the admonition to do no harm, known as nonmaleficence. Nonmaleficence has taken on greater importance as the burdens of common treatment options, such as hospitalization, are recognized, and options for prompt and effective out-of-hospital treatments increase. The era

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recognizing residents’ rights in LTCFs came about after the 1987 passage of the Omnibus Budget Reconciliation Act, with perhaps the most noticeable result being a change of practice in the use of physical and chemical restraints. C. Fidelity Fidelity embraces trust and confidentially and is a fundamental principle underlying the doctor-patient relationship. The doctor-patient relationship remains fundamental to the care of residents in LTCFs; however, certain compromises to this relationship are inevitable because of the high frequency of cognitive impairment found among residents. Issues of trust pertain also to relationships with others on the interdisciplinary team (IDT) and often are important for residents to achieve a sense of control. D. Justice Justice refers to the equitable distribution of resources and treatment and is especially relevant when the interests of residents, staff, the institution, and families come into conflict with each other. Competing demands for staff attention and resources create the need for individuals and systems to negotiate settlements to conflicts so that the needs of residents and others in the LTCF community are most equitably served. E. Everyday Ethics The need for everyday ethical principles to guide practice in LTCFs is derived from the complexity of the organizations, their objectives, and their many participants. The nursing home environment seeks to blend two very different cultures: the autonomous, individually controlled home with the externally regulated, physician-directed structure of a medical institution. The requirement for physician orders to permit basic elements such as diet, activity level, or permission to self medicate sets an overarching framework of paternalism. Affirmation of self occurs with new expressions of autonomy manifested by the residents’ activities being consistent with their personal values and preferences. The LTCF must create systems that encourage consistent decisions by residents to maximize autonomy, despite disability and the institutional setting (3). At times competition exists between interests. The residents are the primary customers of the facility, yet LTCFs have been criticized for a lack of attention to the values and preferences of the individual resident. With limited staffing, residents may compete for staff time and attention. An acutely ill resident becomes the focus of attention, sometimes creating a shortage of staff time to attend to the needs of other residents. Decisions about whether to hospitalize a resident are in-

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fluenced by competing interests, including institutional financial incentives and staffing capacity, in addition to patient preferences. Conflicts may also occur in the interface between the optimum well-being of the residents and the needs and preferences of the staff. Conflict can also be found between staff and facility, and the facility and outside organizations. Families and significant others are important members of the LTCF community and contribute to the caregiving process. Families, however, may add to the conflict between competing interests. The facility needs a system of regular conflict resolution that effectively and consistently resolves conflicts between competing interests and values (3). The resident faces many obstacles to maintaining a self that is capable of autonomous action. Providing opportunities for choice and exertion of control over the environment and participation in the decision-making process have been shown to positively influence resident life. Communication and negotiation are means to achieve the best possible outcomes for the resident as well as the staff and the institution. Many daily infection control decisions have ethical dimensions that require choices between competing concerns or values. Common issues include whether to isolate residents colonized with resistant organisms, whether an ill healthcare worker should be allowed to work, and whether to investigate clusters of infections (5). Additional issues have to do with when to treat, what to treat, whether to hospitalize, how to communicate with residents and families, what to do when treatment attempts become burdensome and residents refuse, how to improve staff behaviors that protect resident safety and health, and when not to treat.

III. GOALS OF CARE The development of individualized goals of care for each resident is a process that creates the best mechanism to maximize autonomy, quality of life, and desirable medical outcomes. In the process of developing goals of care, a comprehensive biopsychosocial assessment is performed. This assessment provides a framework for the integration of disease factors with psychosocial factors and other resident characteristics. This assessment yields measures of resident functional capacity and points out where interventions to improve function and enhance independence might be placed. The values’ history, including information about the resident’s preferences, hopes, fears, basis for meaning, spirituality, and personal goals, is integrated with the comprehensive assessment. The physician and resident (or surrogate) aim to reach a shared understanding of the resident’s health status, care needs and preferences, options for future treatment interventions, and likely outcomes. From this assessment, a blueprint of goals and plans for care can be developed. In this way,

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Table 1 An Example of a Scheme to Prioritize Goals of Care Intensive care First priority

Prolong life

Second priority

Maintain physical and cognitive function

Third priority

Maximize comfort

Comprehensive care

Basic care

Palliative care

Comfort care only

Maintain physical and cognitive function Prolong life

Maintain physical and cognitive function Maximize comfort

Maximize comfort

Maximize comfort

Maximize comfort

Prolong life

Maintain physical and cognitive function Prolong life

Source: Adapted from Ref. 8.

residents of widely differing decisional capacity, health status, and personal preferences have deliberately articulated, personally generated (to the extent possible) plans for care to guide treatment decisions. The health values of the seriously ill vary considerably from person to person, and they cannot be easily predicted from the person’s current state of health. Mental health is an important factor in determining how patients evaluate their health (6). There is no substitute for involving the resident (or surrogate in the event of resident incapacity) in developing goals for care. Practitioners can expect considerable variation in preferences for care based on a variety of factors, including ethnicity (7). Many institutions are developing structured approaches to advance care planning, including prioritization of goals of care. One scheme is shown in Table 1 (8).

IV. THE DOCTOR-PATIENT RELATIONSHIP Over the last several decades, the paternalistic model of medical care in the United States has given way to an increased emphasis on patient autonomy. Residents of LTCFs typically have significant cognitive impairment, physical frailty, and chronic disease that will be with them for the rest of their lives. These residents are likely to benefit from the “enhanced autonomy” model in which an active exchange of ideas and negotiation takes place with the goal of achieving the best possible decision for the resident (9). In many cases, goals of care will be dis-

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cussed with surrogates speaking on behalf of residents who make known their preferences for healthcare interventions. The unequal balance of power in the doctor-patient relationship is exaggerated in the LTCF. Outside the confines of the LTCF, the doctor has an advantage in power by having knowledge of medicine and of the patient, whereas the patient has little knowledge of either the doctor or medicine. In the LTCF, the physician becomes even more powerful and controls many aspects of the resident’s life by writing orders. Choice of physicians is limited to a few staff doctors or others who are willing to be credentialed and to visit the LTCF. Access to the doctor is usually determined by institutional routine, where the nurses serve as gatekeepers of physician access. On this uneven playing field, physicians must find ways to build trust with their patients so that difficult decisions can be made with the greatest possible autonomy and beneficience. Resident rights, such as the right to be given information about proposed or potential treatments and alternatives and the right to refuse treatment, serve as safeguards to counterbalance enhanced physician power. Conflict between patient and doctor over treatment choices usually occur when they disagree about values and when trust is lacking (10). Agreement over the desirability of treatments depends on the ability of the physician and patient to negotiate to develop a shared understanding of the patient’s values and goals for care in the context of the medical treatment options. “. . . autonomy is not a zero-sum game but a complex network of relationship obligations, which can be negotiated in one way under certain circumstances and in another way when the situation changes” (11).

V. DECISIONAL CAPACITY “Rarely is incapacity absolute; even people with impaired capacity usually possess some ability to comprehend, to communicate, and to form and express a preference” (12). Enhancing autonomous decision-making has received considerable attention in recent years, particularly since the Patient Self Determination Act (PSDA) became effective in 1991. The PSDA is a federal statute that requires patients be informed of their right to participate in medical decision-making and to write advance directives. Assessment of decisional capacity is complex. Decisional capacity is decision specific and may vary over time. The resident with decisional capacity must demonstrate the ability to choose among various therapeutic goals, understand and communicate relevant information, and reasonably apply that information to decision-making in keeping with those goals. Substantial numbers of residents of LTCFs may have been excluded from participating in discussions about care preferences because of an inability to determine decisional capacity

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(13). Guidelines for determining decisional capacity are being developed and studied (12). When a resident is judged to lack decision-making capacity around a certain issue, the surrogate (durable power of attorney for healthcare decisions or next of kin) should be consulted to speak on behalf of the resident. A. Quality of Life Quality measures in LTCFs span several domains, including quality of life, quality of care, and residents’ rights. Quality of life is an important goal of care in the nursing home (14). Some evidence shows that overall quality of life has improved for men and women older than 85 living in LTCFs (15). Nursing home leaders and patient care advocates report the three most important components of quality of life items as: dignity, self-determination and participation, and accommodation of resident needs (16). Achievement of these is found in the fabric of nursing home life, especially in the choice and control that residents have over daily issues. Residents attach great importance to choice and control over matters such as bedtime, rising time, food, roommates, care routines, use of money, use of the telephone, trips out of the nursing home, and initiating contact with the physician (17). Measurement of quality of life of cognitively impaired residents may be difficult. Often even elderly persons with significant cognitive impairment can still answer questions about their quality of life (18). In addition, a surrogate often knows only a little about a resident’s satisfaction with care. Physicians and nurses appear to have limited insight into the health-related quality of life of nursing home residents and probably should not be used as proxies when resident-based assessments can be obtained (19). Physicians may be able to affect perceived quality of life by making themselves more accessible to residents for questions and by negotiating and communicating directly with residents about proposed interventions that require trips out of the nursing home (e.g., consultations, diagnostic studies). B. Advance Directives 1. Preferences for Treatment Advance directives are designed to preserve resident autonomy through future states of incapacity. Advance directives are written documents that reflect resident preferences for care, as articulated through developing goals of care and the general care plan. All residents (or their surrogates) should be provided with the opportunity to articulate advance directives. Most LTCFs offer printed educational materials and processes for recording advance directives. Nondepressed, nondemented residents of LTCFs generally exhibit stable preferences for treatment when asked about cardiopulmonary resuscitation, intravenous antibiotics, mechanical ventilation, and artificial nutrition. They distinguish clearly between

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time-limited and indefinite treatment plans. They generally favor receiving intravenous antibiotics and limited mechanical ventilation, but reject most other treatments (20). In advanced chronic illness when death is expected, residents of LTCFs may have advance directives that articulate primary goals of care around the achievement of comfort and dignity. Under such circumstances, residents (or their surrogates) may direct healthcare professionals to implement treatment interventions to manage symptoms (e.g., pain control, relief of dyspnea), but not to prolong life. In such cases, advance directives might call for no cardiopulmonary resuscitation, no ventilator use, no feeding tube, no hospitalization (unless uncomfortable symptoms cannot be controlled in the nursing home), no intravenous fluids, no antibiotic treatment, and no laboratory studies. 2. Designating a Healthcare Proxy Residents should be encouraged to designate a healthcare proxy, that is, someone to speak for them in the event they lose capacity to make healthcare decisions. The physician should communicate with the healthcare proxy (surrogate) when the resident cannot participate in decision-making. In this way, the autonomy of the resident is best preserved, despite the existence of cognitive or functional deficits that preclude personal participation in decision-making. In many cases, the next of kin will serve as the surrogate, but the physician should be aware of the legal standing of the surrogate, to be sure that the authority to speak on behalf of the resident is indeed delegated to the person acting as surrogate. Other kinds of healthcare proxy include durable power of attorney, guardian, and conservator. Differences in healthcare proxy completion rates across different ethnic groups appear to be related to reversible barriers such as lack of knowledge and the perceived irrelevance of advance directives (21). C. Decision to Hospitalize “Transfer rates vary widely among nursing facilities and over time . . . Nursing facilities differ in case mix, in the number of residents with advance directives, and in clinical care resources” (22). Decisions about whether to hospitalize residents with infectious problems arise frequently in LTCFs. Pneumonia is the leading cause of hospitalization among nursing home residents, with a mortality in some studies of 40% to 50% (23). In the past, acute care facilities and LTCFs have offered distinctly different types of health services; treatment capabilities currently overlap. Differences between acute and long-term care settings still potentially include numbers and types of practitioners, sources of financial reimbursement, and philosophy of approach to the management of chronic diseases (24). The desirability and appropriateness of transfers of LTCF residents to hospitals provokes debate because of concern about cost, but also because of adverse

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effects of hospitalization (25). Physically frail long-term residents are the most likely to be hospitalized, but they may also be the least likely to benefit from hospitalization (26). Iatrogenic complications and emotional trauma for residents and families have been cited as adverse effects of hospitalization. Advancing age, lower admission Mini-Mental State Examination scores, and lower preadmission instrumental activities of daily living functional characteristics are independent risk factors for functional decline during hospitalization of older persons (27). Treatment of pneumonia in the LTCF may produce better outcomes for some patients than if they were hospitalized (28). Many patient, institutional, and physician factors affect this decision. Goals of care and the institution’s capacity to provide appropriate diagnostic and treatment interventions in a timely fashion are of particular importance. The physician’s obligation is to determine the course that best serves the needs and goals of the resident. D. Right to Refuse Care Residents who have the capacity to make decisions about healthcare matters have the right to refuse care. A major reason patients refuse a recommended care intervention is that they misconstrue or misunderstand the recommendation. Because much communication in LTCFs is accomplished through the interdisciplinary care team, the physician’s response to a resident refusing care ought to include a personal visit under comfortable, private, unhurried circumstances to discuss the proposed treatment with the resident (or surrogate). If outright disagreement between resident and physician continues, this is likely because of a difference in values. The refusal of amputation of a gangrenous extremity is sometimes encountered in LTCFs. Some regard the prospect of amputation as a fate worse than death (29). It is often helpful to involve other members of the IDT to better understand the reasons for the refusal and to try to create alternative plans for care that would be acceptable to the resident and yield the best available outcomes from the physician’s perspective. E. Advanced Dementia Dementia is an important condition affecting more than half the residents of LTCFs. Although residents with dementia may live many years, the disease is not curable, is inexorably progressive, and eventually ends in death. Decisions about treatment in advanced dementia are best carried out through development of the goals of care, as described above. Surrogates often adjust the goals of care as the disease and the resident’s level of disability progress, when the burdens of treatment loom larger than the benefits. Surrogates and families often choose to shift the emphasis of care from a focus on reactive treatments for medical problems, such as pneumonia or urinary tract infection, to proactive interventions designed

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to enhance pleasure and quality of life, as in freedom from restraints. Guidelines to support decision-making about whether to treat or not treat pneumonia in demented psychogeriatric nursing home patients have proved useful in some settings (30). When the goals of care are totally focused on achieving comfort and death is expected, as in a patient with very advanced dementia, it is not uncommon for families and surrogates to forego treating with antibiotics. F. Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Since the treatment advances of the mid 1990s, the outlook for those living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/ AIDS) has brightened considerably. Long-term care options will be increasingly needed for patients who do not fully respond to antiretroviral therapy or who have significant neuropsychiatric disease (31). The HIV/AIDS residents have a variety of reasons for needing long-term care, including the need for 24-hour nursing/medical supervision, completion of medical treatment, and end-of-life care. Issues pertaining to the need for advance care planning and palliative care are particularly important for HIV/AIDS residents.

VI. HEALTH PROMOTION Health promotion remains an important dimension of high-quality health care in LTCFs. Immunizations are a particular focus of effective health promotion and are safe for even frail residents. Influenza is an important cause of epidemic and endemic respiratory illness in LTCFs and results in considerable morbidity and mortality. The annual vaccination of residents and staff remains the most effective way to prevent influenza and its complications. However, vaccination rates have fallen short of public health targets. Facilities should develop resident and staff vaccination programs to improve the rate of vaccination (32). Pneumococcal vaccine and annual tuberculin skin testing are also recommended. Other health promotion activities, such as maintaining the highest level of mobility and function possible, are important in preventing deep venous thromboses, pressure ulcers, and other conditions associated with immobility.

VII.

ROLE OF THE IDT

Effective IDTs are essential to the provision of high-quality care in LTCFs and can alleviate many of the ethical dilemmas that characterize life in these institu-

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tions. The dominant providers in these facilities are nursing aides who render the majority of the direct care to residents. The ability of the nursing aide to recognize a change in the resident’s status and bring it to the attention of the medical practitioner permits the earliest possible identification of an infectious problem. This system of surveillance compensates for the atypical presentation that commonly characterizes illnesses of the frail elderly resident. Nurses view advocacy as a responsibility of their practice, where advocacy is rooted in the concept of individual rights (33). Social workers also practice an advocacy role, supporting three elements of autonomy: free action (supporting residents’ choices), decision-making (helping residents deliberate effectively), and continuity (maintaining a sense of self) (34). Geriatric nurse practitioners help to achieve optimal coordination of care and reduce emergency department and acute care utilization costs as well as overall costs for some managed care programs for LTCF residents (35). The key to effective IDT functioning is good communication that facilitates the flow of information to the team member who is best able to recognize its significance and respond appropriately.

VIII. INTERVENTIONS: BURDENS AND BENEFITS Diagnostic and treatment interventions bring benefits and burdens for the resident. Resident (or surrogate) decisions to accept or decline treatment may in part be determined by the perceived burdens of treatment interventions. Less burdensome options may exist. In-and-out bladder catheterization, for example, can be a frightening and uncomfortable procedure for a frail, elderly women. Investigators have demonstrated that urine specimens can be collected externally from incontinent female LTCF residents (36). Intravenous antibiotic therapy of a resident with dementia who pulls out the intravenous line on a daily basis brings the burden of repeated needlesticks and perhaps physical restraints. For an extremely debilitated resident, even transportation for a diagnostic test may be exceedingly burdensome because of discomfort from prolonged periods of waiting and riding in a bumpy wheelchair van, fear of uncertainty and a strange environment, and risk of falls from caregivers unfamiliar with the resident’s level of functional capacity. Practitioners often can devise alternative plans that minimize treatment burdens, sometimes with help from the IDT and outside consultants to assure resident comfort, control, and dignity. Consent should be sought from the resident or surrogate before embarking on a burdensome course of diagnostic testing or treatment intervention. Trials of treatment interventions may be helpful when there is ambivalence about declining or accepting an intervention. A time-limited trial (e.g., of tube feeding or hemodialysis) with the option to continue or discontinue treatment after seeing how well it is tolerated may be helpful.

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IX. END-OF-LIFE CARE Long-term care facilities will play an increasingly important role in the care of people nearing the end of life. In 1993, 20% of U.S. deaths occurred in nursing homes. By 2040 this proportion is expected to rise to 40% (37). Improving care near the end of life for LTCF residents goes beyond advance care planning and advance directives. Effective symptom management, maximization of functional capacity, and assistance with issues pertaining to life closure are additional important services that must be offered consistently as part of a system that achieves good care for those nearing the end of life. Over the past few years, the healthcare profession has recognized the need to improve the quality of care for people near the end of life, but consensus about how to accomplish this has not yet been achieved. Those living with serious chronic illness near the end of life are likely to follow one of three trajectories: (1) a relatively brief period of severe functional decline at the end of life (typical of cancer); (2) long-term disability with periodic exacerbations and unpredictable timing of death (as in congestive heart failure and chronic obstructive pulmonary disease); or (3) slow dwindling course to death with significant self-care deficits (usually from extreme frailty or dementia). These trajectories shed light on possible care systems that would serve residents’ needs better (38). A number of studies have identified effective communication and pain management as shortcomings in the care of dying persons. Bereaved family members are generally satisfied with life-sustaining treatment decisions but voice concerns about failures in communication and pain control. Nursing home care has received the smallest proportion of positive comments, including mention of poorly trained or inattentive staff and remoteness of physicians. Families recommend that care could be improved through better communication, greater access to physicians’ time, and better pain management (39). LTCF residents near the end of life are focused on the quality of living rather than dying. They have concerns with day-to-day living, difficulty chewing and swallowing, better pain relief and sense of control, strengthening relationships with loved ones, importance of religious activities, giving care to others, and appreciation of respectful and prompt care (40,41).

X. CONTACT ISOLATION Although prevalence of antibiotic-resistant bacteria in LTCFs has been described, managing residents colonized with antibiotic-resistant organisms has come to represent a significant challenge for practitioners in these settings (42). Contact isolation of a resident colonized with a resistant organism represents an affront to that resident’s freedom created by the obligation to protect the rights

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of other residents to be free from harm, particularly those in subacute settings. Adverse effects of contact isolation include less frequent care and negative psychological consequences (43). There are likely to be significant differences between different types of LTCFs (e.g., the Veterans Affairs nursing home care unit population vs community nursing home population) (44). More needs to be learned about the risk to residents and how to develop antibiotic resistance precautions that are effective, inexpensive, and achievable in LTCFs. The IDT may address the psychological problems that the isolated resident experiences and develop strategies to avoid unnecessary complications of isolation procedures. For example, the IDT might permit a resident to wash his face and hands, don a clean gown, and walk in the halls to physical therapy at the end of the day (see chapters in Part III and Chapter 8).

XI. COST CONCERNS The varied arrangements for financing care in the LTCF create a variety of ethical dilemmas for facilities and practitioners. Every treatment option has a cost that must be factored into the process of clinical decision-making. Financial incentives to accept residents with complex medical needs into the facility exist with some payors but not with others. Some payors encourage transfer of the acutely ill resident to the hospital and others reward the LTCF and the practitioner for treating the resident in the LTCF. The high cost of antibiotics such as vancomycin may create significant dilemmas. In some cases, for cost reasons, residents may not be able to return to the LTCFs they consider home. Significant variation exists in prescribing and the cost of antimicrobials among LTCFs (45), and formularies and guidelines are being developed to standardize prescribing practices.

XII.

INFECTION CONTROL PRACTICES BY STAFF

The LTCF staff plays an important role in infection control through the use of precautions and routines (see Chapters 8 and 9). From an ethics standpoint, these are measures that carry little risk or burden to the staff and are effective in maintaining infection control. Hand washing is perhaps the most obvious low risk strategy, yet marked shortcomings in the use of hand washing and gloves continue to exist in LTCFs (46). Hand-washing practices vary considerably across hospital wards and type of worker, and lack of good hand washing appears to be associated with understaffing (47). A common ethical dilemma is the question of whether a sick employee should be working. Prohibiting a staff member with a contagious illness from working with residents follows from the ethical concept of utility that strives to

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maximize good outcomes while minimizing harm. Institutional staffing shortfalls or the staff member’s reluctance to take a sick day may compete with this value. Another ethical quandary is presented when staff members fail to get influenza vaccines. The medical director should work with infection control professional and other members of the IDT to create an institutional ethic of good infection control practices, supported by strong educational programs for staff and effective employee health services.

XIII. ROLE OF THE MEDICAL DIRECTOR The medical director bears responsibility for the overall quality of care provided in the LTCF. Along with the director of nursing and the facility administrator, the medical director should develop a basic ethics policy framework (48). Effective implementation of ethics policies requires a shared vision by the leadership, adequate support for the process, and explicit guidelines for the staff and practitioners, residents, and families. A mechanism to resolve disputes should be developed. Ethics committees have fulfilled this role in some facilities. Measuring outcomes that reflect quality of care in LTCFs is an important dimension of quality management for which the medical director has oversight. The Minimum Data Set (MDS) has provided some quality indicators for LTCFs (such as pressure ulcers, use of psychotropic medications, falls) but other measures need to be developed. Needs for pain relief and spiritual support are not routinely addressed by the MDS and Resident Assessment Protocol (RAP) triggers. Indicators are likely to vary for different subsets of LTCF residents. Key indicators for the care of terminally ill residents include communication of advance directives, attention to pain management, and relief of dyspnea (49). For residents who desire antibiotic treatment for infectious diseases, early empiric antibiotic therapy has an important impact on the outcomes of pneumonia (50); thus, percent of residents who received antibiotics within 4 hours of diagnosis of infection might be a worthwhile quality indicator.

XIV. RESEARCH ISSUES IN INFECTION CONTROL Research is an important avenue in improving treatment and preventing infectious disease in LTCF residents. There are multiple facets of ethical obligation in the LTCF research endeavor. Guidelines for ethical investigations have been put forth (51). The Ethics Committee of the American Geriatrics Society has outlined guidelines for appropriateness of the informed consent process for patients with dementia who are research subjects (52). The interest of the individual resident may be at times in opposition to the interests of the population within the facility.

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A mandate to do no harm and protect confidentiality exists for both the individual and the population. However, the individual resident seeks privacy and autonomy, whereas the concern of the population lies in investigating, reporting, and achieving justice. Infection control activities ought to investigate clusters of adverse outcomes, identify and implement cost-effective interventions, safeguard the health of residents and staff, measure the efficacy of interventions, and avoid conflicts of interest around recommendations of products and equipment. Residents who become subjects for research (or their surrogates) must provide informed consent, and they must be assured that their welfare, privacy, and confidentiality will be protected. Staff members should be protected from harm (taking precedence over staff freedom)(5). Although basic standards of research ethics are not usually reported in nursing home research, the instructions of a journal for the author or other features of peer review can affect the quality of reporting research ethics (53). Well-written policies on the protection of cognitively impaired research subjects is an important way that research institutions can demonstrate that serious attention is paid to the rights and welfare of cognitively impaired residents (54).

XV. FUTURE Long-term care facilities are likely to continue to be places where functionally dependent persons receive medical and personal care, either episodically or as a final place of residence toward the end of life. The ethical issues interwoven into

Table 2 Promises to Those with Advanced Stages of Serious Illness 1. GOOD MEDICAL TREATMENT—You will have the best of medical treatment, aiming to prevent exacerbation, improve function and survival, and ensure comfort. 2. NEVER OVERWHELMED BY SYMPTOMS—You will never have to endure overwhelming pain, shortness of breath, or other symptoms. 3. CONTINUITY, COORDINATION, AND COMPREHENSIVENESS—Your care will be continuous, comprehensive, and coordinated. 4. WELL PREPARED, NO SURPRISES—You and your family will be prepared for everything that is likely to happen in the course of your illness. 5. CUSTOMIZED CARE, REFLECTING YOUR PREFERENCES—Your wishes will be sought and respected, and followed whenever possible. 6. USE OF PATIENT AND FAMILY RESOURCES (financial, emotional, and practical)—We will help you and your family consider your personal and financial resources, and we will respect your choices about the use of those resources. 7. MAKE THE BEST OF EVERY DAY—We will do all we can to see that you and your family have the opportunity to make the best of every day. Source: Adapted from Ref. 55.

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this environment are powerful determinants of the outcomes that LTCF residents experience. An articulation of a vision for the future guides practitioners and others to achieve the best possible quality of life and care for LTCF residents (Table 2) (55).

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Garibaldi RA. Residential care and the elderly: The burden of infection. J Hosp Infex 1999; 43 Suppl:S9–S18. Yoshikawa TT, Norman DC. Approach to fever and infection in the nursing home. J Am Geriatr Soc 1996; 44:74–82. Dubler NN. Reflections on some ethical issues in long-term care. In: Binstock RH, Cluff LE, Von Mering O (eds). The Future of Long-Term Care: Social and Policy Issues. Baltimore, Johns Hopkins Press, 1996:238–251. Olson MD. “The heart still beats, but the brain doesn’t answer.” Perception and experience of old-age dementia in the Milwaukee Hmong community. Theoretical Med Bioethics 1999; 20(1):85–95. Herwaldt LA. Ethical aspects of infection control. Infect Control Hosp Epidemiol 1996; 17:108–113. Tsevat J, Cook F, Green ML, Matchar DB, Dawson NV, Broste SK, Wu AW, Phillips RS, Oye RK, Goldman L, for the SUPPORT Investigators. Health values of the seriously ill. Ann Intern Med 1995; 122:514–520. Vaughn G, Kiyasu E, McCormick WC. Advance directive preferences among subpopulations of Asian nursing home residents in the Pacific Northwest. J Am Geriatr Soc 2000; 48:554–557. Gillick M, Berkman S, Cullen L. A patient-centered approach to advance medical planning in the nursing home. J Am Geriatr Soc 1999; 47:227–230. Quill TE, Brody H. Physician recommendations and patient autonomy: Finding a balance between physician power and patient choice. Ann Intern Med 1996; 125: 763–769. Lantos JD. Futility assessments and the doctor-patient relationship. J Am Geriatr Soc 1994; 42:868–870. Helft PR, Siegler M, Lantos J. The rise and fall of the futility movement. N Eng J Med 2000; 343:293–296. Mezey M, Teresi J, Ramsey G, Mitty E, Bobrowitz T. Decision-making capacity to execute a health care proxy: Development and testing of guidelines. J Am Geriatr Soc 2000; 48:179–187. Bradley E, Walker L, Blechner B, Wetle T. Assessing capacity to participate in discussions of advance directives in nursing homes: Findings from a study of the Patient Self Determination Act. J Am Geriatr Soc 1997; 45:79–83. Ouslander JG, Osterweil D. Physician evaluation and management of nursing home residents. Ann Intern Med 1994; 121:584–592. Liao Y, McGee DL, Cao G, Cooper RS. Quality of the last year of life of older adults: 1986 vs 1993. JAMA 2000; 283:512–518. Harrington C, Mullan J, Woodruff LC, Burger SG, Carrillo H, Bedney B. Stakehold-

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porting of research ethics in publications of nursing home research? J Am Geriatr Soc 1999; 47:76–81. 54. Cahill M, Wichman A. Research involving persons with cognitive impairments: Results of a survey of Alzheimer disease research centers in the United States. Alzheimer Dis Assoc Disorders 2000; 14:20–27. 55. Lynn J, Schuster JL, Kabcenell A. Improving Care for the End of Life: A Sourcebook for Health Care Managers and Clinicians. New York, Oxford University Press, 2000.

8 Nursing Management of Infections Donna L. Barton Lake Eustis Care Center, Eustis, Florida

Janet D. Register Leesburg Regional Medical Center, Leesburg, Florida

I. INTRODUCTION When caring for residents in a long term-care facility (LTCF), infections are frequently encountered. Each facility must have an infection control program as mandated by Federal regulation (1). This program is designed to investigate, control, and prevent infections in the facility; decide what procedures, such as isolation, should be applied to an individual resident; and maintain a record of incidents and corrective actions related to infections. In the August 1991 Journal of Infection Control, the Association for Practitioners in Infection Control (APIC; now called Association for Professionals in Infection Control and Epidemiology), published “APIC guideline for infection prevention and control in the long-term care facility” (2). This article assists in establishing an infection control program for LTCFs. It provides information on how to establish an effective surveillance program. Total surveillance is recommended for all residents for whom antibiotic therapy is prescribed while residing in LTCFs. This includes reviewing the medical history of residents admitted to the facility with antibiotic orders (community-acquired infections), as well as those who developed infections and were given antibiotic therapy while residing in an LTCF (nosocomial infections).

II. SURVEILLANCE The purpose of surveillance is to identify trends that may be occurring so that a potential outbreak can be avoided and to determine educational needs for the en99

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tire staff caring for the residents. An important part of surveillance is to establish criteria for identifying infections of various body systems. In February 1991, the American Journal of Infection Control published an article entitled “Definition of infections for surveillance in long-term care facilities,” which can serve as a reference in establishing these criteria (3). Contributors to this informative article included representatives from APIC, Centers for Disease Control and Prevention (CDC), and many teaching hospitals throughout the United States and Canada. Using this as a guide and working with the facility medical director, criteria can be formulated for those symptoms that best signal an infection (see the appendixes of this book for summary of these criteria). A reliable method to help the nurse identify the presence of infection in residents is the basic “nursing process” of assessment, diagnosis, planning, implementation, and evaluation (4) (Table 1). All items of the nursing process should be reviewed by the nurse before the physician is given the assessment findings of a resident suspected of having an infection. The purpose of the nursing process is to compile an accurate, concise, comprehensive resident assessment to present to the physician. Important information includes the following: • • • • • •

Current physician orders The most recent physician progress notes The resident’s current medications Vital signs, if applicable Any abnormal laboratory or radiology finding available A brief history of the resident’s current problem

Table 1 Basic Nursing Process Assessment

Diagnosis Planning

Implementation Evaluation

Use criteria adopted for presence of infection in specific body system. Collect data through interview with resident for subjective and objective complaints, review of history, medical record, and physical examination. Compile the assessment findings and laboratory results in a systematic method for presentation to physician for diagnosis. Obtain physician orders, list needed comfort measures, identify appropriate room placement for containment, identify necessary isolation precautions as indicated by symptoms and physician diagnosis. (Care Planning Process for significant change.) Carry out individualized plan of care as established. Follow-up on outcomes of implementation of plan of care. If symptoms continue, return to assessment, presentation of information to physician for diagnosis, alteration of Care Plan, implementation of new Care Plan, and evaluation of outcomes.

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The nurse should keep the resident’s chart available for writing any new physician orders or for access to any additional information.

III. IDENTIFICATION OF INFECTIONS A. Clinical Manifestations Once criteria for identifying nosocomial infections have been formulated by the facility’s infection control committee, it is important to remember that not all LTCF residents with infection will present with these symptoms. Atypical clinical manifestations are not unusual in the elderly. Often a temperature elevation is thought to be the first sign of an infection. In the elderly, however, fever may be absent or the body temperature may be below normal (see Chapter 6). And an early sign of pneumonia may only be tachypnea (5–7). There is a need to profile each individual resident as to past symptoms and signs of a specific infectious process. There are instances in which the only evidence of an infectious process is a change in normal behavior patterns, a change in mentation, a decrease in the resident’s normal activity level, or poor fluid and food intake. Some residents may have symptoms compatible with an infection, but due to dementia, aphasia, or nonresponsiveness, they are unable to communicate their presence. Every LTCF has at least one resident who has been labeled a “chronic complainer.” Regardless of past experience with this type of resident, each new complaint necessitates a thorough nursing assessment and physician notification, if indicated. B. Diagnostic Specimens and Microbiology The physician may ask for a specimen to be obtained for culture and sensitivity. Nurses need to be trained in the proper technique of obtaining specimens as indicated by the receiving laboratory. Nurses will also review the findings in the culture and sensitivity reports for communication to the physician. If no organism was found and the physician has prescribed an antibiotic, it is imperative for the nurse to notify the physician of the culture results. If an organism is found, the sensitivity report will identify whether the antibiotic ordered for treatment is effective or if the organism is resistant to the drug. If the infecting organism is resistant, the nurse must relay this information to the physician, along with a list of antibiotics to which the organism is sensitive. Antibiotic use must be closely monitored for its appropriateness to assist in decreasing the possibility of drug-resistant pathogens. C. Communication The identification of infections is a team effort. All staff must be involved: nurses, nursing assistants, therapists, environmental, dietary, and any other facility staff.

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Family members, visitors, and volunteers who come in contact with the resident routinely can also identify a change in that resident and provide information for nurses. It is important to establish lines of communication with all team members, families, visitors, and volunteers. Most frequently, these individuals will communicate their concerns to the nurse in charge of the resident’s care. The nurse must listen and be aware that a potential problem may exist that requires further resident assessment. It is particularly vital to investigate the concerns of nursing assistants regarding residents for whom they are caring. Nursing assistants are the direct caregivers who spend the most time with the residents and will most often be first to identify changes in the resident’s behavior. However, because their medical education is limited, they do not always have the terminology to describe their findings, and nursing follow-up of their observations is often lacking.

IV. PREVENTING INFECTIONS Knowing how infections spread is the first step in preventing their spread to staff members or other residents. The CDC recently published its Guidelines for Isolation Precautions in Hospitals (8). The categories for isolation precautions are standard, droplet, airborne, and contact. A. Standard Precautions Standard precautions combines the features of universal precautions and body substance isolation. It applies these precautions to all persons receiving care in any type of medical establishment, regardless of diagnosis or presumed infection status. Standard precautions apply to blood and all body fluids; secretion and excretions (except sweat), regardless of whether these fluids contain visible blood; nonintact skin; and mucous membranes. 1. Hand Washing The practice of standard precautions first addresses the importance of hand washing. A 15-second hand washing will be performed (9). • After touching blood, body fluids, secretions, excretions, nonintact skin, mucous membranes, contaminated items • Upon reporting to work at the start of the shift • Before and after each resident contact (it may be necessary to wash hands between tasks and procedures on the same resident to prevent cross-contamination of different body sites) • After using the restroom

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Before handling food Before and after eating or smoking Before and after handling patient care items Before and after glove usage Before leaving work area to go home After blowing or wiping one’s nose

Hand washing is to be performed at these times regardless of whether gloves are worn. With the increased encouragement of activities in LTCFs, residents are frequently found out of their room and in communal areas participating in the activities offered. With this increased mobility, residents themselves may be a source of infection to other residents. Just as hand washing is the key factor in preventing the spread of infection from the hands of the healthcare worker, so is frequent hand washing by the residents a deterrent in spreading infection to other residents (10). 2. Personal Protective Equipment (PPE) a. Gloves: These should be worn (clean, intact, nonsterile gloves are adequate) whenever the employee comes in contact with: • Moist body substances (e.g., blood, body fluids, secretions, and excretions) • Mucous membranes (mouth, nose, eyes, genitals, and rectum) (Put on clean gloves just before touching mucous membranes and instilling eye drops.) (11) • Nonintact skin (Put on clean gloves just before touching nonintact skin.) • Any resident care items that may be contaminated with moist body substances (e.g., bedpans, urinals, linens) Remove gloves promptly after use and wash hands before touching noncontaminated items, environmental surfaces, and before going to another resident. This helps to prevent transferring microorganisms to other residents or the environment. Gloves should be removed and hands washed before leaving a resident’s room. b. Gown: Wear a clean, nonsterile gown to protect skin and to prevent contamination of clothing during resident-care activities that are likely to generate splashes or sprays of blood, body fluids, secretions, or excretions. Remove a soiled gown promptly and wash hands to avoid transfer of microorganisms to other residents or the environment. c. Goggles, face shields, and masks: Wear these items to protect mucous membranes of the eyes, nose, and mouth during resident care activities that are likely to generate splashes or sprays of blood, body fluids, se-

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cretions, and excretions (e.g., emptying Foley bags, during resident suctioning, emptying suction canisters). d. Masks: These will be worn by staff members when a resident has an undiagnosed cough. This protects the healthcare worker who may be susceptible to an undiagnosed airborne disease carried by the resident. e. Resident care equipment: Handle all soiled resident-care equipment in a manner that prevents exposure to skin, mucous membranes, clothing, other residents, and the environment. • Reusable equipment must be cleaned and reprocessed appropriately before use by another resident, (e.g., intravenous poles, walkers, wheelchairs). • Ensure that single-use items are discarded properly. f. Linen: Handle, transport, and process used linen in a manner that prevents skin and mucous membrane exposures and contamination of clothing. Proper handling of linen will avoid transfer of microorganisms to other residents and the environment. 3. Occupational Health and Bloodborne Pathogens • Use safety devices, needleless systems, and procedures that help to minimize needlesticks and sharps injuries (e.g., never recap, bend, or break needles). • Place used disposable syringes, needles, scalpel blades, razor blades, and other sharp items in appropriate puncture-resistant containers. These containers should be located as close as practical to the area in which the items were used. The containers should be changed when two-thirds to three-quarters full. • Use care in handling sharp instruments after use, including razor blades. • Use mouthpieces, resuscitation bags, or other ventilation devices as an alternative to mouth-to-mouth resuscitation. B. Airborne Precautions In addition to standard precautions, use airborne precautions for residents known or suspected of being infected with microorganisms transmitted by airborne droplet nuclei (small-particle residue [5 microns or smaller in size] of evaporated droplets containing microorganisms that remain suspended in the air and can be dispersed widely by air currents within a room or over long distances). Airborne precautions are practiced to protect staff members, as well as any individual entering the precaution room. These precautions should be used for all residents diagnosed with or suspected of having active tuberculosis (TB), measles (rubeola), chickenpox (varicella), or herpes zoster.

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1. Resident Placement Residents should be placed in an isolation room. The room should: • have monitored negative air pressure in relation to the surrounding areas • have 6 to 12 air changes per hour • have appropriate discharge of air outdoors or monitored high-efficiency filtration of room air before the air is circulated to other areas in the facility • have the door closed at all times If there is no negative air pressure room in the facility, it will be necessary to transfer the resident to a facility that has appropriate accomodations. After the resident has been taking antituberculosis medications for at least 10 days, there is a marked improvement in symptoms, and the sputum smears are negative, the patient is no longer considered communicable and may return to the LTCF. (Note: criteria for proven cases of TB to be allowed to return to home or LTCF may vary from state to state). To maintain confidentiality, post a sign outside the room advising anyone preparing to enter the room to report to the nurses’ station. 2. Respiratory Protection • A particulate respirator mask, having the capacity to filter to 5 microns or less, should be worn by all employees and visitors entering the room of a resident with known or suspected TB or other airborne infections. • Employees who have not had measles or chickenpox, or been immunized for these infections, should not enter the room of residents with these infections, if other immune caregivers are available. • Persons immune to measles or chickenpox need not wear respiratory protection when caring for a resident with these infections. 3. Resident Transport Limit the transport of the resident from the room to essential purposes only. • Have diagnostic tests and procedures done in resident’s room rather than transporting the resident to other departments, when possible. • When resident must be transported out of the room to other departments, the resident is to wear a mask and the receiving department is to be alerted to the resident being on airborne precautions. 4. Education • Educate the resident and alleviate resident concerns about airborne precautions.

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• Inform resident to cover mouth and use tissues when coughing or sneezing, and teach the resident proper disposal of used tissues. • Educate visitors on the proper use of masks. • Keep employee and visitor traffic to a minimum. The termination of airborne precautions in a diagnosed or suspected TB case is permitted if: • TB has been excluded by smear and culture • The criteria for noncommunicability of an active TB case are met (see earlier discussion) • Resident is discharged home. C. Droplet Precautions In addition to standard precautions, use droplet precautions for a resident known to be or suspected of being infected with microorganisms transmitted by droplets (large particle droplets [larger than 5 microns in size] that can be generated by the resident during coughing, sneezing, talking, or during the performance of procedures). Droplet precautions are used to protect the staff, other residents, and families from infections transmitted by the droplet route. Droplet precautions should be instituted for all diagnosed or suspected cases of infections transmitted by droplets, for example, pertussis, diphtheria, Haemophilus influenzae, among others. 1. Resident Placement • All residents requiring droplet precautions will be admitted to a private room. • If a private room is not available, place the resident in a room with a resident who has active infection with the same microorganism but with no other infection (cohorting). • A notice will be placed outside the room requesting that everyone report to the nurses’ station before entering the room. 2. Mask In addition to standard precautions, all staff must wear a mask when working within 3 feet of the resident. 3. Resident Transport Transport the resident from the room only for essential purposes. • Whenever possible, have diagnostic tests and procedures done in resident’s room rather than transporting the resident to other departments.

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• When resident must be transported out of the room to other areas, the resident is to wear a mask to minimize dispersal of droplets. The receiving department should be notified of the droplet precautions. 4. Education • Educate the resident and alleviate resident’s concerns about droplet precautions. • Inform resident to cover mouth and use tissues when coughing or sneezing; teach the resident the proper disposal of used tissues. D. Contact Precautions In addition to standard precautions, use contact precautions for a specified resident known to be or suspected of being infected or colonized with important microorganisms that can be transmitted by direct contact with the resident (hand, or skin-to-skin contact that occurs when performing resident-care activities that require touching the resident’s dry skin) or indirect contact (touching) with environmental surfaces or resident care items in the resident’s environment. 1. Resident Placement • All residents requiring contact precautions will be admitted to a private room. • Place a resident who contaminates the environment or who does not (or cannot be expected to) assist in maintaining appropriate hygiene or environmental control in a private room. • When a private room is not available, place the resident in a room with a patient who has active infection with the same microorganism, but with no other infection (cohorting). • When a private room is not available and cohorting is not achievable, consider the epidemiology of the microorganism and the relative risk to the other resident(s) occupying the same room when determining placement. 2. Gloves and Hand Washing • Wear gloves as outlined under standard precautions. • While providing care for a patient, change gloves after having contact with infective material that may contain high concentrations of microorganisms (e.g., fecal material and wound drainage). • Remove gloves before leaving the resident’s environment and wash hands immediately with an antimicrobial agent or a waterless antiseptic agent.

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• After glove removal and hand washing, ensure that hands do not touch potentially contaminated environmental surfaces or items in the resident’s room to avoid transfer of microorganisms to other residents or the environment. 3. Gown • Wear a clean, nonsterile gown when entering the room if you anticipate that your clothing will have substantial contact with the resident, environmental surfaces, or items in the resident’s room. If the resident is incontinent or has diarrhea, an ileostomy, a colostomy, or wound drainage not contained by a dressing, a gown should be used to protect clothing. • Remove the gown before leaving the resident’s room and discard. • After gown removal, ensure that clothing does not contact potentially contaminated environmental surfaces to avoid transfer of microorganisms to other residents or the environment. 4. Patient Transport • Limit transport of the resident from the room to essential purposes only. • If the resident is transported out of the room, ensure that precautions are maintained to minimize the risk of transmission of microorganisms to other residents and contamination of environmental surfaces or equipment. Notify the receiving department that the resident is on contact precautions. 5. Patient Care Equipment • When possible, dedicate the use of noncritical resident-care equipment to a single resident (or cohort residents infected or colonized with the same pathogen) to avoid sharing equipment with noninfected residents. • Equipment dedicated to a single resident for use during contact precautions that will not be discarded is to be disinfected before being used by another resident. • Handle, transport, and process used linen in a manner that will not contaminate clothing and that avoids transfer of microorganisms to other residents or the environment. E. Antibiotic-Resistant Microorganisms Today, residents are becoming infected with antibiotic-resistant microorganisms more frequently than ever before. In LTCFs, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci are two of the most important resistant pathogens encountered. Extensive discussions on these organisms are found elsewhere in this book (see Chapters 22 and 23).

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Because of the scarcity of private rooms, criteria must be developed for the optimum selection of appropriate room placement and roommates for the residents diagnosed with infections caused by these resistant microorganisms. 1. Definitions Colonized. A resident is culture positive for the organism but exhibits no symptoms or signs of infection. Infected. A resident is culture positive for the organism and exhibits symptoms and signs of infection (e.g., purulent drainage from a wound, elevated temperature, productive cough, urinary frequency with pain or burning). Contained. • Wound. A draining wound is covered by an absorbent dressing that contains the wound drainage • Urinary. The resident has a Foley catheter or is continent. • Respiratory. The resident is competent to cover his mouth with tissues when coughing or sneezing and disposes tissues in a plastic bag. Uncontained. • Wound. Drainage from a wound is too profuse to be contained by a covering dressing. • Urinary. The resident is consistently incontinent of urine. • Respiratory. The resident is confused and consistently coughs, sneezes, and expectorates without using tissues. Resident’s culture status. • It is known that the resident’s cultures are negative for resistant microorganisms. • It is known that the resident’s cultures are positive for resistant microorganisms and the resident has an active infection. • It is known that the resident’s cultures are positive for resistant microorganisms, but the resident is exhibiting no symptoms or signs of active infection (colonized). • It is known that the resident is culture-negative at this time but has had a positive multiresistant microorganism culture in the past • It is NOT known if the resident has now or has had in the past, a positive culture for a multiresistant microorganism. 2. Risk for Acquiring an Infection with a Resistant Microorganism If a resident falls into any of the categories below, he or she is a greater risk for acquiring a colonization or infection with a resistant microorganism.

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• • • • •

Bed/chair confined Poor functional status Urinary incontinence (males) Open wounds or pressure ulcers Invasive devices present (e.g., Foley catheter, urostomy, colostomy, feeding tubes, tracheostomy, intravenous lines) • Frequent (or is currently on) antibiotic therapy • Prior infection or colonization with a resistant microorganism 3. Room Definition • Private. A single-bed room or a semiprivate room with no other resident. • Cohort. Placing a resident who is infected in a room with a resident who is infected with the same organism but with no other infectious organism. A colonized resident may also be placed in a room with another resident who is colonized with the same organism.

Table 2 Guidelines for Room Placement of Residents with Antibiotic-Resistant Microorganisms Room type: new admission

With a resident at low risk

Private room

Cohorting*

Resident culture negative

Yes

Resident culture positive for infection Resident culture positive, no infection, colonized Resident culture negative now, culture positive in the past

Yes

Yes, if new resident has been assessed as a low risk Yes

Yes

Yes

Yes

Yes, if new resident is now assessed as a low risk

Yes

Resident culture status unknown

Yes

Yes, if new resident has been assessed as a low risk

Yes

Yes

Yes, if no other placement is available Yes

With a resident at high risk Yes, if new resident has been assessed as a low risk No

No

Yes, when no other placement is available and resident is assessed as a low risk Yes, if new resident has been assessed as a low risk

* Residents, each colonized or infected with a different resistant microorganism, for example, methicillinresistant Staphylococcus aureus and vancomycin-resistant enterococci, respectively, should never be cohorted.

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• A room with a resident at low risk for acquiring an infection with a resistant microorganism. • A resident who has never had colonization from a resistant microorganism. • A resident who has no invasive devices present. • A resident who is not confined to bed or wheelchair. • A resident who has no incisions or open wound. • A room with a resident with high risk for acquiring an infection from a resistant microorganism (see earlier discussion). Guidelines for room placement are described in Table 2. The benefits of isolating residents should always be weighed against the potential adverse effects on psychosocial status and quality of life.

V. EDUCATION A. Infection Control Professional Long-term care facilities should make available educational opportunities to expand knowledge in infection control practices for the staff member designated to perform the duties of infection control professional (ICP). The APIC frequently offers, throughout the country, educational training in basic infection control practices. This program includes topics of surveillance methodology, basic microbiology, immunology, infectious process, infection-control precautions, and outbreak investigation. This will provide the staff member a good foundation for establishing an infection control program and setting up surveillance protocols. Advance training and certification programs are also available from APIC for the ICP. Membership in APIC affords the opportunity for networking with other ICPs in an exchange of ideas and problem-solving. Also, subscriptions to periodicals or Internet links give access to information on infection control practices. This information is essential to maintain updated and current information on changes and trends in the field of infection control (10). B. Staff Education The ICP should provide ongoing infection control education for all levels of LTCF staff, both for the direct caregivers (nurses, nursing assistants, therapist, etc.) and ancillary staff (maintenance, dietary, housekeeping, etc.) Education should include information on: • How infections are transmitted • What makes residents susceptible to infections • Standard and transmission-based precautions

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• Antibiotic-resistant microorganisms • The importance of basic hand washing • How the infection control program functions The ICP must be aware of staff concerns related to caring for residents with infections. For example, a resident with a Foley catheter is newly diagnosed with urinary tract infection with MRSA. The caregivers are concerned that they have been caring for this resident and the resident has not been on contact precautions. Additional training in standard precautions, non-resistant staphylococcal versus MRSA infections, and the role of susceptibility in acquiring infection may be required to alleviate staff concerns. C. Tips on Nursing Care for Infection Prevention 1. Proper Foley catheter insertion using aseptic technique and proper/frequent Foley catheter care will assist in decreasing the number of urinary tract infections (12). Adequate fluid intake should be maintained, when not medically contraindicated, to help prevent urinary tract infections. 2. Preventive measures for decreasing the development of pressure ulcers and related infection complication include the following: • Schedule toileting for incontinent residents. • Turn schedule/pressure relieving mattresses for residents at risk while in bed. • Elevate heels off the mattress with pillows. • Position devices in bed, recliners, wheelchairs. • Maintain good nutritional and fluid intake. • Use lift sheets and two employees when changing resident’s position. • Adhere to a position change schedule when a resident sits in a chair, recliner, or wheelchair. 3. When a resident is on antibiotic therapy, offering yogurt or buttermilk may help prevent yeast infections and assist in maintaining normal bacterial flora. 4. A policy that residents do not have contact with staff members who are diagnosed with an infection should be enforced. Infected staff members should also use appropriate protective equipment, (e.g., mask when infected with a respiratory infection) to safeguard the residents. 5. Employees should use gait belt when transferring, repositioning in a wheelchair, and ambulating residents to decrease the chance of skin tears or lacerations that would put the resident at risk for infection. 6. An active immunization program for current residents, new admissions, and employees should be implemented (13). Although these types of programs may be expensive, it will be more costly to treat multiple active infections.

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a.

Residents • Annual influenza vaccination should be administered after the last week in October to assure continued antibody levels throughout the “flu” season. • D/T (diphtheria/tetanus toxoid) booster when source of skin tears, lacerations, or puncture wounds is unknown and resident has not had a booster in more than 10 years. • D/T booster every 10 years when no major injuries have occurred. • D/T booster in the case of a major injury if no booster administered in more than 5 years. • Pneumococcal vaccine for all new residents without prior immunization. b. Staff • Measles, mumps, and rubella vaccine for all employees born after December 31, 1956 if they are unable to provide verification of prior immunization • Influenza vaccine annually • Hepatitis B vaccination 7. Tuberculin skin testing with purified protein derivative (PPD) is recommended for all new residential admissions using a two-step Mantoux method. New staff, staff exposed to active tuberculosis, and staff as part of their annual employment examination should receive a PPD skin test. VI. CONCLUSION The staff will need continuing education on changes that occur with aging and how symptoms and signs of infection may manifest differently in the geriatric population. The staff should understand what is “normal” for each resident under their care. The nurse must give careful attention to the culture and sensitivity reports to assist the physician in decreasing the inappropriate use of antibiotics. The staff needs to continue to improve resident assessment skills to identify the presence of infection and to work on effective communication skills to relay this information to the physician and other personnel, as appropriate. Knowledge of and adherence to infection control procedures and practices are essential in preventing infections and outbreaks. REFERENCES 1.

U.S. Department of Health and Human Services, Health Care Financing Administration. Medicare and Medicaid requirements for long term care facilities. Federal Register September 26, 1991; 56:48826–48879.

114 2. 3.

4. 5. 6.

7.

8. 9. 10. 11.

12.

13.

Barton and Register Smith PW, Rusnak P. APIC guideline for infection prevention and control in the long-term care facility. Am J Infect Control 1991; 19(4):198–215. McGeer A, Campbell B, Emori TG, Hierholzer WJ, Jackson MM, Nicolle LE, Peppler C, Rivera A, Schollenberger DG, Simor E, Smith PW, Wang EE-L. Definitions of infection for surveillance in long-term care facilities. Am J Infect Control 1991; 19(1):1–7. Christensen PJ, Kenney JW. Nursing Process Application of Conceptual Models, 3rd ed. St. Louis, The C. V. Mosby Company, 1990. Shua-Haim JR, Ross S. Pneumonia in the elderly. Clinical Geriatrics (on-line). Available at: http://www.mmhc.com/cg/articles/CG0001/shua.html. Fune L, Shua-Haim JR, Ross JS, Frank E. Infectious diseases in the elderly. Clinical Geriatrics (on-line). Available at http://www.mmhc.com/cg/article/CG9803/ShuaHaim.html. Rajagopalan S, Moran D. Infectious disease emergencies in older adults. Clinical Geriatrics (on-line). Available at: http://www.mmhc.com/cg/article/CG101/ raja.html. Garner J. Guideline for isolation precautions in hospital. Infect Control Hosp Epidemiol 1996; 17(1):53–80. Barrs AW, Fahey P. Infection control across the board. Nurs Homes Long Term Care Management 2000; 49(11):38–43. Pritchard V. Joint Commission standards for long-term care infection control: Putting together the process elements. Am J Infect Control 1999; 27(1):27–34. Smith PW, Rusnak PG. Infection prevention and control in the long-term-care facility. Am J Infect Control 1997; 25(6):488–512. http//www.nih.gov/ninr/vol3/Infection.html. Fune L, Shua-Haim JR, Ross JS, Frank E. Infectious disease among residents of nursing homes. Ann Long-Term Care 1999; 7(11):410–417. Available at: http://www. mmhc.com/nhm/articles/NHM9911/shuahaim.html. Drinka PJ, Gravenstein S. Management of influenza in the nursing home. Ann LongTerm Care 2000; 8(9):23–30.

9 Establishing an Infection Control Program Janet Nau Franck Consulting Professionals, Inc., St. Louis, Missouri

Elizabeth Owens Schwab BJC Health System, St. Louis, Missouri

David W. Bentley Saint Louis University School of Medicine, and St. Louis VA Medical Center, St. Louis, Missouri

I. INTRODUCTION In one’s lifetime, the potential for entering a long-term care facility (LTCF) continues to increase along with its risk. It is estimated that more than 40% of persons aged 65 and older will require an LTCF, such as a skilled nursing facility, sometime during their lifetime. Because of their multiple underlying risk factors, the possibility of infection increases, but chronic illness, dementia, overuse of antibiotics, and lack of diagnostic resources all contribute to the delay or inability to promptly recognize and treat infection (1). It is no surprise, therefore, that infection control practices in LTCFs are being recognized as a critical component in the prevention and control of infections. This chapter provides practical guidelines for establishing and maintaining an effective infection control program in the LTCF, including useful practices and resources for the beginning infection control professional (ICP). A resource that provided much of the focus for this chapter was previously published (2) (see also Chapters 8 and 10.)

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II. THE CASE FOR ESTABLISHING AND MAINTAINING AN EFFECTIVE INFECTION CONTROL PROGRAM A. Increased Infection Risk in the Elderly The increasing numbers of frail older persons requires that more care be provided in LTCFs such as nursing homes, especially skilled nursing facilities. Many of these residents are immunocompromised because of comorbidities, medications, and functional disabilities. These residents require comprehensive infection control programs targeted toward the high risks of infection imposed by the special conditions of the LTCF and the residents’ own susceptibilities. High employee turnover rates and multiple facility priorities continually thwart effective infection control programs. Such challenges undermine even the best, most organized infection control effort. The nature of the LTCF resident’s immune suppressed state, combined with the challenges of day-to-day facility operations require constant vigilance toward infection control and prevention. B. Regulatory Requirements 1. Mandated Federal, State, and Local Requirements Mandated requirements from federal regulatory and advisory agencies, such as the Health Care Financing Administration (HCFA) (3) and the Occupational Safety and Health Administration (OSHA) (4), require that LTCFs comply with their written directives as outlined in their survey manuals. These requirements reflect a number of infection control issues. The OSHA Bloodborne Pathogen Standard (4) focuses primarily on minimizing exposure of bloodborne pathogens to health care workers, for example human immunodeficiency virus (HIV) and hepatitis B. Additionally, regulatory requirements by HCFA and the Omnibus Budget Reconciliation Act (OBRA) (5) address federal regulations that mandate that LTCFs establish prevention and control of infections associated with admission to, or employment in, such a facility. It is most helpful to take a core set of requirements from these and other agencies and adapt them to the LTCF’s needs. The infection control program also needs to be compliant with local and state requirements that relate to the prevention and control of infections in LTCFs (6). This information can be obtained from an LTCF administrator or the state Department of Health. Many of these agency requirements are similar. For example, recommendations overlap in addressing policies regarding (1) admissions, (2) tuberculin testing of residents, (3) employee health, (4) immunizations, (5) HIV-infected residents, and (6) infection control (6). It is essential to focus on the adaptation of standards applicable to your facility’s needs to obtain licensure and comply with regulatory requirements.

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2. Voluntary Organization Requirements An example of voluntary organization requirements is the Joint Commission on Accreditation of Healthcare Organization (JCAHO), which publishes long-term care standards (7). These standards address a number of infection control issues, and compliance with these standards is necessary to attain JCAHO accreditation. An additional resource is published by the American Health Care Association (8).

III. ESSENTIAL ELEMENTS OF AN EFFECTIVE INFECTION CONTROL PROGRAM A. Program Elements 1. Oversight Committee A committee with oversight responsibilities for an infection control program should be organized to provide the necessary authority and decision-making functions for an effective program. Although the committee may meet only as needed or be combined with the work of other committees, such as quality improvement, pharmacy review, or occupational health and safety, its purpose should be to oversee the process of reducing the risks of facility-acquired infections in residents and healthcare workers (7). The committee also serves to review and analyze surveillance data and collectively approve recommendations for ongoing prevention and control measures. It acts as the enforcing body within the organization for continuous application of good infection control practice throughout the facility and takes action, as necessary, to implement emergency control measures during an outbreak. The oversight committee should have appropriate authority from the administrative and medical leadership. The committee, therefore, should include the medical director, the director of nursing, the ICP, and a representative from each of the following areas: nursing staff, administration, and other clinical departments such as rehabilitation, dietary, pharmacy, housekeeping/maintenance, and others. If the ICP and quality improvement professional are not one and the same, the group should also include the individual responsible for coordinating the facility’s performance improvement process (7). The essential elements of an effective infection control program in LTCFs have been identified (8–10) and include the oversight committee and other elements shown in Table 1 and described below. 2. Infection Control Professional One author describes the ICP as the “eyes, ears and feet of the infection control program” (11). The ICP assesses, gathers information (surveillance), and moves throughout the facility not only to gather information but to implement or enhance

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Table 1 Essential Elements of an Effective Infection Control Program in the Long-Term Care Facility Oversight committee Infection control professional Infection control program elements Infection surveillance Infection control interventions Outbreak investigation and control Education for employees, residents, and visitors Policy and procedure development Employee health program Resident health programs Antibiotic resistance management Antibiotic utilization and review Effective interdepartmental partnerships Disease reporting to public health departments

existing prevention and control measures. The designated person responsible for coordinating the infection control program is usually a staff nurse. It is ideal for this person to be a registered nurse and work closely with the director of nursing. Appropriate delegated authority, clinical background, infection control training, and nursing’s multiple roles in the LTCF are important variables in the ultimate success of the ICP role. Each of these factors plays a vital role in how the ICP will function on a day-to-day basis and consequently, may largely contribute to, or detract from, the efficacy of the overall infection control program. The LTCF must wholly support the ICP and the efforts for surveillance and infection prevention. Without this support, access to important information may be blocked, partnerships with other departmental managers may fail, and most importantly, the facility may not receive vital data on facility-acquired infection, which will be needed to improve resident care. It is important that the ICP have a clinical background—ideally in nursing, preferably in caring for the elderly. Knowledge of microbiology and a general understanding of antibiotic use are also helpful. Infection control training and exposure to available resources are the foundations of the ICP’s successful job role. Basic knowledge of infection control standards, methods of surveillance, and requirements for an effective program can be obtained via textbook, journal, and Internet access. To access these resources, the professional must be allocated the time and financial resources to purchase or borrow from a medical library such items and digest the information they offer. Several websites for infection control information have been included at the end of this chapter. To use these websites, the ICP must have access to a personal computer with Internet connection and, again, the time to review the information. Several courses given

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by national or regional groups are also available. The Association for Professionals in Infection Control and Epidemiology (APIC) offers a training course for hospital and LTCF ICPs (202-296-2742). The Missouri Chapters of APIC offer the “Essentials of Infection Control Annual Conference” yearly in mid-Missouri (573-893-3700), and the Nebraska Infection Control Network offers a basic training course specifically for LTCF ICPs (402-552-2360). 3. Infection Surveillance a. Endemic Rates. Routine infection surveillance is the cornerstone of the infection control program. The facility should use surveillance data to drive infection control interventions and decision-making for infection prevention. If surveillance data are given to clinicians and staff on a regular basis, the information can serve to initiate improvement in resident care. It can also be used to display successes in infection rate reduction as a means to reach administrators or others who allocate resources for infection control and prevention. Essential elements of surveillance are described in Table 2. The surveillance program should include a consistent and systematic data collection process with written definitions. The population(s) of interest, for example, residents with Foley catheters or pressure ulcers, should be defined. Data should then be collected and consolidated for routine but meaningful reporting and evaluation. Analysis and interpretation should be conducted regularly. Surveillance data should be used

Table 2 Essential Elements of Surveillance for Infection Control Element

Description

Comment

1. Data collection

Systematic data collection

2. Documented surveillance process 3. Review and analysis

Documented surveillance

Defined numerator/denominator Written process with written definitions Include type of infection and date of onset

4. Rate calculation and reporting 5. Data used for IC intervention planning

Frequent data review/swift control measures as appropriate Periodically calculate and report rates (monthly, quarterly) Use surveillance data to drive IC efforts

Abbreviation: IC, Infection control. Adapted from Ref. 9.

Use standardized rate calculation/1000 resident days Short-term planning and long-term priority setting

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in the short term to plan immediate infection control measures or educational programs, detect epidemics, or identify individual resident problems for intervention or treatment. For the long term, surveillance data can be used to determine ongoing educational needs, resource allocation for upcoming years, and objectives for infection control planning in subsequent years. Definitions for LTCF-acquired infection. Although standard definitions for nosocomial infection in acute care have long been available (12), no similar set of definitions has been validated for LTCFs. A panel of experts published a set of LTCF-acquired infection definitions by body site established by consensus conference methods that have been widely adopted by LTCF infection control programs (13) (see Appendixes). The definitions should be written and kept in a central location such as the infection control manual or on personal computer disk so that the ICP or other members of the organization can access them at any time. This becomes particularly important in the LTCF where turnover rates can be high and new individuals will frequently need to be trained on the surveillance process. Data collection reporting and rate calculations. Ideally, the ICP will use standardized data collection methods and tools to obtain surveillance information. This approach, along with the use of specific definitions, helps assure consistency of data collection and analysis for comparison over time. Sources for obtaining infection information are described in Table 3. The ICP’s presence in the resident care areas shows staff that infection control is important and that administration supports infection control and values adherence to good infection control practice. Infection rates are used to provide a common basis for entering surveillance data. Rates require a numerator, or number of nosocomial infections in a given period, for example, the number of urinary tract infections in July, and a denominator, which in LTCFs is the population at risk or total number of resident-days in July. For example, if the LTCF had an average daily census of 140 for July and 14 new infections were detected, the rate would be 14/140 31 1000 3.2 infections per 1000 resident-days. For further details on data collection, reporting,

Table 3 Sources for Infection Information Patient-based Resident assessment, hall rounds, staff communication, medical record, X-ray reports, Kardex review, temperature logs, medication/pharmacy records/treatment logs Laboratory-based Microbiology reports, antimicrobial susceptibility reports Other departments or agencies Admissions/social work/rehabilitation, physician offices or outpatient clinics, home care/home infusion agencies, acute care facilities, state and local health departments

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and rate calculations and their use in infection control programs in LTCFs, other reference sources are available (11). b. Epidemic Rates. Surveillance data provide the basis upon which the ICP may identify an epidemic or outbreak of a particular infection type. Day-to-day collection of surveillance data allows the opportunity for early detection of such epidemics. Epidemic rates are infection rates of a particular type or organism that are higher than expected. For some organisms, one or two cases may be considered an epidemic, for example, hepatitis A or group A Streptococcus. For others, several isolates with similar antibiotic susceptibility patterns or other common features, such as common body site or common resident location, must be present to initiate outbreak or cluster investigation. Examples of the latter include methicillin/oxacillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE). 4. Outbreak Investigation and Control As discussed above, an outbreak or epidemic is an occurrence of similar infections at a rate that exceeds the rate normally expected in a given location and period. Although most facility-acquired infections in LTCF are endemic, a portion do occur from outbreaks. Aggressive detection and control are important because of potential morbidity and mortality to residents and staff, subsequent cost of investigation and treatment, and public relations difficulties often related to outbreak occurrence. An outbreak can be one case of a disease of unusual virulence or public health importance, as noted above. For less virulent organisms, an outbreak can be defined as three or more cases related by time, place, and person within the same population (see also Chapter 10). Knowing the usual endemic baseline rates, the ICP can also suspect an outbreak by noticing infection rates equal to 2 1/2 times above the usual rates. Some experts in infection control in LTCFs have suggested identifying outbreaks by threshold testing, which uses a simplified table of binomial distributions to calculate probabilities of infection frequency at selected endemic levels (mean number of infections per month) and compares these probabilities to observed infection frequency. This method is straightforward and does not require knowledge of statistics, special computer software, denominators, or calculation of rates (14,15). Table 4 lists the appropriate steps to outbreak investigation in a LTCF. 5. Education for Employees, Residents, and Visitors Infection control inservice education should be provided by the ICP and department supervisors to all employees on a timely basis, particularly during their orientation. Documentation of training should reflect the dates, times, attendees, and evaluations. Topics should reflect the goals identified in the infection control pro-

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Table 4 Steps to Outbreak Investigation in a Long-Term Care Facility Request help, notify state and local health departments Control the known Determine case definition Compile line list of initial cases; seek additional cases that fit definition Initiate additional/extend original control measures to more areas based on case finding Inform and educate staff, residents, families Check for daily new cases until occurrences cease Present follow-up report to administration and health department: compile all documentation (epidemiologic curve, line list, description of control measures)

gram plan and concerns identified from surveillance data. For example, before the influenza season, presentations should identify symptom recognition, transmission of the infection, vaccination and chemoprophylaxis policies, the importance of hand washing and other hygienic practices, appropriate waste disposal, bagging at the point of contact and universal precautions. Coordinated effective educational programs will result in improved infection control activities (8,16,17). Infection control-related education of residents and visitors can help reduce the risk of transmission of pathogens by resident-to-resident or resident-to-visitor contact and decrease the level of stress for both parties. For example, the APICOrange County Patient and Family Education Task Force has developed a series of 20 education pamphlets that can be accessed by computer disk and customized for individual LTCF needs. These educational pamphlets can be adapted to enhance resident and family understanding of how to minimize the transmission of infection. These could be translated to other languages when such barriers are a concern. For additional information, see the Appendix at the end of this chapter. 6. Policy and Procedure Development An important aspect of the infection control program is the development, review, and updating of policies and procedures (P&Ps). This requires the ICP to be available to make rounds, provide educational input, and monitor compliance of P&Ps to ensure adherence. Many areas should be considered when establishing infection prevention and control. Resources are available to assist in the development and writing of these P&Ps (9,18) (see also the Appendix at the end of this chapter for additional sources). Table 5 lists a good sampling of P&P topics to include. The P&Ps need to be clearly written, updated, and referenced on a timely basis. Staff should be oriented to them as they pertain to the performance of their job. Departmental supervisors should be consulted in the drafting of their P&Ps and present them to the infection control committee for final approval. These P&Ps require regular review and approval for example, every 2 years. An inter-

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disciplinary approach is essential when developing these P&Ps, including administration, nursing, medical, and support services/departments. The infection control committee minutes should document this approach for accreditors and serve to track their review and expansion. Policies and procedures are critical to the success of the program. They serve as the basis for procedural inservices, staff performance, and they demonstrate competency and program evaluation. As a resource, they should be closely aligned with the mission and vision of the organization to promote a team focus (19). 7. Employee Health Programs The health of the employee is important to the delivery of safe care for all residents. This includes the requirements that employees should be hired without communicable diseases (3) and are protected from occupational exposure to bloodborne pathogens (4). Guidelines for infection in hospital personnel are available (20) and are generally adaptable to the LTCF (9). Other important issues that are not mandated but on which employees should be instructed are the sick and accident policy and post-exposure follow-up or preventative programs for certain infections, such as HIV, hepatitis B virus, and scabies or lice (9). Tuberculosis screening and education is a key element in the employee health program. Major components for instruction by the ICP include the two-step tuberculin skin test, interpretation of test results, follow-up of positive skin tests, and staff awareness of their symptoms and signs that may represent Table 5 Sample List of Policies and Procedures for Infection Control in Long-Term Care Facilities Role of administration Hand washing Universal precautions/isolation Housekeeping, e.g., cleaning processes, waste disposal, and environmental surveillance Laundry, e.g., handling of soiled linen Dietary, e.g., food preparation and cleaning Rehabilitation services, e.g., physical therapy, occupational therapy Respiratory therapy, e.g., humidifier cleaning Employee health, e.g., tuberculosis screening and vaccinations and leave of absence Admission to the long-term care facility Transfer to an acute care facility Vaccination history, e.g., influenza, pneumococcal, and tetanus Management of residents with infections Infection surveillance and data collection Outbreak identification, investigation, and control Review antibiotic prescribing

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active tuberculosis pulmonary disease (21). Employee vaccination programs should include influenza, hepatitis B vaccine, varicella, and hepatitis A virus, in certain circumstances (9). (See other chapters in this book relevant to these topics for further details). Organizations such as APIC and health departments can provide literature, media material, and “tool kits,” that is, work sheets and educational aids, to further promote the understanding of and compliance with these challenging employee health issues (see also the Appendix at the end of this chapter for these sources). 8. Resident Health Program Residents need to be screened on admission to the LTCF to assess their risk for transmitting an infection, as well as their need for preventive interventions to reduce their risk for contracting infection (22). A major component of a resident health program is immunizations for influenza, pneumococcal disease, and tetanus (9) (see Chapter 20). In addition, all residents on admission should undergo tuberculin skin testing and a follow-up chest X-ray if the skin test is positive or the patient is symptomatic (21) (see Chapter 15). Other interventions should be targeted toward the prevention of urinary tract infections, skin and soft tissue infections, and aspiration pneumonia (9) (see chapters on these topics in this book). 9. Antibiotic Resistance Antibiotic resistance is a major concern in LTCFs. Residents most likely to develop infections caused by resistant organisms are those with wounds such as pressure ulcers, underlying chronic diseases, poor functional status, invasive devices such as urinary catheters, and prior antibiotic therapy. Because these resistant organisms may enter the facility through colonized or infected hospital patients and become endemic, strategies must be established by LTCFs to control their spread. Person-to-person transmission via the hands of healthcare workers appears to be the most important means of spread (23). Strategies to control transmission of antibiotic-resistant pathogens in LTCFs is limited, and strategies used in hospitals often are inapplicable. The Society for Healthcare Epidemiology of America (SHEA) position paper (23) provides a good discussion of this problem. In addition, Section III of this book provides several chapters on antimicrobial resistance in LTCFs. 10. Antibiotic Utilization An important contributing factor to the growing problem of antibiotic resistance is the overusage and inappropriate prescribing of antibiotics in LTCFs. To improve antimicrobial use, a second SHEA position paper (24) recommended that LTCFs develop and implement several control measures. Infection control pro-

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grams should include antibiotic utilization review of the antibiotics that are being prescribed in the LTCF to help limit the potential for the spread of resistant organisms. Others have recommended that the key data to collect include: (1) incidence (number of antibiotic courses started per 1,000 resident-care days) and (2) antibiotic utilization ratio (ratio of number of antibiotic-days to number of resident-care days). Because the costs of antibiotics are often easily available from administration and pharmacy and appear to reflect overall antibiotic use, data on antibiotic costs per resident-care-day can serve as an alternative to the intensive utilization review items noted (25) (see Chapter 11). 11. Effective Partnerships a. Alliance with Administration, Medical Director, and Director of Nursing. Before establishing a new (or enhancing an existing) infection control program, the facility administrator must fully appreciate the importance of infection control. Not only must the administrator understand the increased infection risk for the resident, but also the increasing regulatory requirements for infection control as a condition of participation in Medicare. To educate the administrator on the value of an excellent infection control program will require the full support and promotion by those who first see it as valuable: the medical director (MD) and the director of nursing (DON). Depending on the LTCF, the education process for the administrator by these healthcare professionals may require first demonstrating the need for an ICP. Collaboration between the MD and DON or ICP is critical in making the process a success. After the MD/DON team has educated the administrator on these components, the administrator should be presented with a proposal for resources needed. Each program should include several essential elements for success, for example surveillance program, isolation policies, employee education, and others as noted in Table 1. The overall program will require several resources to ensure its success. The key resources include: an ICP with knowledge of or supporting resources for fundamentals of infection control, Internet access and, if possible, appropriate computer software and hardware to manage a surveillance database, adequate workspace, and sufficient medical and administrative support to influence others in the facility, even without having direct authority over them. b. Alliance with Department Manager/Supervisors/Nursing. In all areas, the ICP must communicate closely with staff to ensure that they have the knowledge, expertise, and supplies necessary to comply with standard precautions, isolation practices, aseptic technique, and other problem-specific issues. An effective strategy to identify unsafe practices is to perform walking rounds, document issues of noncompliance, and distribute the findings to the individual department manager/supervisors. Noting practices such as breaks in aseptic technique is essential in recognizing opportunities for improvement, such as wearing gloves inappro-

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priately or not bagging and knotting bags of soiled items at the point of use. Is there an availability of personal protective equipment (PPE) in soiled utility rooms when cleaning reusable medical devices? Does the trash that is placed in biohazardous waste containers meet the definition of being blood “soaked or caked,” as mandated by OSHA? Is the facility paying for additional poundage of regular trash to be transported by special waste handlers? Are food products labeled and dated, and are refrigerators being cleaned after spillage on a routine basis? If not, education can act as a critical means of modifying behavior. c. Quality Improvement. Long-term care facilities have continued to emphasize quality improvement (QI) processes. There are a number of similarities between QI and infection control programs. Both use methods to collect data, then search for adverse outcomes or risk-reducing strategies. Both programs demonstrate the value of education to change behavior and both perform follow-up evaluations to determine if outcomes have improved. Infection control continues to be recognized as a performance improvement process due to the analytic process of collecting surveillance data, identifying areas of concern, and recognizing opportunities for improvement. For this reason, many LTCFs have used the QI committee meetings as a successful means of discussing and documenting infection control program activity (26). d. Environmental Hygiene. The LTCF must be monitored for cleanliness and proper maintenance because residents may often soil with body secretions and discharges with which the physical environment they come in contact. This can then serve as a reservoir for spreading infections to other residents and staff. These housekeeping policies must delineate the process and persons responsible for cleaning and disinfecting the environment. Cleaning schedules need to be closely followed, ensuring that cleaning products are facility-approved and dilutions are appropriate and standardized. Hand-washing facilities should be conveniently located and accessible to all staff. Insects and rodents must be eliminated and prevented from gaining access to the LTCF. Maintenance also plays a vital role in assessing and maintaining safe plumbing and ventilation systems of the facility. For example, their policies should indicate that air filters are changed routinely to avoid contaminating the environment or themselves. For laundry services, the ICP needs to monitor that bagging of linens at the site of use, that clean linens are covered, and that carts are cleaned between uses. In the laundry, separate areas must be designated for clean and soiled items. Physical therapy equipment, especially hydrotherapy equipment, should be disinfected regularly and anytime there is visible soiling with bloody fluids. In food service, because of the risk of foodborne illnesses, it is important that the food preparation and services environment be clean and strict attention given to food handlers. The infection control program, with support from risk management, maintenance, and housekeeping, should establish and monitor policies and procedures for disposing

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of infectious or other waste materials, as defined and regulated by federal, state, and local regulations, including OSHA regulations (4), to minimize cost and occupational exposure risk to healthcare personnel (27). e. Admissions/Social Worker. Admissions and Social Work have key roles in facilitating the transfer of patients from the hospital to the LTCF, with special emphasis on infection control issues. The admission process should include clear and accurate information regarding the infection control risks of the patients before their transfer to the LTCF. For example, the transferring hospital facility should notify the LTCF regarding a patient harboring an antibiotic-resistant organism, the results of tuberculin skin testing, or other conditions for which additional precautions should be considered. All employees need to be reminded of the importance of confidentiality, whether the infection is HIV or MRSA. It is helpful for hospitals and LTCFs to formalize joint transfer agreements in advance to expedite processes and clarify policies. Of course, transfer of residents to hospitals require that equally clear and accurate infection control-related information be transmitted to the hospital prior to transfer. IV. BARRIERS TO ESTABLISHING AN EFFECTIVE PROGRAM Despite the LTCFs best efforts to create an effective infection control program, most facilities face formidable barriers in maintaining the program. The complicated work of resident care is strenuous and fast-paced, often leading to high turnover rates even among LTCF administrators, DONs, and ICPs. This necessitates frequent retraining and resecuring of infection control resources. Direct resident care staff also turnover quickly, which presents education challenges on a daily basis. Because many LTCFs are small (fewer than 200 beds), the ICP is often assigned multiple roles. Although not unimportant, these other responsibilities may serve to distract the ICP from constant focus on infection surveillance and control measures. Other barriers include lack of infection prevention and control training, lack of necessary resources to implement an effective program and perhaps, most importantly, lack of strong administrative or medical support in the form of true delegated authority. As described above, basic infection control training is the foundation of a successful ICP role and is often both inexpensive and easy to access. The ICP must, however, have the time and means to access such educational resources. Other necessary resources that may be lacking include: desk/office space, Internet access and, possibly, computer hardware and software, secretarial or data entry support, time away from resident care for staff to attend infection control inservice education, access to local/regional resources, and time to attend local and regional APIC meetings.

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V. LOCAL, REGIONAL, AND NATIONAL RESOURCES A. Local APIC Chapter Becoming a member of a local chapter enables the ICP to take advantage of numerous products, services, and educational opportunities that are timely and stateof-the-art. Whether it is the cutting-edge training courses the ICP needs, information regarding practice standards, networking opportunities, information technology resources, or practice guidelines, becoming a member of a national infection control association such as APIC can initiate the ICP’s training and support needs (see the Appendix at the end of this chapter for additional information). B. County and State Departments of Health Another important element of the infection control program is to submit reportable diseases to the public health department. The ICP needs to know which diseases must be reported by law and the process most efficient to ensure complete and accurate reporting. Depending on the surveillance system established, the ICP needs to determine who will report diseases when the ICP is on vacation or not available. The reportable diseases are critical data to the public health departments, which rely on this information to provide educational and laboratory services for program planning and development. The State Communicable Diseases section also can serve as valuable consultants and provide useful information on current clusters or outbreaks of infection control problems in other LTCFs in the same locale. C. APIC/SHEA Several professional associations provide significant resources to ICPs and LTCF staff. The Association for Professionals in Infection Control and Epidemiology provides a quarterly Long Term Care Newsletter, journal articles in the American Journal of Infection Control, and a Long Term Care Section that meets at annual conferences and provides resources accessible from their web site. The Society of Health Care Epidemiology of America has a Long-Term Care Committee and publishes in the journal, Infection Control and Hospital Epidemiology, helpful guidelines on pertinent infection control-related topics that are frequently seen in LTCFs (see the Appendix at the end of this chapter for websites).

VI. PROGRAM EVALUATION AND IMPROVEMENT Developing an annual plan and an evaluation and improvement program can start the ICP’s efforts to maintain administrative support and confidence in the infec-

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tion control program. Because each facility is unique, every effort should be made to address concerns that are specific to one’s own LTCF. Risk factors, resident population, and the nature of the LTCF will determine the criteria used for program planning and evaluation (28). As long as the outcome invites an opportunity for improvement, the quality of care will be positively enhanced. An excellent tool to use when evaluating your program is the APIC toolkit, “Assessing and Developing an Infection Control Program.” Although this was written with the acute care setting in mind there is little difference between the program processes and methods to evaluate the effectiveness of the LTCF program (see the Appendix for source information).

APPENDIX Supplementary Reading List APIC Text of Infection Control and Epidemiology, 2000. APIC National Office, 1275 K Street NW, Suite 1000, Washington, DC 20005-4006. Can be ordered by phone: (202) 789-1890. Contains all current APIC Guidelines, State of the Art Reports, Position Papers, Commentaries, CDC and OSHA Guidelines. Arias K (ed). Assessing and Developing an Infection Control Program in the Acute Care Setting (and adaptable to LTCF). Infection Control Tool Kit Series, 2000; APIC National Office, 1275 K Street NW, Suite 1000, Washington, DC 20005-4006. Can be ordered by phone: (202) 789-1890. Contains useful guidelines, sample forms, documents and references. Benenson AS (ed). Control of Communicable Diseases in Man, 15th ed. 1990. American Public Health Association, 1015 Fifteenth Street NW, Washington, DC 20005. Lists infectious diseases with signs, symptoms, epidemiology, contagious periods and treatment. Heaton WH, Thayer NL. Infection Control Program: Policy and Procedure Manual (for LTCFs). National Health Publishing, 428 E. Preston St., Baltimore, MD 21202, tel. 301528-4000. Useful resource for developing an IC program. Patient and Family Education (Pamphlets) disk, APIC Orange County: APIC National Office, 1275 K Street NW, Suite 1000, Washington, DC20005-4006. Can be ordered by phone. (202) 789-1890. Contains educational infection control pamphlets that can be customized. Selected Internet Websites Association for Professionals in Infection Control and Epidemiology (APIC) http://www.apic.org/ Center for Disease Control and Prevention (CDC) http://www.cdc.gov/ Occupational Health and Safety Administration (OSHA) http://www.osha.gov/ Society for Healthcare Epidemiology of America (SHEA) http://shea-online.org World-Wide Web Virtual Library: Epidemiology http://www.epibiostat.ucsf.edu/ epidem/epidem.html/

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Bentley DW, Bradley S, High K, Schoenbaum S, Taler G, Yoshikawa TT. Practice guideline for evaluation of fever and infection in long-term care facilities. Clin Infect Dis 2000; 31:640–653. Smith PW. Infection control program organization. In: Smith PW (ed). Infection Control in Long-Term Care Facilities, 2nd ed. Albany, NY, Delmar Publishers, 1994: 105–114. U.S. Department of Health and Human Services, Health Care Financing Administration. Medicare and Medicaid requirements for long term care facilities. Federal Register September 26, 1991; 56:48826–48879. Department of Labor, Occupational Safety and Health Administration. Occupational exposure to blood-borne pathogens: Final rule. Federal Register December 6, 1991; 56(235):64004–64182. Omnibus Budget Reconciliation Act of 1987. Pub L No. 100–203, December 22, 1987, subtitle C, part 1, 4201:160–170. Crossley K, Nelson L, Irvine P. State regulations governing infection control issues in long-term care. J Am Geriatr Soc 1992; 40:251–254. The Joint Commission on Accreditation of Healthcare Organizations. Comprehensive Accreditation Manuals for Long Term Care. Chicago, IL, Joint Commission on Accreditation of Healthcare Organizations, 1998. American Healthcare Association. Infection Prevention and Control for Long-Term Care Facilities: Handbook and Instructor’s Guide. Washington, DC, AHCA, 1995. Smith PW, Rusnak PG. Infection prevention and control in the long-term care facility. Am J Infect Control 1997; 25(6):488–512. Rusnak PG. Long-term care. In: Pfeiffer J (ed). APIC Text of Infection Control and Epidemiology. Washington, DC, APIC, 2000:17-1–17–31. Rusnak PG, Horning LA. Surveillance in the long-term care facility. In: Smith PP (ed). Infection in Long-Term Care Facilities, 2nd ed. Albany, NY, Delmar Publishers 1994, 10:117–130. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections. Am J Infect Control 1988; 16:128–140. McGeer A, Campbell B, Emori T, Hierholzer WJ, Jackson MM, Nicolle LE, Peppler C, Rivera A, Schollenberger DG, Simor AE, Smith PW, Wang EE-L. Definitions of infection for surveillance in long term care facilities. Am J Infect Control 1991; 19:1–7. Mylotte JM. Analysis of infection control surveillance data in a long-term care facility: Use of threshold testing. Infect Control Hosp Epidemiol 1996; 17:101–109. Smith PW. Epidemic investigation. In: Smith PW (ed). Infection Control in LongTerm Care Facilities, 2nd ed. Albany, NY, Delmar Publishers, 1994:131–146. Smith PW, Daly PB, Rusnak PG, Roccaforte JS. Design and dissemination of a multiregional long-term care infection control training program. Am J Infect Control 1992; 20:275–277. Daly PB, Smith PW, Rusnak PG, Jones MB, Guiliano D. Impact on knowledge and practice of a multi-regional long-term care facility infection control training program. Am J Infect Control 1992; 20(5):225–233.

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Rusnak PG, Boehle MC. Regulation, policies and procedures. In: Smith PW (ed). Infection Control in Long-Term Care Facilities, 2nd ed. Albany, NY, Delmar Publishers, 1994:161–168. Pritchard V. Joint commission standards for long-term care infection control: Putting together the process elements. Am J Infect Control 1999; 27:27–34. Diekema DJ, Doebbeling BN. Employee health and infection control. Infect Control Hosp Epidemiol 1995; 16:292–301. Centers for Disease Control. Prevention and control of tuberculosis in facilities providing long-term care to the elderly. MMWR 1990; 39(No. RR-10):7–20. Yoshikawa TT, Norman DC. Infection control in long-term care. Clin Geriatr Med 1995; 11:467–480. Strausbaugh LJ, Crossley KB, Nurse BA, Thrupp LD. Antimicrobial resistance in long-term-care facilities. Infect Control Hosp Epidemiol 1996; 17:129–140. Nicolle LE, Bentley DW, Garibaldi R, Neuhaus EG, Smith PW, and the SHEA LongTerm-Care Committee. Antimicrobial use in long-term-care facilities. Infect Control Hosp Epidemiol 2000; 21:537–545. Mylotte JM. Antimicrobial prescribing in long-term care facilities: Prospective evaluation of potential antimicrobial use and cost indicators. Am J Infect Control 1999; 27:10–19. Smith PW. Infection control program organization. In: Smith PW (ed). Infection Control in Long-Term Care Facilities, 2nd ed. Albany, NY, Delmar Publishers, 1994: 105–114. Haberstich NJ. Infection control measures: The environmental reservoir. In: Smith PW (ed). Infection Control in Long-Term Care Facilities, 2nd ed. Albany, NY, Delmar Publishers, 1994:211–216. Smith PW. Infection surveillance in long-term care facilities. Infect Control Hosp Epidemiol 1991; 12:55–58.

10 Epidemiologic Investigation of Infectious Disease Outbreaks Chesley L. Richards, Jr., and William R. Jarvis Centers for Disease Control and Prevention, Atlanta, Georgia

I. INTRODUCTION Infectious disease outbreaks in long-term care facilities (LTCFs) are common, can cause serious morbidity and mortality for residents, and can be time consuming to investigate and control. Epidemiologic investigation of these outbreaks can be as complicated as outbreak investigation in hospital settings, and yet fewer infection control resources are generally available in LTCFs. Despite these challenges, interdisciplinary infection control programs that include infection control professionals (ICPs), administrators, clinicians (e.g., physicians, nurse practitioners, physician assistants), pharmacists, laboratorians, and nursing staff can prevent many infectious disease outbreaks and successfully control those outbreaks that do occur. This chapter will review the principles of epidemiologic investigation as they apply to outbreaks in LTCFs, review aspects of selected infectious disease outbreaks, and discuss approaches to their prevention and control. Although LTCFs encompass a broad range of facilities from nursing homes for the elderly to long-term psychiatric facilities, the focus of this chapter is on outbreak investigation in nursing homes for the elderly. Many of the recommendations contained in the chapter, however, can be adapted and used in other LTCF settings. II. CHARACTERISTICS OF LONG-TERM CARE FACILITIES (LTCFs) Long-term care facilities are an increasingly important site of medical care and drug prescribing for the elderly. More than 40% of adults in the United States will 133

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spend some time in LTCFs before death, and the majority (53%) of residents in LTCFs will spend 1 year or longer (1,2). An important distinction between LTCFs and acute care facilities is that LTCFs are residential and persons in LTCFs are generally referred to as “residents” instead of as “patients.” Even though medical care is provided to LTCF residents, other aspects of a resident’s life take on greater importance than in acute care facilities. Socialization through group activities, both inside and outside the LTCF, is key to promoting good mental health for residents, although these activities may increase the risk of exposure to infectious agents, such as influenza. Group settings for eating and physical therapy, vital to the maintenance of resident independence and functional status, may increase risk for foodborne outbreaks, person-to-person transmission, or exposure to potential fomites, such as physical therapy equipment. Not surprisingly, the management of infectious disease outbreaks in LTCFs is complicated because the focus of LTCF care is on the preservation of physical function and socialization, not exclusively on diagnosis and treatment of infectious diseases. The availability of clinicians to evaluate febrile residents may be limited, and diagnostic studies, including microbiologic cultures, are generally less available than in acute care facilities. Consequently, nursing assistants usually perform the initial resident assessment, and licensed nurses relay important findings to clinicians, usually by telephone (3). In an effort to improve the evaluation of LTCF residents with fever or suspected infection, recommendations for the minimal evaluation of patients who develop fever in LTCFs were published recently (4). These guidelines specify tasks appropriate for nursing assistants and licensed nurses. In LTCFs, antimicrobials for the empiric treatment of suspected infection often are prescribed without onsite clinician evaluation or diagnostic testing (5,6). When diagnostic testing is performed, only limited tests are available in most LTCFs. This, together with outsourcing of most laboratory tests, may lead to suboptimal timeliness of reporting and, in some situations, inaccurate or misleading results. When residents are acutely ill or diagnostic testing is not available in LTCFs, residents often are transferred to the emergency departments of acute care hospitals. Not surprisingly, evaluation and management of infection accounts for approximately one-quarter of resident transfers from LTCFs to hospitals (7).

III. RISK FACTORS FOR OUTBREAKS IN LTCFs Risk factors for outbreaks include both resident and institutional factors (Table 1). The typical resident in an LTCF is female, older than 80 years of age, cognitively impaired, and living with several underlying medical conditions. Individual risk factors for infection include immunologic senescence, malnutrition, multiple chronic diseases, medications (e.g., immunosuppressants, central nervous system agents that diminish cough reflex), cognitive deficits that may complicate resident

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Table 1 Potential Risk Factors for Infectious Disease Outbreaks in Long-Term Care Facilities Resident level Decreased immunity to infection Malnutrition Chronic disease Functional impairment including diminished cough reflex, urinary incontinence, fecal incontinence, immobility Medications, especially psychoactive medications that diminish cough reflex and consciousness Invasive devices, such as urinary catheters, enteral feeding tubes, tracheostomies, etc. Institutional level Larger size (e.g., larger number of residents) Facility design (e.g., single versus multiple resident rooms) Group activities such as meals, physical therapy, recreational activities Low immunization rates Excessive antimicrobial use Widespread colonization of residents with antimicrobial-resistant organisms

compliance with basic sanitary practices (e.g., hand washing), functional impairments (e.g., fecal and urinary incontinence, immobility, diminished cough reflex), or invasive device use (e.g., urinary catheters, enteral feeding tubes, tracheostomies) (3,5,6,8). Institutional factors associated with increased risk for outbreaks are varied. Frequent group activities such as meals, physical therapy, recreational activities, or the common use of shared facilities (e.g., showers or whirlpool baths) increase the risk for outbreaks (3,5,6,8). Risk for outbreaks caused by specific pathogens (e.g., influenza, Streptococcus pneumoniae) is increased in settings where resident and healthcare worker immunization coverage is low. Finally, widespread excessive antimicrobial use and high rates of colonization with antimicrobial-resistant organisms increase the risk of outbreaks from these organisms. In a study of outbreaks among New York LTCFs, institutional risk factors for respiratory or gastrointestinal infection outbreaks included larger LTCFs (risk ratio 1.71 per 100 bed increase), LTCFs with a single nursing unit, or LTCFs with multiple units but shared staff (9). Risk for outbreaks was lower in LTCFs with paid employee sick leave. IV. KEY ASPECTS OF INFECTIOUS DISEASE OUTBREAK INVESTIGATION The epidemiologic investigation of infectious disease outbreaks in LTCFs should be conducted in a systematic fashion. Key components of the investigation are described below and are listed in Table 2.

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Table 2 Key Aspects of Outbreak Investigation in Long-Term Care Facilities 1. Have an infection control plan and program 2. Ask two important questions Is this surveillance artifact? Is an epidemiologic investigation needed? 3. Develop the case definition and line listing 4. Ascertain cases 5. Determine person, place, and time Host factors (person) Geographic assessment (place) The epidemic curve (time) 6. Develop preliminary hypotheses 7. Evaluate hypotheses Cohort and case-control studies Observational studies Microbiologic studies 8. Implement intervention(s) 9. Evaluate impact of intervention(s)

A. Infection Control Plan and Program Unlike hospitals, most LTCFs do not have substantial resources committed to infection control (10). Every infection control program should have an infection control plan outlining personnel, responsibilities, reporting relationships, and surveillance activities (see also Chapters 8 and 9). Designating a staff member as the “infection control person” is not sufficient; ideally, a trained, experienced ICP should be responsible for the program, either as a staff member at the facility or on a consulting basis. Knowing who is responsible within a facility for conducting surveillance and identifying, investigating, intervening, and reporting an outbreak is critical if the outbreak is to be identified and controlled as early as possible. Finally, establishing an infection control committee with active participation by the LTCF administrator, medical director, ICP, and nursing staff is important not only for support and guidance during an outbreak but for continued vigilance in optimizing infection control prevention efforts to avoid outbreaks. B. Is This Surveillance Artifact? An important first question to ask in a potential outbreak situation is whether the “outbreak” actually represents surveillance artifact (11). Common causes of surveillance artifact include (1) introduction of new infection definitions or surveillance methods; (2) a new ICP or inexperienced infection control staff; (3) new laboratory tests or populations; and (4) change in frequency of microbial cultures. For exam-

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ple, surveillance data may demonstrate a markedly increased rate of pneumonia in LTCF residents. This increase may represent a true outbreak; however, broadening the definition used for pneumonia or increasing the number of residents admitted with severe neurological impairment and frequent aspiration also may increase the rate of pneumonia without representing a true infectious disease outbreak. C. Deciding When to Conduct an Investigation The decision to conduct an epidemiologic investigation may be complicated and is generally driven by three situations: (1) identification of unusual infections or organisms with high potential for morbidity or mortality (e.g., a single case of meningococcal meningitis); (2) identification of organisms or infections that, although relatively common, have high risk for morbidity, mortality, and transmission to other residents (e.g., influenza, Norwalk virus); or (3) identification of epidemiologically important organisms (i.e., several cases of methicillin-resistant Staphylococcus aureus [MRSA] pneumonia). The definition for what constitutes an outbreak depends on the type of infection and, to some extent, the facility. If, for example, a single episode of a highly contagious, potentially lethal infection, such as meningococcal meningitis, is identified in an LTCF resident, an epidemiologic investigation and early, aggressive infection control interventions are necessary. In contrast, knowing when to call a cluster of several LTCF residents with acute respiratory infections or gastroenteritis an outbreak is more difficult. Generally, most authorities suggest that when the rate of infections is significantly higher than baseline endemic rates, an epidemic is occurring and an epidemiologic investigation is warranted (11,12). This definition depends on two factors to be helpful: the LTCF should have a surveillance system in place for detecting infections and calculating and comparing infection rates. More important, the LTCF should have a clinical staff member who understands basic principles of infection control and infectious disease epidemiology and is knowledgeable about changes in the LTCF’s resident population and infection trends in the facility. An important early consideration is whether and when to seek additional outside assistance to assist in the epidemiologic investigation. If the facility has a trained ICP, the initial investigation for most types of infectious disease outbreaks can be conducted and appropriate infection control interventions instituted by the ICP. If the facility lacks an ICP, then the clinical staff member charged with conducting the epidemiologic investigation may wish to seek assistance from an ICP or healthcare epidemiologist, a professional organization such as the Association of Professionals in Infection Control and Epidemiology (APIC) or the Society for Healthcare Epidemiology of America (SHEA), a state or local public health agency, or the Centers for Disease Control and Prevention (CDC). Regulations vary from state to state, but in general, LTCFs are required to report infectious disease outbreaks to local or state public health agencies.

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Table 3 Example of a Line Listing—Influenza Outbreak Case 1 2 3 4 5

Age

Sex

87 90 99 80 90

M F F F M

Ward/Room 4A 3A 2A 2A 2B

401 304 208 208 240

Onset

Cough

Fever

3/01/01 3/02/01 3/02/01 3/03/01 3/05/01

Yes Yes Yes Yes Yes

Yes No Yes No Yes

CXR Culture

Meals

Physical therapy

In room On ward Main dining room Main dining room Main dining room

Yes Yes Yes Yes Yes

Abbreviations: CXR, chest X-ray; M, male; F, female.

D. Case Definition and Line Listing Some challenges to conducting an epidemiologic investigation in an LTCF are unique; however, the basic approach to epidemiologic investigation is the same, whether the investigation occurs in a hospital or LTCF (11,12). The initial step in an investigation is usually a case review. When clinical staff or ICPs note increases in rates of infection, an unusual clustering of infections, or infections with unusual agents, all residents thought to fit in the cluster should be reviewed. The easiest tool for this review is a line listing containing demographic, clinical, and exposure information for each patient (Table 3). As early as possible, investigators should develop a tentative case definition. The case definition should include who, what, where, and when—a description of the infectious disease (what) along with three important parameters: person (who), place (where), time (when). For example, a case definition that could be used in a hypothetical pneumonia outbreak caused by influenza might include (see Table 4): Table 4 Example of a Case Definition—Influenza Outbreak What (Disease)

Person (Population) Place Time

Respiratory illness with at least two of the following symptoms/signs New or increased cough New or increased sputum production Fever (temperature 38°C) Pleuritic chest pain New or increased shortness of breath Respiratory rate 25 breaths per minute Worsening mental or functional status X-ray compatible with pneumonia Positive respiratory tract culture for influenza A Elderly residents Ward B of LTCF A. From January 1 to January 30, 2001

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If necessary, the initial case definition may be modified during the course of the investigation. For example, the above case definition might need to be changed in several ways: the definition of the respiratory illness might be made more general or specific, employees might be added to the population considered, the time frame might be broadened or narrowed, and additional wards in LTCF A might be considered. In general, the case definition should be changed judiciously; each change of the definition will affect the number of cases identified and modify results of comparative studies that are conducted during the course of the investigation. An alternative to changing the case definition completely is to modify the case definition to allow for “definite” cases and “possible/probable” cases. Using the example above, a “definite” case might be a resident with clinical symptoms and a positive respiratory tract culture for influenza A, whereas a “possible” case might be a resident with clinical symptoms but no culture or negative culture results. Although difficult, some attempt should also be made to identify the first case-patient (e.g., index case) especially if the presumed transmission is personto-person. By designating an index case, assumptions important to the investigation, such as incubation period and duration of the outbreak, can be made. As with the case definition, additional cases found during case ascertainment also may lead to a change in the designated index case. E. Case Ascertainment Case ascertainment should be as comprehensive as possible. Multiple sources of information and data are potentially available. Interviews with nursing staff, including nursing assistants, may be a quick way to ascertain cases; however, because many LTCFs experience rapid staff turnover and chronic understaffing, relying solely on what staff can recall may result in incomplete case ascertainment. Microbiology and radiology reports may be helpful, especially if the case definition includes results of these studies. In addition to chart review, existing infection control surveillance records may be helpful, especially in determining the endemic rate of infection. Because most LTCFs have a single pharmacy provider, antimicrobial prescription data may be a potential source to ascertain cases. Finally, medical records for residents transferred to hospitals may be another source for case ascertainment and to evaluate resident outcomes (e.g., death). F. Person, Place, and Time 1. Host Factors (Person) In addition to clearly defining the persons (or populations) affected by the infectious disease outbreak, investigators should review characteristics of case-patients on the line listing to identify specific host factors that may increase risk. The usual

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risk factors to be considered include intrinsic host factors (e.g., age, sex, race, underlying disease, nutritional status) and extrinsic factors (e.g., urinary catheters, feeding tubes, central vascular catheters, environmental exposures, receipt of medications, personnel exposure, food or nutritional product received). 2. Geographic Assessment (Place) Determining the geographic relationship between cases involved in the outbreak may be difficult and is influenced by a number of interrelated factors. Determining whether the cases occurred in a single area of the LTCF is critical. Using a spot map to identify the room of each case is important and usually can be made using a blueprint of the LTCF. Geographic clustering around a single living area may be readily apparent. In contrast, identifying common facilities (e.g., dining rooms, shower/bath facilities) that may be shared by residents from different parts of the LTCF may be both more subtle, yet more productive in some outbreak investigations in which a geographic pattern is not readily apparent. If the outbreak is believed to be due to an airborne or water borne organism, reviewing ventilation or plumbing diagrams may be helpful. 3. The Epidemic Curve (Time) The epidemic curve is a simple graphical tool using information from the line listing to display the time relationship of cases in the outbreak. Epidemic curves generally display time on the horizontal axis and number of cases on the vertical axis. Epidemic curves have some important features; first, the time axis should be shorter than the presumed incubation period of the infection. Secondly, the time period should include both the pre-epidemic (e.g., time before the index case) and epidemic periods. The shape of the epidemic curve is important. An abrupt rise in cases is suggestive of a point source for the outbreak (e.g., contaminated product or food). A more prolonged series of cases suggests person-to-person transmission. On some occasions, the epidemic curve may have features of both modes of transmission, suggesting that transmission may be occurring by several routes. G. Preliminary Hypotheses Once an initial set of cases is identified, an attempt should be made to generate hypotheses about what may be causing the outbreak. Sometimes, with a distinct cluster in time and space and an obvious source, quick action can be taken. More often, several potential sources and modes of transmission may be suggested by the preliminary data. At a minimum, hypotheses about the potential sources and the potential mode of transmission are needed to properly design comparative studies (described below). Once hypotheses are developed, comparative studies can be

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designed and used to test the hypotheses, with the aim of identifying the most likely causative factors for the outbreak. H. Studies 1. Cohort and Case-Control Studies Two types of comparative studies are generally used in outbreak investigations to identify risk factors for the outbreak: cohort or case-control studies (11,13). In cohort studies, all members of a defined population (i.e., cohort) are evaluated. The data can be collected retrospectively or prospectively. In cohort studies, relative risk, a quantitative measure of the strength of association between the exposure and the risk of developing the adverse condition, can be calculated; this quantitates the strength of association between the presumed exposure and the event. The primary advantage of cohort studies is that the whole population is assessed; bias through the process of selecting controls is not introduced. The primary drawbacks to the cohort design are that the appropriate population may not be defined, and cohort studies require significantly more resources to complete, especially if the frequency of cases is low. In case-control studies, known cases are compared to selected control residents. Selecting appropriate controls is important. It usually is advisable to randomly select controls from the population affected. Confounding may be a concern and can be controlled by using stratification or multivariate analyses. In some case-control studies, cases and controls may be “matched” on a particular characteristic, especially if a particular group of residents appears to be at significantly greater risk (e.g., only females are affected or only individuals in a particular wing of the LTCF). However, variables on which controls are matched cannot then be analyzed as risk factors. The advantage of case-control studies is that, especially with low frequency events or outbreaks occurring over a long period, the resources needed to collect data (e.g., chart reviews, microbiologic reviews, etc.) will be less than with a cohort study. In case-control studies, odds ratios are calculated and represent approximations of relative risk. Odds ratios indicate whether cases are more likely to have been exposed to a risk factor than controls. 2. Observational Studies Often, outbreaks may involve suboptimal compliance by healthcare workers with facility policies and procedures (i.e., hand hygiene, food preparation, sanitation) (11). Observational studies in which ICPs actually observe compliance with these procedures may be an important part of the overall epidemiologic/investigation. Before observation, infection control personnel should review policies and procedures with administrative personnel and identify changes or modifications that have occurred. The actual observations should occur for short periods (i.e., 1 hour)

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on all shifts and in locations where both case- and non-case patients reside, especially if within a facility there are areas of high attack rate and other areas with few or no cases. It is important that observers have a clear understanding of what constitutes the indication for a particular procedure and what constitutes failure to comply. For example, in an observational study on hand hygiene, the observer must know if hand hygiene is expected to occur before a patient encounter, before the healthcare worker leaves the patient room, or before another resident or patient care device is touched. 3. Microbiologic/Studies In outbreak investigations, microbiologic studies should be based on epidemiologic/findings. In addition to identification of bacteria or viruses from case-patient clinical specimens, several potential microbiologic studies may be considered, depending on epidemiologic results. First, in outbreaks where colonization may play an important role (e.g., antimicrobial-resistant bacteria), culture surveys of residents or healthcare workers may be useful. Important considerations include determining the best methods for culture collection, planning for the number of cultures or site of cultures, laboratory support for rapid processing of specimens, consistency of obtaining specimens, and appropriate record-keeping to correctly identify the resident or healthcare worker, site of culture, and type of specimen. Environmental cultures alone should be considered in situations in which the presumed pathogen and the epidemiologic findings suggest an environmental source. Widespread culturing of residents, healthcare workers, or environment before the epidemiologic investigation is not recommended and may often lead to erroneous conclusions about the outbreak. Furthermore, such widespread culturing is burdensome on personnel, costly and, often in the absence of epidemiologic direction, fails to identify the outbreak source. I. Implementing Interventions Once risk factors and potential sources are identified, interventions to terminate the outbreak should be instituted. These interventions must be fully discussed with the LTCF administrator, nursing director, medical director, and healthcare staff. Implementation of the interventions depends on support and acceptance by the staff. Especially in large, explosive outbreaks, some interventions, such as cohorting infected and colonized residents, institution of facility-wide vaccination of residents or healthcare workers, or increased glove use may be easily understood and accepted by staff. However, in longer duration, lower intensity outbreaks, acceptance may be suboptimal for interventions (e.g., improved compliance with hand hygiene, changes in food preparation policies, etc.), and more focus on education and training may be necessary. In these situations, incorporating ongoing

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process measurement of the intervention (e.g., observational study of hand hygiene among nursing assistants) with feedback periodically to staff may help to increase compliance with the intervention.

V. SELECTED INFECTIOUS DISEASE OUTBREAKS Examples of the more common types of infectious disease outbreaks that occur in LTCFs are presented below. The reader should also refer to other chapters devoted to these specific infections. A. Respiratory Tract Infections Outbreaks of respiratory tract disease in LTCFs are relatively common. In a recent report from five Canadian LTCFs, 16 outbreaks involving 480 of 1,313 residents were reported, occurring year-round with no seasonal predilection (14). The most common symptoms among residents during these outbreaks were cough (83%), fever (40%), and coryza (45%), and a minority (15%) of residents developed pneumonia. The most common pathogens included influenza, parainfluenza, or respiratory syncytial viruses; Legionella spp; or Chlamydia pneumoniae. Approximately 12% of residents were transferred to hospitals and 8% died. 1. Influenza The most important cause of respiratory tract disease outbreaks in LTCFs is influenza (see Chapter 13). Outbreaks of influenza A or B usually occur from early October to April but may sometimes extend into summer. Of the 20,000 deaths from influenza each year, 90% occur in persons aged 65 and older (15). Recent reports exemplify important aspects of influenza in LTCFs. In a report of an outbreak of influenza A affecting 68 residents, the LTCF had four separate buildings, one of which was newly constructed (16). Interestingly, the attack rate in the new building was significantly lower than the other buildings. Key differences in the new building included: (1) a ventilation system that did not recirculate air, (2) more public space per resident, and (3) no office space in the building serving the entire facility. Even widespread use of immunization, the cornerstone of influenza prevention, may be insufficient to prevent some LTCF outbreaks (see Chapter 20). In an LTCF with high rates ( 85%) of resident influenza vaccination, outbreaks involving 172 residents were reported despite a match between the vaccine strain and outbreak strain (17). Especially in older residents, influenza vaccine effectiveness may be diminished, increasing the risk for influenza outbreaks (18). These failures may be secondary to poor immunologic response to the vaccine in this elderly population. When influenza outbreaks do occur, chemoprophylaxis

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with antiviral agents such as amantadine, rimantidine, zanamivir, or oseltamivir should be considered in order to minimize morbidity and mortality (see Chapter 13). Prophylaxis should be given for 14 days or until 7 days after the onset of the last confirmed influenza infection in residents or staff (19). A recent review provides excellent detail on the use of specific antivirals for influenza prophylaxis (20). In a recent LTCF outbreak of amantidine-resistant influenza A, acceptance of inhaled zanamivir for chemoprophylaxis was high (92%), although 22% of the 128 treated residents had difficulty with the inhalations; this was especially true among residents who were fully dependent for activities of daily living (58%) (21). In the 2 weeks after chemoprophylaxis, no new infections occurred and no side effects were identified among zanamivir-treated residents. 2. Other Respiratory Viruses In addition to influenza, infections with parainfluenza virus, respiratory syncytial virus (RSV), adenoviruses, and rhinoviruses can cause respiratory tract disease in LTCF residents (see Chapter 13). Parainfluenza virus type 3 was associated with an outbreak of respiratory disease on a 50-bed nursing unit of a large Wisconsin LTCF. The attack rate was 50% and resulted in 16% mortality within 9 days of symptom onset (22). In contrast, a study of 30-day mortality suggested that noninfluenza viruses have lower mortality than influenza viruses, with mortality ranging from 6.1% (influenza B) and 5.4% (influenza A) to virtually nil for Respiratory Syncytial Virus (RSV) and rhinoviruses (23). The key observations from reports on respiratory tract outbreaks are that early identification of the infectious agents, institution of appropriate treatment or prophylaxis, and aggressive use of infection precautions, especially isolation of residents and improved healthcare worker compliance with hand hygiene recommendations, are critical to minimize serious morbidity and deaths. 3. Streptococcus pneumoniae Although not a common cause of outbreaks in LTCFs, Streptococcus pneumoniae is the most common pathogen identified in endemic respiratory tract disease in LTCF residents, is an important cause of invasive disease, and is increasingly resistant to antimicrobials. In a recent review of 26 S. pneumoniae outbreaks since 1990, the majority occurred in elderly patients in LTCFs or hospitals (24). The most common serotypes identified in these outbreaks were 23F, 14, and 4, all of which are included in current formulations of the pneumococcal vaccine. Recent outbreaks of S. pneumoniae pneumonia and bacteremia in Oklahoma, Massachusetts, and Maryland LTCFs were associated with low pneumococcal vaccination rates (25,26) (see Chapter 20). An LTCF outbreak of S. pneumoniae pneumonia in Massachusetts was associated with a 20% case-fatality rate. Antecedent infection with human parainfluenza virus was associated with increased risk of S. pneumoniae infection (27).

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4. Legionnaire’s Disease Legionnaire’s disease, caused by Legionella pneumophilia, remains an important consideration during respiratory tract disease outbreaks. Outbreaks in both LTCFs and hospitals are generally associated with contaminated water systems. Several reports of persistence of L. pneumophilia in hospital water systems despite the use of various interventions have been published (28–30). An outbreak of Legionnaire’s disease caused by L. pneumophila serogroup 1 in a new LTCF illustrates that water system contamination can occur quickly and lead to outbreaks of Legionnaire’s disease (31). To identify these outbreaks earlier, clinicians and ICPs should maintain a high index of suspicion for Legionnaires’s disease and obtain the proper laboratory support for microbiologic testing to identify L. pneumophila. B. Gastrointestinal Infections Outbreaks of gastroenteritis and diarrhea in LTCFs are common and commonly include Eschericia coli, Salmonella spp., or enteric viruses (see Chapter 18). The usual mode of transmission for these outbreaks is foodborne or person-to-person transmission. In a 250-bed LTCF in Tennessee, 14% of residents developed gastronenteritis due to Salmonella hadar (32). Among the 244 healthcare workers, the attack rate was 27% in laundry workers, but only 3% in nursing staff and 4% in kitchen staff. The index case was probably a member of the kitchen staff, but the high attack rate among the laundry staff was probably secondary to inconsistent use of gloves and lack of protective clothing while handling increased volumes of soiled linen during the outbreak. In an Australian LTCF, 25 residents developed gastroenteritis caused by Clostridium perfringens contamination of pureed food (33). Apparently, once food was liquified, it was not reheated and subsequently became contaminated. Consequently, the authors recommended that pureed food be reheated to 70°C to inactivate potential contaminating pathogens before consumption. Outbreaks caused by viruses occur frequently in LTCFs. In Virginia LTCFs during 1 year, caliciviruses, including the Snow Mountain Agent, and other small round structured viruses, were responsible for eight different reported outbreaks (34). In a Maryland LTCF with 121 residents, 51% of residents and 47% of the staff developed gastroenteritis because of a small, round-structured virus over a 4month period (35). The index case in the outbreak was a nurse who continued to work for 2 additional days after becoming ill. The outbreak illustrates the need to exclude ill employees in a timely fashion by providing sick leave and not expecting staff to take annual or vacation leave for illnesses. A Norwalk-like virus was responsible for an outbreak of gastroenteritis in a Washington LTCF. Among 91 residents, the majority (57%) developed acute gas-

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troenteritis after exposure to an ill LTCF resident, the index case (36). In the residents, prominent symptoms included vomiting (90%), diarrhea (70%), and fever (12%). Four residents required hospitalization and three died. Many healthcare workers (35%) also developed gastroenteritis. Based on molecular typing, the outbreak appeared to be among debilitated residents and the nurses caring for them, implying that it was propagated through LTCF staff rather than ambulatory residents. Cohorting of ill patients and strict adherence to infection control practices, such as hand hygiene, glove use, and barrier precautions, stopped the outbreak. C. Skin Infections Previous LTCF skin infection outbreaks include Streptococcus pyogenes-associated cellulitis, Pseudomonas aeruginosa associated with a contaminated whirlpool bath, group A Streptococcus, or antimicrobial-resistant organisms causing infections of pressure ulcers (6,37,38). Scabies is an important parasitic skin infection that not infrequently causes outbreaks in LTCFs (see Chapter 17). Transmission of scabies may occur by contact with mite-contaminated inanimate objects (e.g., bed linens) or direct person-to-person contact. Outbreaks of scabies in three Norwegian LTCFs lasted 5 months and involved 27 patients or healthcare workers (39). Initial treatments with permethrin were not successful; however, benzyl benzoate was effective. Ultimately, more than 600 residents and staff were treated. A key observation from these outbreaks was the need for simultaneous treatment of residents and staff and disinfection of bedding, clothing, and the environment. In France, oral ivermectin was used along with disinfection to successfully control an outbreak of scabies in 42 affected residents of a 128-bed LTCF (40). Ivermectin is not approved for use for scabies treatment in humans in the United States; however, this report illustrates a potentially useful oral therapy for scabies mass treatment. As with other outbreaks, early identification is optimal for management of scabies outbreaks and may occasionally require dermatological consultation or skin biopsy for diagnosis. D. Infections with Antimicrobial-Resistant Organisms (see Chapters 21 through 25) Recent reports suggest that antimicrobial-resistant pathogen outbreaks affect the elderly in both hospitals and LTCFs (6,41). Important antimicrobial-resistant pathogens include (MRSA); multiply resistant gram-negative bacilli such as E. coli, Acinetobacter, Enterobacter, or Pseudomonas aeruginosa; or vancomycinresistant Enterococcus (VRE) (42,43). Widespread colonization of residents in LTCFs with antimicrobial-resistant organisms provides a potential reservoir for subsequent transmission and outbreaks. In Chicago, a city-wide outbreak of multidrug-resistant Klebsiella pneumoniae and E. coli demonstrated that LTCFs were

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important reservoirs for antimicrobial-resistant organisms (41). Furthermore, in a single Chicago skilled nursing facility, 43% of residents were colonized with at least one antimicrobial-resistant organism (44). Recent studies have demonstrated success in reducing VRE colonization or infection and may offer important intervention strategies for the future (45,46). These studies have documented the importance of resident screening, isolation, healthcare worker hand hygiene, and decreased inappropriate antimicrobial use. In addition to cross-transmission, widespread antimicrobial use is a potential risk factor for the development of antimicrobial resistance within LTCFs. In Maryland, 8% of LTCF residents were documented to be receiving antimicrobial therapy at a given time, and over a year, 54% of residents received at least one course of antimicrobial therapy (47). In four New York LTCFs, the percentage of resident-days during which antimicrobials were given ranged from 2.7% to 6.8% (48). In a Veterans Affairs LTCF, the majority (54%) of resident febrile episodes resulted in the initiation of antimicrobial therapy, with upper respiratory tract illnesses, bronchitis/pneumonia, or urinary tract infections accounting for the majority of indications (49). After diagnostic evaluation, 39% of residents continued to receive antimicrobials despite negative laboratory and radiographic studies for bacterial infections. In general, previous studies have found substantial inappropriate use of antimicrobials in LTCF residents, ranging from 25% to 75% (50). Inappropriate antibiotic use adds to patient care costs, may place the patient at risk for adverse medication reactions, and increases the risk of colonization or infections with antimicrobial-resistant organisms (48,50).

VI. PREVENTION AND CONTROL OF OUTBREAKS The primary means to prevent and control infectious disease outbreaks in LTCFs include a well-organized infection control program, the timely use of recommended immunizations, and prudent use of antimicrobials (see also Chapters 8 and 9). A. Infection Control Several reviews, guidelines and position statements for infection control in LTCFs have been published previously (51–53). In addition, guidelines from CDC for many aspects of infection control are available through the internet (www.cdc. gov/ncidod/hip). The key components of a well-organized infection control program in LTCFs include: (1) an infection control professional (ICP) to head the program, (2) an infection control committee, (3) a written infection control plan, and (4) sufficient administrative support to undertake core infection control functions.

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The two most important aspects of an LTCF infection control program are that the ICP is trained in infection control and that the LTCF administrator provides support and resources for the program. In a survey of LTCFs in the northeastern United States, most ICPs were registered nurses (90%) who performed infection control duties on a partime basis (median 8 hours per week) (10). However, only half (52%) had formal training in infection control and most had additional clinical or administrative nursing duties. These sobering statistics point out the difficulty encountered in obtaining significant resources for LTCF infection control. However, the second component of the program, an infection control committee, can be instrumental in assisting the ICP in developing the infection control program. In smaller LTCFs, the committee may consist of the ICP, nursing director, medical director, and administrator. In larger LTCFs, the infection control committee also might include consultant pharmacists, an infectious disease expert, representatives from physical therapy or rehabilitation, and environmental services. The limited availability of diagnostic studies in LTCFs is a particular challenge for managing infectious disease outbreaks (4). Diagnostic studies, such as microbiology cultures, routine chemistry and hematologic tests, and radiologic studies seldom are available. Isolation facilities often are not available and may necessitate resident transfer to acute care facilities (4). Access to expert infectious disease consultation may be limited. Long-term care facility ICPs faced with an outbreak, but who have resource and expertise limitations, should seek assistance from their local and state health departments in a timely fashion. In addition, the formation of teams including both geriatric clinicians, ICPs, and nursing staff may be especially beneficial in outbreak management (54). Another important resource during outbreaks is the consultant pharmacist. During an influenza outbreak in a 570-bed nursing home facility, pharmacists assumed responsibility for educating families and patients about amantadine prophylaxis, providing individualized dosing, monitoring and evaluating adverse events, and handling drug distribution (55). Overall, acceptance of chemoprophylaxis was high (91%) and most of the 22 adverse reactions were resolved through dose reduction as opposed to drug discontinuation. B. Immunization Currently, LTCF residents should have yearly influenza vaccination and pneumococcal vaccination once after age 64 (56,57) (see Chapter 20). Overall vaccination rates among LTCF residents for influenza vaccine (64%) and pneumococcal vaccine (28%) are suboptimal and many LTCFs have inadequate policies addressing routine vaccination (58). To diminish the likelihood of an influenza outbreak, LTCFs should develop an active immunization program. The components of a well-organized immunization program include defining the facility’s policy on immunization, developing an implementation manual, training staff members in-

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cluding physicians on the plan, collecting and recording baseline vaccination rates for current residents, and then initiating vaccination of both current residents and new arrivals (16). To monitor for outbreaks and institute timely control measures, LTCF infection control personnel should include suveillance for acute febrile respiratory tract illnesses. Furthermore, LTCF personnel should develop the surveillance system in conjunction with local and state health departments to enhance communication and ensure compliance with public health requirements (16). Recently, implementation of standing orders for influenza and pneumococcal vaccination in LTCFs has been proposed as an effective intervention to increase vaccination rates (58). C. Antimicrobial Use and Isolation Precautions Antimicrobials are used frequently in LTCF residents and their use usually is initiated by telephone order. To minimize inappropriate antimicrobial use, recent recommendations include (1) monitoring clinicians’ use of antimicrobials, (2) establishing a formal antimicrobial review program, and (3) developing facility-specific antimicrobial use guidelines (50). Whether these interventions will reduce outbreaks with antimicrobial-resistant organisms remains to be proven (see Chapter 11). Transmission-based isolation precautions are recommended, effective, and widely used in hospitalized patients who are colonized or infected with selected antimicrobial-resistant organisms (59). Consistent national guidelines for the use of isolation precautions in LTCF residents with infections caused by antimicrobial-resistant organisms do not currently exist. Strict isolation and use of barrier precautions in colonized LTCF residents have not been shown to consistently reduce infections from antimicrobial-resistant organisms; however, glove use and good hand hygiene have been shown to be effective (52). Often with bed-bound residents, healthcare workers are the usual vectors for transmission of pathogens. Because good hand hygiene is vital to reduce cross-transmission, LTCFs should consider the use of newly developed, waterless, alcohol-based hand hygiene agents to promote hand hygiene. Decisions about isolation of LTCF residents colonized or infected with antimicrobial-resistant organisms must be considered on an individual resident and facility basis and must incorporate both an assessment of risk for cross-transmission and the impact on the resident’s social and psychological health (51–53).

VII.

CONCLUSIONS

Infectious disease outbreaks in LTCFs are an important public health concern, can result in serious illnesses and death in LTCF residents, and can be disruptive to

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LTCF staff. Most outbreaks are, at least in theory, preventable. The major patient risk factors include chronic illnesses, incontinence, and poor respiratory function. These risk factors may not be amenable to interventions. However, institutions can attempt to prevent outbreaks by ensuring residents receive appropriate immunizations, promote judicious use of antimicrobials, and ensure that the LTCF has a well-staffed and organized infection control program. Once infectious disease outbreaks occur, epidemiologic investigation of the outbreak should proceed quickly. The key components of the investigation should include developing a case definition, compiling a line listing of known case-patients, conducting additional case ascertainment, constructing an epidemic curve and geographic plots, and developing working hypotheses as to the source, mode of transmission, and possible organisms. The types of studies (e.g., case-control, cohort, observational, microbiologic) performed will depend on the available resources. Interventions to terminate the outbreak should be consistent with epidemiologic findings and be effectively communicated to administrators, staff, and public health officials. Over the next several decades, the population of elderly LTCF residents will grow dramatically; resources for infection control programs and outbreak prevention in the LTCF will be an important investment toward improving the quality of care in this increasingly important healthcare setting.

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11 An Approach to Antimicrobial Therapy Shobita Rajagopalan Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California

Jay P. Rho University of Southern California University Hospital, Los Angeles, California

Thomas T. Yoshikawa Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California

I. GENERAL ISSUES OF ANTIMICROBIAL THERAPY A. Clinical Relevance The overall approach to antimicrobial chemotherapy remains an important topic of practical and clinical significance. Antimicrobial agents are among the most widely prescribed drugs in long-term care facilities (LTCFs). An estimated one fifth of all LTCF residents receive an antimicrobial agent at any given time. Antimicrobial usage may seem disproportionately low compared to the 1.5 million infections observed in the long-term care setting annually (1), but indiscriminate prescribing of antimicrobial agents with lack of adequate documentation of infection, potential adverse drug reactions, and emergence of antimicrobial resistance are major concerns (2). Clinicians must thus exercise caution in their approach to antimicrobial prescription; vulnerable populations, for example elderly persons residing in LTCFs, need particular consideration because of the additional increased morbidity and mortality associated with age-related decline in immune function, debility, and comorbid illnesses (diabetes mellitus, cerebrovascular accidents, alcoholism, malnutrition, etc.). There should be a rational approach to an155

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timicrobial prescribing in residents of LTCFs, with focus on age-related physiologic, pharmacokinetic, and pharmacodynamic changes that can affect the selection and dosing of such chemotherapeutic agents. B. Assessment of Antimicrobial Use in LTCFs Significant data evaluating the appropriateness of the therapeutic utility of antimicrobial agents in LTCFs suggest that a substantial proportion of antibiotic treatments are often initiated in the absence of important diagnostic information, such as the presence of fever, leukocytosis, or culture information (3–5). One study surveying 42 nursing homes and 11 affiliated intermediate care facilities suggested that systemic antibiotics were initiated in 62.4% of cases with inadequate initial diagnostic evaluation (6). Another study that included 3,899 residents from 52 nursing homes indicated that 22% of all antibiotics prescribed were unnecessary, that is, viral upper respiratory infection and asymptomatic bacteriuria (4). A similar study that focused on the usage pattern of a specific antibiotic, ciprofloxacin, in a long-term care setting found that only 25% of orders for that agent were appropriate and 23% were prescribed for inappropriate indications; 49% were considered inappropriate because of more effective and/or less expensive available alternatives (7). One study demonstrated that antibiotic prescribing for 282 elderly residents of an LTCF who received an antibiotic for a presumed urinary tract infection was inappropriate in 40% of cases; 222 (78.7%) cases, however, showed clinical improvement (8). Using a Medication Appropriateness Index (MAI) (9) to measure appropriateness of antibiotic prescribing, 113 antibiotics orders (39.7%) were considered inappropriate. The three antibiotics most often inappropriately prescribed were ciprofloxacin (too expensive), trimethoprim-sulfamethoxazole (TMP-SMX) (incorrect duration), and nitrofurantoin (improper dosage). In addition, inappropriate prescribing accounted for an additional $560 per day in treatment costs.

II. OPTIMIZING THE USE OF ANTIMICROBIAL AGENTS IN THE LTCF The optimal use of antimicrobials in LTCFs remains problematic largely because of a delay in the diagnosis and initiation of appropriate treatment of infections. Typical manifestations of infection, such as fever, may be absent or blunted in many elderly patients with serious or life-threatening infections (10,11) (see Chapter 6). Limited availability of laboratory and radiological data may, in addition, preclude a precise diagnosis. General principles for initiating antimicrobial therapy are described in Table 1.

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Table 1 Approach to Antimicrobial Prescribing in Long-Term Care Facilities 1. Not all clinical or functional changes in LTCFs residents should be attributed to infections. 2. Antibiotics should be administered only when there is potential clinical benefit. For example, studies have clearly shown that both men and woman residing in LTCFs derive no benefit from treatment of asymptomatic bacteriuria. 3. Chronic suppressive therapy with antibiotics or antimicrobial chemoprophylaxis should be restricted unless there is documented evidence of clinical efficacy and therapeutic benefit. 4. Continuation of antibiotic therapy beyond standard recommended periods should be discouraged. For example, catheter-related urosepsis should be treated until clinical sepsis is improved but should not be continued in an attempt to maintain sterile urine. 5. In circumstances in which a specific pathogen is isolated and antibiotic sensitivity studies are available, the initial broad-spectrum antibiotic should be changed to a more narrowspectrum agent, if the organism is susceptible to such an agent. Abbreviation: LTCF, long-term care facility.

A. Minimum Criteria for Initiation of Antibiotics Minimum criteria for initiating systemic antibiotics for bacterial infections have been proposed by a consensus group of physicians, geriatricians, microbiologists, and epidemiologists (12). These criteria were developed to provide guidelines for the appropriate initiation of empiric antibiotics in clinically stable LTCF residents; critically ill patients with sepsis or sepsis syndrome necessitating transfer to an acute care facility were not included. Empirical regimens for common infections found in LTCF residents such as skin and soft-tissue infections, respiratory infections, and urinary infections, as well as fever of unknown origin were outlined (Table 2). Other potential infections, such as intravenous catheter-related infections or infections of mucous membranes and conjunctivae; topical antibiotic use; use of antiviral and antifungal agents; prophylactic antibiotics; and chronic suppressive antibiotics were not addressed. Prospective assessment of these guidelines for appropriate antibiotic use has not been analyzed. B. Empirical Antimicrobial Therapy An empirical antimicrobial regimen should be directed against the most likely pathogens and able to achieve the desired therapeutic concentrations at the suspected site of infection. The choice of a specific empirical antimicrobial regimen should be based on the severity of the patient’s illness, the nature of underlying diseases, prior exposures to antimicrobials, and history of drug allergies. The Society of Healthcare Epidemiology of America (SHEA) has published a position paper on antimicrobial use in LTCFs that provides recommendations for empiri-

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Table 2 Minimum Criteria for Initiation of Antimicrobials in Long-Term Care Facilities Skin and soft tissue infections Either new or increasing purulent drainage at a wound, skin, or soft tissue site, or at least two of the following: 1. Fever (temperature 37.9°C [100°F] or and increase of 1.5°C [2.4°F] above baseline temperatures taken at any site 2. Redness 3. Tenderness 4. Warmth 5. Swelling that was new or increasing at the affected site Respiratory infections 1. If the resident is febrile with a temperature 38.9°C [102°F], at least one of the following: (1) respiratory rate 25 breaths per minute (2) productive cough 2. If the resident has a temperature 37.9°C [100°F] or 1.5°C [2.4°F], increase above baseline temperature, minimum criteria for initiating antibiotics requires presence of cough and at least one of the following: (1) pulse 100/minute (2) delirium (3) rigors (shaking chills) (4) respiratory rate 25/minute 3. For afebrile residents known to have COPD, classified as high-risk because of age 65, minimum criteria for initiating antibiotics for a suspected respiratory infection include a new or increased cough with purulent sputum production. 4. For afebrile residents who do have COPD, minimum criteria for initiating antibiotics include a new cough with purulent sputum production and a least one of the following: (1) respiratory rate 25 breaths per minute (2) delirium Urinary tract infection 1. For residents who do not have an indwelling catheter, minimum criteria for initiating antibiotics include acute dysuria alone or fever ( 37.9°C [100°F] or 1.5°C [2.4°F] increase above baseline temperature) and at least one of the following: (1) new or worsening urgency (2) frequency (3) suprapubic pain (4) gross hematuria (5) costovertebral angle tenderness (6) urinary incontinence

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Table 2 (Continued) 2. For residents who have a chronic indwelling catheter (either an indwelling Foley catheter or a suprapubic catheter), minimum criteria for initiating antibiotics include the presence of at least one of the following: (1) fever (37.9°C [100°] or 1.5°C [2.4°F] increase above baseline temperature) (2) new costovertebral tenderness (3) rigors (shaking chills) with or without identified cause (4) new onset of delirium Fever in which the focus of infection is unknown Presence of fever ( 37.9°C [100°F] or 1.5°C [2.4°F] increase above baseline and at least one of the following: (1) new onset of delirium (2) rigors Abbreviation: COPD, chronic obstructive pulmonary disease. Source: Ref. 12.

cal antimicrobial therapy for the most frequent types of infections in nursing home residents including upper and lower respiratory tract infections, urinary tract infections, skin and soft-tissue infections, urinary tract infection, skin and soft-tissue infections, diarrhea, and fever of unknown origin (13) (Table 3). (See also specific chapters on each of these infections). The common cold, pharyngitis, and sinus infections are the most frequent infections of the upper respiratory tract. Because the vast majority of upper respiratory tract infections are viral in etiology, empirical antibiotic therapy is seldom indicated. However, if a throat culture or a reliable streptococcal screening test documents the presence of group A streptococci, penicillin would be the drug of choice. For acute bacterial sinusitis, first-line therapy includes any of the following antibiotics: trimethoprim-sulfamethoxazole, amoxicillin, and cefuroxime axetil. The selection of amoxicillin-clavulanic acid for acute bacterial sinusitis should be reserved for patients who respond poorly to treatment with one of the first-line antibiotics. C. Antimicrobial Utilization Review Promoting the optimal use of antimicrobials in LTCFs requires diligent antimicrobial utilization review. Surveillance and control activities are the major foci of these programs. Antimicrobial utilization is logically within the purview of the infection control program. Infection control programs traditionally have advocated education, isolation techniques, and hand washing to control nosocomial infections; however, they now are beginning to address problems of antimicrobial use. A recent survey found that more than one half of LTCFs had an antimicrobial utilization program (14).

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Table 3 Empirical Antimicrobial Therapy for Common Infections Clinical syndrome Upper respiratory infection Coryza/common cold Pharyngitis Sinus infection

Lower respiratory infection Acute bronchitis Acute exacerbation of chronic bronchitis Pneumonia

Urinary tract infection Skin/soft tissue Cellulitis Infected pressure ulcer*

Candidiasis Diarrhea Clostridium difficile Salmonella, Shigella Escherichia coli O157:H7

Empiric antimicrobial None None; treat only if group A Streptococcus TMP-SMX amoxicillin, cefuroxime axetil, macrolide; second line: amoxicillin-clavulanic acid, quinolone Most cases viral, no antibiotics indicated Amoxicillin, TMP-SMX, doxycycline TMP-SMX, amoxicillin, cefuroxime axetil, macrolide, doxycycline; second line: amoxicillin-clavulanic acid, quinolone, clindamycin (aspiration pneumonia) TMP-SMX, quinolone, aminoglycoside (parenteral) Dicloxacillin: second line: cephalexin, clindamycin Metronidazole or clindamycin and TMP-SMX or quinolone; amoxicillin-clavulanic acid Topical antifungal Metronidazole TMP-SMX, quinolone None

Abbreviation: TMP-SMX, trimethoprim-sulfamethoxazole. * May require surgical debridement; if severe systemic symptoms, initial parenteral therapy should be considered. Source: Ref. 12.

D. Adverse Drug Events Approximately 350,000 adverse drug events, 20,000 of which are fatal, occur each year among the 1.5 million residents of LTCFs in the United States (15). Studies that have evaluated the patterns and quality of medication prescribing in nursing homes (15,16) have found antimicrobials to be among the most frequently implicated drugs in causing adverse drug events. In a study of 18 community-based nursing homes located in eastern Massachusetts encompassing 28,839 nursing home resident-months, 546 adverse drug events (1.89 per 100 resident-months)

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and 188 potential adverse drug events (0.65 per 100 resident-months) were identified (15). Overall, 51% of the adverse drug events were judged to be preventable, including 171 (72%) of the 238 fatal, life-threatening, or serious events and 105 (34%) of the 308 significant events. Antibiotics were associated with 36% of nonpreventable adverse drug events, but fewer than 5% of the adverse drug events were considered preventable. The majority of adverse drug events associated with antibiotics were rashes and confirmed Clostridium difficile diarrhea. Clinicians should be aware that adverse drug events occur more frequently in frail elderly and, therefore, a systematic examination of adverse events to identify risk factors should be undertaken. E. Cost of Inappropriate Use of Antimicrobial Agents The consequences of inappropriate use (or overuse and misuse) of anti-infective agents and resultant financial implications include exposing patients to the potential risk of adverse drug reactions, selection of resistant bacteria, and high rates of nosocomial infections—all of which will increase healthcare costs (17,18). The total cost of inappropriate prescribing of antimicrobials can only be grossly estimated. These agents are among the most costly of all drugs prescribed in the United States, accounting for sales between $3 to 4 billion (18). If a quarter of all prescriptions for anti-infective agents are considered inappropriate for various reasons, this could account for an additional annual cost to the healthcare system of $1 billion. Further, the increased costs of treating adverse drug reactions, infections, and their complications resulting from drug resistance also have to be considered. Because the geriatric population is becoming the highest user of healthcare services and the largest consumers of drugs, it is essential that a rational approach to prescribing drugs for the elderly, including antimicrobial agents, be emphasized.

III. DRUG FACTORS TO CONSIDER IN PRESCRIBING ANTIMICROBIAL THERAPY Once an antimicrobial agent is selected on the basis of known or anticipated activity against the pathogen(s), the goal of therapy is to deliver that drug to the site of infection in concentrations sufficient to inhibit or kill the organism(s). Most serious infections require antibiotic concentrations to exceed the minimum inhibitory concentration (MIC) of the infecting organism at the site of infection. Some drugs, such as aminoglycosides and fluoroquinolones, exhibit concentration-dependent antimicrobial effects, with high drug concentrations exerting more rapid bactericidal action and longer post antibiotic effects (PAE) than lower concentrations. The elderly undergo age-related physiologic changes that directly influence the dispo-

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sition and efficacy of various antimicrobial agents (19). The progressive decrease in the ability of vital organ systems of the elderly to maintain homeostasis can lead to alterations in drug clearance and drug receptor sensitivity. A. Pharmacokinetics Pharmacokinetics describes the fundamental mechanics of drug movement through the body over time, including factors that describe the absorption, distribution, metabolism, and elimination, or the overall fate of a drug in vivo (20). A summary of age-related physiological changes are shown in Table 4 (20,21). 1. Absorption Age-related changes in the gastrointestinal tract may influence drug absorption. A decrease in gastric acid secretion and an increase in gastric pH are associated with the aging process. The absorption of antimicrobials that are dependent on increased acidity (e.g., sulfonamides, ketoconazole) may be decreased, whereas drugs that are degraded in an acidic environment will have greater bioavailability. The significance of these changes is generally minimal and rarely affects dosing requirements. 2. Distribution Age-related changes that can affect the distribution of drugs include changes in body composition and cardiac output. In the elderly, the ratio of body fat to total Table 4 Physiological Changes Associated with Aging Pharmacokinetic parameter Absorption

Distribution

Elimination

↓ decrease activity or function. ↑ increase activity or function. ↑↓ no increase or decrease activity or function.

Physiological change with aging ↓Gastric emptying ↓Gastric acidity ↓Gastrointestinal motility ↓Absorptive surface ↓Lean body mass ↑Body fat ↑Serum 1-acid glycoprotein ↑↓Enzyme activity ↓Hepatic (liver) blood flow ↓Renal (kidney) blood flow ↓Glomerular filtration rate ↓Tubular secretion

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body water is increased compared with younger individuals. A decrease in lean body mass, coupled with a decrease in total body water, is associated with a decreased volume of distribution for water-soluble drugs. Thus, with older adults, antimicrobials that are distributed primarily in body water or lean mass may have higher blood concentrations than in younger adults, which can lead to potential toxicity. Conversely, in the elderly, lipid-soluble drugs have a greater body fat distribution, which may reduce blood concentrations and lead to potential subtherapeutic blood concentrations. 3. Metabolism Age appears to have no effect on the functional activity of various cytochrome P450 isoenzymes either in terms of in vitro protein content, immunohistochemical content, or in vivo enzyme activity for older patients as compared to younger patients. 4. Clearance Age-related changes in renal function are probably the most significant contributors to alteration in drug clearance. Reduction in kidney mass, renal blood flow, and the subsequent number of functioning nephrons, glomerular filtration rate, and the rate of tubular secretion accounts for the decreased renal excretory capacity observed with aging (20,21). Diminishing renal function and lack of compensatory increases in nonrenal clearance in elderly patients have been associated with prolongation of the serum half-lives of beta-lactams, aminoglycosides, glycopeptides, sulfonamides, and fluoroquinolones. B. Tissue Penetration Some drugs, such as aminoglycosides, macrolides, and fluoroquinolones bind extensively to certain tissue components. Intracellular accumulation of aminoglycoside is slow, however, because of its poor membrane permeability. Intracellular aminoglycoside concentrations tend to be low after initial drug exposure but are high after more sustained exposure and multiple dosing. However, the drug is microbiologically inactive in an acidic environment, such as in the phagolysosome. Indeed, the high intracellular aminoglycoside concentrations achieved in the renal cortex after multiple doses may be the cause of their nephrotoxicity. C. Pharmacodynamics Pharmacodynamics refers to the action of drugs or the biological effects resulting from the interaction of a drug and its receptor site. Pharmacodynamics describes the antimicrobial effect at the site of infection as well as toxic effects in relation to the concentrations of the antimicrobial drug during the course of drug therapy.

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For drugs with concentration-dependent bactericidal activity, such as aminoglycosides and fluoroquinolones, the rate and extent of bactericidal action increase with increasing drug concentrations above the minimum bactericidal concentration (MBC) up to a point of maximum effect, usually 5 to 10 times the MBC. In addition, the duration of the PAE is concentration-dependent with these drugs, with longer PAEs induced by higher drug concentrations. In contrast, the bactericidal activity of most beta-lactam antibiotics against gram-negative bacilli is relatively slow and continues as long as the concentrations are in excess of the MBC. It does not increase as the drug concentration is increased, that is the bactericidal action of beta-lactams is time-dependent and not concentration-dependent. For time-dependent agents that exhibit short or no postantibiotic intervals—such as extended-spectrum beta-lactams effective against most gram-negative bacilli—multiple, small, frequent doses or continuous intravenous infusion produces similar or superior bactericidal effects compared with infrequently administered larger doses.

IV. POTENTIALLY USEFUL AND SAFE ANTIMICROBIAL AGENTS FOR LTCF RESIDENTS The vast majority of common bacterial illnesses in LTCF residents respond promptly to broad-spectrum oral antibiotics, but parenteral therapy is occasionally necessary for more severe infections. Some LTCFs have the capacity to provide parenteral therapies. There are antibiotics that may be administered via the intramuscular route, for example select third-generation cephalosporins such as ceftriaxone that, when administered intramuscularly, demonstrate similar efficacy compared with the intravenous injection. In addition several antibiotics, such as quinolones, have oral formulations that achieve systemic concentrations comparable to a parenteral route (22). Such advances should mitigate the need for transfer of LTCF residents to an acute care facility for mild to moderate or uncomplicated infections (23). A. Aminoglycosides Aminoglycosides in the elderly must be prescribed with caution because of the well-described risks of enhanced ototoxicity and nephrotoxicity associated with these agents and the availability of safer and less toxic drugs with comparable spectra (i.e., cephalosporins, monobactams, carbapenems, beta-lactam/beta-lactamase inhibitor combination antibiotics, and quinolones). However, these agents are rapidly bactericidal against staphylococci and gram-negative aerobic bacteria, including Pseudomonas sp, and often provide synergy with other agents (e.g., beta-lactams) for treatment of serious or life-threatening infections such as enterococcal endocarditis (24). Renal impairment (generally reversible) and ototoxic-

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ity (generally irreversible) are the two most common and important potential adverse effects of these antibiotics (25). Because plasma half-life is increased in patients with decreased renal function (most elderly persons), the dose should be reduced on the basis of the creatinine clearance. Nephrotoxicity is less likely with once-daily dosing compared with the conventional every 8-hour dosing and is usually reversible (26). Nephrotoxicity, however, may lead to high serum levels of aminoglycosides, which can cause irreversible ototoxicity. Risk of ototoxicity increases with age and is highest in patients with pre-existing hearing deficiencies. Thus, aminoglycoside use in older LTCF residents should be reserved for those with serious or life-threatening infections that require hospitalization and are caused by pathogens susceptible to aminoglycosides (27). B. Beta-Lactams Select beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors) may be useful in the management of infections in LTCFs because of their broad spectrum, favorable pharmacokinetics and favorable safety profiles. These would include parenteral cefotetan, ceftriaxone, cefoperazone, and cefipime, as well as oral agents such as penicillin, dicloxacillin, amoxicillin, amoxicillin-clavulanate, cephalexin, cefuroxime axetil, and cefixime (27). C. Macrolides Erythromycin, clarithromycin, and azithromycin have a limited role in the management of infections in the elderly in general. Clarithromycin and azithromycin have more favorable dosing regimens, improved antimicrobial activity, and lower gastrointestinal intolerance compared with erythromycin. These agents are moderately active against most strains of streptococci, methicillin-sensitive Staphylococcus aureus, anaerobes, Moraxella catarrhalis, Haemophilus influenzae, Legionella, Mycoplasma pneumoniae, and Chlamydia pneumoniae, as well as atypical mycobacteria such as Mycobacterium avium complex. Limited data are available regarding pharmacokinetics of these newer macrolides in elderly persons; decrease in drug clearance has been attributed to reduce renal clearance. The indications for the newer macrolides in elderly LTCF residents are no different than for the general population. Although macrolides have been recommended in community-acquired pneumonia treated in an ambulatory setting (28), their role as therapy for nursing home-acquired pneumonia is unclear (29). D. Clindamycin This agent is commonly used for anaerobic and staphylococcal infections and for life-threatening group A beta-hemolytic streptococcal infections (streptococ-

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cal toxic shock syndrome, necrotizing fasciitis), the latter necessitating acute care facility transfer. Residents of LTCFs are particularly susceptible to antibiotic-associated colitis caused by C. difficile; clindamycin use is a relatively common association. The drug has utility in the LTCF for treating mild to moderate infections such as skin and soft tissue infections, including infected pressure ulcers, oral and dental infections, and respiratory tract infections caused by susceptible bacteria. E. Fluoroquinolones The fluoroquinolones are a group of synthetic antibiotics that have a broad spectrum of antimicrobial activity, good absorption from the gastrointestinal tract, a unique mechanism of action (inhibition of bacterial topoisomerases), favorable pharmacokinetic properties, and a good safety profile (30). As a group, the fluoroquinolones have excellent in vitro activity against a wide range of gram-positive bacteria and many gram-negative bacteria such as Enterobacteriaceae and Aeromonas, Brucella, Campylobacter, Haemophilus, Legionella, Moraxella, Neisseria, and Vibrio. These agents are active against Pseudomonas aeruginosa but are significantly less active against other pseudomonal species, including P. capacia and P. fluorescens. Ciprofloxacin is the most active quinolone against P. aeruginosa. The newer generation fluoroquinolones have activity against gram-positive bacteria including Streptococcus pneumoniae and staphylococcal species, i.e., methicillin-sensitive S. aureus (MSSA) and coagulase-negative species. The fluoroquinolones have less activity against streptococcal species and enterococci. These agents in general have very poor activity against anaerobes and Nocardia organisms. Ciprofloxacin and ofloxacin are active in vitro against Chlamydia trachomatis, C. pneumoniae, Mycoplasma hominis, and M. pneumoniae. Ciprofloxacin and ofloxacin are active against many species of Mycobacterium, including M. tuberculosis, M. kansasii, M. fortuitum, and M. xenopi. Cipro-floxacin initially was introduced to North America in 1987. Since its release, it has been widely used in LTCFs (22). These agents are used because they allow the convenience of oral therapy with an agent with good bioavailability, are easily administered by once- or twice-daily dosing, are perceived to be safe, and have wide spectrum of activity. In the elderly, quinolones are useful in the treatment of complicated urinary tract infections, bacterial prostatitis, skin and soft tissue infections, pneumonia, malignant external otitis, and bacterial diarrhea caused by susceptible pathogens (22). The newer generation fluoroquinolones (e.g., levofloxacin, gatifloxacin, moxifloxacin) with improved gram-positive (including S. pneumoniae) activity over that of the older agents in this class are now considered agents of choice for the treatment of community-acquired pneumonia in adults, including the elderly (28). Adverse effects of quinolones in the elderly occur in 5%

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to 15% of cases, including gastrointestinal (nausea, vomiting, diarrhea) and central nervous system (dizziness, headache, insomnia) effects. Associated drug interactions with other medications include decreased theophylline clearance associated with increased serum levels of ciprofloxacin, but not norfloxacin or levofloxacin, and multivalent ions (e.g., calcium, iron, aluminum) contained in foods or drugs that significantly reduce absorption of quinolones from the upper gastrointestinal tract. With the intense quinolone use in many LTCFs, quinolone resistance of organisms has increased. Resistance via mutations in the genes encoding topoisomerase II and IV along with increased drug efflux is common in clinical isolates. Quinolone resistance (methicillin-resistant S. aureus (MRSA), Enterococcus faecalis, S. pneumoniae, and P. aeruginosa) complicates management of infections by requiring parenteral therapy with other antibiotics for organisms resistant to these oral agents, as well as increasing the burden of resistant organisms (31). Hence, the appropriate use of quinolones in LTCFs must be periodically assessed. F. Trimethoprim-Sulfamethoxazole This antibiotic is commonly prescribed in the elderly, for urinary tract infections, chronic bacterial prostatitis, lower respiratory tract infections, and bacterial diarrhea caused by susceptible pathogens. Data are limited on the pharmacokinetics of this drug in elderly persons (32). Oral drug absorption does not appear to be affected by age. Renal clearance of trimethoprim is decreased in older persons. The recommended doses for use in the elderly are comparable to those prescribed in younger persons: with renal impairment and a creatinine clearance of less than 30 mL/min but greater than 15 mL/min, the dosage is reduced by half. The drug should be avoided if the creatinine clearance is less than 15 mL/min. G. Miscellaneous Antibiotics Other antibiotics that could be prescribed in residents of LTCFs and deserve brief mention include vancomycin, the new FDA-approved antibiotics quinupristin dalfopristin (Synercid®) and linezolid (Zyvox®), and metronidazole. Vancomycin is a glycopeptide antibiotic used primarily for gram-positive bacterial infections. It is highly active against staphylococci (including MRSA) and streptococci (including vancomycin-sensitive enterococci). In the elderly, studies have indicated that reduced clearance of vancomycin is a consequence of reduced systemic and renal clearance as well as enhanced tissue binding of the drug. Lower parenteral doses are recommended for the frail elderly, and the dose should be adjusted according to the serum peak and trough levels as well as the creatinine clearance (33). The side effect profile in the elderly is no different from that in the general population. Quinupristin-dalfopristin, which is a streptogramin, is indicated in adults, including the elderly, for the treatment of serious and life-threatening or bac-

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teremic infection with vancomycin-resistant enterococci (VRE) and complicated skin and skin structure infection with MSSA and Streptococcus pyogenes (34). The pharmacokinetics of this agent are similar to that in younger adults. Linezolid, an oxazolidinone, is active against infections caused by sensitive gram-positive bacteria as well as MRSA and VRE (35). This agent’s availability, both in parenteral and oral formulations, as well as its relatively safe profile, is particularly advantageous in management of infections caused by such gram-positive-resistant organisms commonly encountered in elderly LTCF residents (see Section III). The indications, doses, and toxicities of metronidazole are no different in the elderly. The drug is commonly prescribed in combination with agents active against aerobic gram-positive and gram-negative bacteria to treat mixed infections in the elderly, such as infected pressure ulcers, diabetic foot ulcers, intra-abdominal infections, or pyogenic brain abcesses (27). Oral metronidazole is the agent of choice for the treatment of C. difficile colitis. Administered orally, this agent is absorbed well and achieves excellent tissue levels. Gastrointestinal intolerance is a common side effect. H. Antituberculous Agents Because most tuberculosis cases in the elderly are caused by isoniazid-sensitive and rifampin-sensitive Mycobacterium tuberculosis, the primary drugs for the treatment of active tuberculosis disease in this age group are isoniazid and rifampin. Isoniazid also should be used for the treatment of latent tuberculosis infection when the appropriate indications are present (see Chapter 15). I. Antifungal Agents Similar to younger adults, the commonly prescribed systemic antifungal agents in the elderly include amphotericin B, fluconazole, and itraconazole. Because of the potential toxicity of amphotericin B to renal function in the elderly, this agent must be used with caution. Fluconazole, because of its relative safety and efficacy and excellent bioavailability when administered by parenteral and oral routes, is prescribed more often in aging individuals. Itraconazole, available by parenteral and oral formulations, is an acceptable alternative, when indicated (see chapter 25). J. Antiviral Agents The antiviral agents commonly prescribed in the elderly include amantadine, rimantadine, acyclovir, valacyclovir, and famciclovir. Amantadine and rimantadine are recommended for influenza A infection within 48 hours of illness onset in the ambulatory elderly to reduce the duration and severity of illness; in institutional-

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ized elderly, these drugs are recommended for prophylaxis during an influenza A outbreak within the institution (see Chapter 13). Both drugs are continued for a minimum of 2 weeks or until approximately 1 week after the end of the outbreak. The neurominidase inhibitors, zanamivir and oseltamivir, are available for use in influenza A and B infections; efficacy and safety in elderly patients have not been extensively studied. Acyclovir, valacyclovir, and famiciclovir are effective agents for the treatment of herpes simplex and herpes zoster infection. Pain from herpes zoster and chronic pain (postherpetic neuralgia) may be relatively diminished by administering these agents within the first 72 hours of the onset of illness (see Chapter 17).

REFERENCES 1. 2. 3. 4. 5.

6. 7.

8. 9. 10. 11. 12.

13.

Haley RW, Culver DH, White JW. The nationwide nosocomial infection rate: A new need for vital statistics. Am J Epidemiol 1985; 121:159. Yoshikawa TT. VRE, MRSA, PRP, and DRGNB in LTCF: Lessons to be learned from the alphabet. J Am Geriatr Soc 1998; 46:241–243. Katz PR, Beam TR Jr, Brand F, Boyce K. Antibiotic use in the nursing home physician practice patterns. Arch Intern Med 1990; 150:1465–1468. Warren JW, Palumbo FB, Fitterman L, Speedie SM. Incidence and characteristics of antibiotic use and aged nursing home patients. J Am Geriatr Soc 1991; 39:963–972. Lee YL, Thrupp LD, Friis RH. Nosocomial infections and antibiotic utilization in geriatric patients: A pilot prospective surveillance program in skilled nursing facilities. Gerontology 1992; 38:223–232. Zimmer JG, Bentley DW, Valenti WM, Watson NM. Systemic antibiotic use in nursing homes: A quality assessment. J Am Geriatr Soc 1986; 34:703–710. Pickering TD, Gurwitz JH, Zalenznik D, Noonan JP, Avorn J. The appropriateness of oral fluoroquinolone-prescribing in the long-term care setting. J Am Geriatr Soc 1994; 42:28–32. Miller SW, Warnock R, Marshall LL. Appropriateness of antibiotic prescribing for urinary tract infections in long-term care facilities. Consult Pharm 1991; 14:157–177. Hanlon JT, Schmader KE, Samsa GP. A method for assessing drug therapy appropriate. J Clin Epidemiol 1992; 45:1045–1051. Norman DC. Fever and aging. Infect Dis Clin Pract 1998; 7:387–390. Yoshikawa TT, Norman DC. Fever in the elderly. Infect Med 1998; 15:704–706. Loeb M, Bentley DW, Bradley S, Crossley K, Garibaldi R, Gantz N, McGeer A, Muder RR, Mylotte J, Nicolle LE, Nurse B, Paton S, Simor AE, Smith P, Strausbaugh LJ. Development of minimum criteria for the initiation of antibiotics in residents of long-term-care facilities: Results of a consensus conference. Infect Control Hosp Epidemiol 2001; 22:120–124. Nicolle LE, Bentley DW, Garibaldi R, Neuhaus EG, Smith PW, the SHEA LongTerm Care Committee. Antimicrobial use in long-term-care facilities. Infect Control Hosp Epidemiol 2000; 21:537–545.

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Rajagopalan et al. Crossley K, Henry K, Irvine P, Willenbring K. Antibiotic use in nursing homes: Prevalence, cost, and utilization review. Bull NY Acad Med 1987; 63:510–518. Gurwitz JH, Field TS, Avorn J, McCormack D, Jain Shailavi, Eckler M, Edmonson AC, Bates DW. Incidence and preventability of adverse drug events in nursing homes. Am J Med 2000; 109:87–94. Gurwitz JH, Sanchez-Cross MT, Eckler MA, Matulis J. The epidemiology of adverse and unexpected events in the long-term care setting. J Am Geriatr Soc 1994; 42:33– 38. Rho JP, Yoshikawa TT. The cost of inappropriate use of anti-infective agents in older patients. Drugs Aging 1995; 6:263–267. Mylotte JM. Antimicrobial prescribing in long-term care facilities: Prospective evaluation of potential antimicrobial use and cost indicators. Am J Infect Control 1999; 27:10–19. Myers BR, Wilkinson P. Clinical pharmacokinetics of antibacterial drugs in the elderly: Implications for selection and dosage. Clin Pharmacokinet 1989; 17:385–395. Kinirons MT, Crome P. Clinical pharmacokinetic considerations in the elderly: An update. Clin Pharmacokinet 1997; 33:302–312. Bennett W. Geriatric pharmacokinetics and the kidney. Am J Kidney Dis 1990; 26:283–288. Guay DRP. Quinolones. In: Yoshikawa TT, Norman DC, eds. Antimicrobial Therapy in the Elderly Patient. New York, Marcel Dekker, Inc., 1994:237–310. Ernest ME, Ernst EJ. Effectively treating common infection in residents of long-term care facilities. Pharmacotherapy 1999; 19:1026–1035. Bouza E, Munoz P. Monotherapy versus combination therapy for bacterial infections. Med Clin North Am 2000; 84:1357–1389. Zaske DE. Aminoglycides. In: Yoshikawa TT, Norman DC, eds. Antimicrobial Therapy in the Elderly Patient. New York, Marcel Dekker, Inc., 1994:183–235. Dew RB III, Susla GM. Once-daily aminoglycide treatment. Infect Dis Clin Pract 1996; 5:12–24. Rajagopalan S, Yoshikawa TT. Antimicrobial therapy in the elderly. Med Clin North Am 2001; 85:133–147. Marrie TJ. Community-acquired pneumonia in the elderly. Clin Infect Dis 2000; 31:1066–1078. Naughton BJ, Mylotte JM. Treatment guidelines for nursing-home acquired pneumonia based on community practice. J Am Geriatr Soc 2000; 48:82–88. Owens RC Jr, Ambrose PG. Clinical use of fluoroquinolones. Med Clin North Am 2000; 84:1447–1469. Strausbaugh LJ, Crossley KB, Nurse BA, Thrupp LD, the SHEA Long-Term Care Committee. Antimicrobial resistance in long-term-care facilities. Infect Control Hosp Epidemiol 1996; 17:129–140. Williams L, Bender BS. Trimethoprim-sulfamethoxazole. In: Yoshikawa TT, Norman DC, eds. Antimicrobial Therapy in the Elderly Patient. New York, Marcel Dekker, Inc., 1994:169–181. Yoshikawa TT. Antimicrobial therapy for the elderly patient. J Am Geriatr Soc 1990; 38:1353–1372.

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Nichols RL, Graham DR, Barriere SL, and the Synercid Skin and Skin Structure Infection Group. Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: Two randomized, multicenter studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. J Antimicrob Chemother 1999; 44:263–273. 35. Chien JW, Kucia ML, Salata RA. Use of linezolid, an oxazolidinone, in the treatment of multidrug-resistant gram-positive bacterial infections. Clin Infect Dis 2000; 30:146–151.

12 Urinary Tract Infection Lindsay E. Nicolle Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada

I. INTRODUCTION The most common infection that occurs in elderly residents of long-term care facilities (LTCFs) is urinary tract infection (1). It is the most frequent source of bacteremia, and a common reason for transfer of residents to acute care facilities. Urinary infection is also one of the most common indications for antimicrobial therapy in these facilities, and much of the antimicrobial use for urinary infection in LTCFs is inappropriate (2). Thus, an understanding of urinary infection in residents of LTCFs is important for optimal resident care and to promote appropriate antimicrobial use in this setting. The term urinary tract infection simply means the presence of a microbial pathogen within the normally sterile urinary tract. However, it is generally used in the context of isolation of organisms in the urine at a quantitative level that excludes contamination (3). Urinary infection may be asymptomatic—also called asymptomatic bacteriuria—when microorganisms are present in the urinary tract but there are no symptoms or signs referable to urinary infection in the host (4). Individuals with asymptomatic infection usually have evidence of an inflammatory or immune host response in the urinary tract. The term “colonization” is sometimes used, rather than asymptomatic bacteriuria. However, this term does not have any clinical relevance and is not used in this chapter. An important group of individuals with urinary infection in LTCFs are those patients with bladder drainage who are using chronic indwelling catheters (5). The epidemiology of infection, including morbidity, differs for residents with longterm use of catheters compared with elderly individuals with urinary infection 173

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without long-term indwelling catheters. Thus, patients in LTCFs with long-term indwelling catheters are generally discussed separately. Observations herein should be considered relevant only for residents without indwelling catheters, unless stated otherwise.

II. EPIDEMIOLOGY AND CLINICAL RELEVANCE A. Prevalence and Incidence The prevalence of urinary infection in elderly residents of LTCFs is high (Table 1). Approximately 30% to 50% of women have positive urine cultures at any time. The prevalence in men is only slightly lower, at 20% to 40%. This remarkable prevalence has been consistently reported from different countries over many years (6–12). The incidence of both symptomatic and asymptomatic urinary infection is also high in these populations (Table 2). In prospective studies of nursing homeacquired infections, symptomatic urinary infection is reported as the first or second most frequent infection, with an incidence of 1.07 to 1.9/1,000 resident days (Table 2). The definitions used for symptomatic urinary infection, however, lack specificity and may overestimate urinary infection. Studies that have used more restrictive definitions report rates of symptomatic infection of 0.14/1,000 days (20), or 0.5/10,000 days for infection with fever (21). Similarly, symptomatic in-

Table 1 Prevalence of Urinary Infection in Long-Term Care Facility Populations Female Population (reference) Nursing home, USA (6) incontinent, mean age 85 yr Nursing home, Greece (7) mean age 78 yr Psychiatric long-term care, Denmark (8) mean age 78 yr Veteran’s, Canada (9) mean age 80 yr Nursing homes, USA (10) incontinent, mean age 88 yr Long-term care, Canada (11) mean age 83 yr Nursing home, USA (12) mean age 83 yr

Male

Number

% positive

Number

% positive

158

57

56

25

231

27

121

19

178

15

79

13

59

37

101

29

101

53

160

18–33

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Table 2 Incidence of Urinary Infection Reported in Long-Term Care Facility Populations Institution Men Veteran’s, Canada (9) Veteran’s, Tennessee (14) Veteran’s, Portland (17) Women Skilled nursing facility, Canada (11) Both/Not Stated Veteran’s (13) Nursing homes, San Diego (15) Nursing homes, Wisconsin (16) Nursing homes, Maryland (18) Skilled nursing facility, NY (19)

Asymptomatic

Symptomatic

1.23

1.37 1.17 1.07

3.52

1.41 1.9 1.26 1.6 1.2–1.3 2.4

Episodes/1000 patient days.

fection in women is reported to occur at a rate of 1.41/1,000 days with inclusive criteria for identification of urinary infection, but only 0.22/1,000 days with more restrictive criteria that require genitourinary symptoms (11), and in men, 1.37/1,000 days with inclusive and only 0.38/1,000 days with more restrictive criteria. The frequency of asymptomatic bacteriuria has also been characterized through the “turnover” of bacteriuria with repeated prevalence surveys in the same population. One study (9) reported an initial prevalence of bacteriuria of 19% for men and 27% of women in a Greek home for the aged. At 1 year, 11% of men and 23% of women with initially negative urine cultures had developed positive cultures; 22% and 27% with initially positive urine cultures had become negative. Another study (12) reported an initial prevalence of bacteriuria of 25% in women, with 8% of residents with negative urine cultures becoming positive every 6 months, and 31% of residents with initial positive urine cultures becoming negative. A third study (22) reported an initial prevalence of bacteriuria of 15% in a group of elderly women residents in both community housing and long-term care. The monthly probability of transition from positive to negative cultures was 0.30, and 0.12 from negative to positive. In another study in elderly institutionalized men, 10% of all nonbacteriuric residents became bacteriuric in a 3-month period (9). Some residents have persistent bacteriuria, whereas others have acquisition of new organisms or clearing of bacteriuria. Thus, bacteriuria within a nursing home population is dynamic. Factors that contribute to the variation, including antimicrobial use, are not well studied.

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B. Risk Factors Urinary infection in residents of LTCFs is predictably associated with certain aspects of functional status. Residents with cognitive impairment, or who are incontinent of urine or bowel, are likely to have bacteriuria (23,24). In one study, 78% of men with persistent bacteriuria had dementia compared with 42% of those without bacteriuria, and 96% and 25%, respectively, were incontinent of urine (23). Impaired mobility and more prolonged duration of admission to the LTCF are also associated with bacteriuria in some studies (24,25). No association between specific medication use and urinary infection has been reported (26). Risk factors for symptomatic and asymptomatic infection appear to be similar (27). The most important determinant of bacteriuria in the long-term care population appears to be the presence of a neurogenic bladder. Chronic neurologic diseases, such as Alzheimer’s, Parkinson’s, or cerebrovascular disease, are often accompanied by a neurogenic bladder. These illnesses frequently lead to institutionalization and are associated with cognitive impairment and incontinence of bladder and bowel. A neurogenic bladder results in incomplete voiding and increased likelihood of ureteral reflux, promoting both acquisition and persistence of infection. Drainage devices used to manage incontinence may also increase the frequency of urinary infection. The use of an external condom catheter for men with incontinence is associated with at least twice the occurrence of urinary infection compared with men who are incontinent but who do not use external condom catheters (28). Previous indwelling catheter use may have initiated bacteriuria and prostatic infection. Once prostatic infection is established, it often cannot be eradicated and may be a source for bacteriuria causing relapsing symptomatic or asymptomatic infection (29). Physiologic aging changes also have been associated with urinary infection in well, community-living elderly populations and may contribute to urinary infection in the nursing home setting. Women with prior genitourinary surgery or who have cystoceles are more likely to have recurrent urinary infection (30). The use of topical vaginal estrogen decreases the occurrence of both symptomatic and asymptomatic infection (31), but the extent to which estrogen deficiency independently contributes to urinary infection in this population is not established. Prostatic hypertrophy is a uniform accompaniment of aging in men. This may lead to urethral obstruction and urinary retention requiring instrumentation, and promotes turbulent urethral urine flow, which facilitates ascension of organisms into the bladder (29). Thus, a variety of factors contribute to the high frequency of urinary infection in elderly residents of LTCFs. Different influences will, of course, have different importance depending on the individual resident. C. Microbiology The diversity of infecting organisms isolated is greater in the LTCF than from urinary infection in community populations (Table 3). The Enterobacteriaceae are

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Table 3 Distribution of Infecting Organisms Isolated in Surveys of Bacteriuria in Nursing Home Residents Number of isolates (%) reported in studies (references) indicated Organisms Escherichia coli Klebsiella spp Enterobacter spp Citrobacter spp Serratia spp Proteus mirabilis Providencia stuartii Morganella morganii Providencia spp Pseudomonas aeruginosa Other gram-negative Enterococcuss spp Coagulase-negative staphylococci Staphylococcus aureus Other gram-positive Candida spp

9*

11†

14*

19‡

13 (11) 7 (5.9) 2 (1.7) 3 (2.5)

30 (53)

67 (50) 20 (15) 5 (3.8) 1 (0.8)

36 (30) 5 (4.2) 3 (2.5) 14 (11.8) 23 (19)

14 (25)

38 (12) 26 (8.3) 3 (1.0) 12 (3.9) 20 (6.4) 57 (18)

60 (19) 34 (11)

5 (3.8)

2 (0.6) 34 (11) 2 (0.6) 2 (0.6) 3 (1.0)

6 (4.5) 6 (4.5) 1 (0.8)

6 (5.0) 2 (1.7) 3 (2.5) 2 (1.7)

11 (19) 1 (1.8) 1 (1.8)

22 (17)

* male † female ‡ 80% female

the most common infecting organisms for both symptomatic and asymptomatic infection. Escherichia coli is the most frequent bacteria isolated in women, with Proteus mirabilis usually second. For men, E. coli and P. mirabilis occur with equal frequency, or P. mirabilis is more common. Other Enterobacteriaceae isolated include Klebsiella pneumoniae and urease-producing organisms such as Providencia stuartii and Morganella morganii. Providencia stuartii has a unique predilection for the institutionalized population (32). Pseudomonas aeruginosa and gram-positive organisms including Enterococcus spp and coagulase-negative staphylococci, are also common. Group B streptococci and Staphylococcus aureus are less frequent but are identified in some patients in most series. Yeast infection, principally caused by Candida albicans, may occur but is uncommon. The determinants of candiduria in LTCF residents are not well described. Yeast infection may be more common in women with associated vulvovaginal candidiasis and in diabetic patients. The distribution of organisms isolated from symptomatic infection is similar to that for asymptomatic infection, although coagulase-negative staphylococci are uncommon in symptomatic infection.

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Polymicrobial infection is present in 10% to 25% of bacteriuric residents (9,11). Men with external condom catheters used for voiding management often have infection with more than one organism (33). Bacterial isolates from urinary infection in LTCF residents are also characterized by increased antimicrobial resistance (34,35). This is a result of the intense use of antimicrobials in nursing homes (2), as well as the transmission of organisms between residents in the institutional setting. D. Host Response Asymptomatic bacteriuria is not simply the presence of bacteria in the bladder. In fact, at least 50% of women with asymptomatic infection have bacteria localized to the kidneys (36,37). Pyuria is present in more than 90% of bacteriuric subjects (38,39). The level of pyuria does not correlate with the presence of symptomatic infection (40). Increased urinary cytokine levels and increased local urinary or systemic antibodies to the infecting organism are further evidence of a host response with asymptomatic infection (41,42). Symptomatic subjects uniformly have pyuria. There are also elevated levels of urinary cytokines and local urinary antibody (41,42). With resolution of the symptomatic episode, urinary antibodies may decrease, particularly with E. coli infection (42). In clinical presentations with systemic manifestations such as fever, an elevated C-reactive protein is usually present, and there is an increase in systemic antibody to the infecting organism (43). E. Clinical Impact The majority of urinary infections in residents of LTCFs are clinically asymptomatic (4). Persistent asymptomatic bacteriuria has not been associated with negative long-term outcomes, such as renal failure or hypertension. Despite the very high prevalence of urease-producing organisms, including P. mirabilis and P. stuartii, renal or bladder stones have not been identified as a significant clinical problem in LTCF residents without chronic indwelling catheters (9). Asymptomatic bacteriuria also does not affect survival (23,40). Where an association between decreased survival and bacteriuria in residents has been observed, bacteriuria is not an independent association of mortality (24). Episodes of febrile urinary infection have been reported with a frequency of 1 to 1.5/10,000 resident days, comprising about one tenth of episodes of fever of any cause in this population (21). The urinary tract is the most common source of bacteremia in LTCF residents (44,45), although this occurs primarily in residents with an indwelling urinary catheter (46). It is also a reason for transfer of LTCF residents for acute hospitalization (47), contributing 8% of transfers at one facil-

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ity (48). Despite this, urinary infection is infrequently identified as a direct cause of death in residents (1,20). Urinary infection is one of the most common indications for antimicrobial prescriptions in LTCFs. From 20% to 60% of systemic antimicrobial courses are given for treatment of urinary infection (2). This intensive use of antimicrobials contributes to the emergence and persistence of antimicrobial resistance in the long-term care setting. F. Chronic Indwelling Catheter From 5% to 10% of residents of LTCFs have voiding managed with a long-term indwelling urethral catheter (49,50). The daily incidence of new infection for individuals with a long-term indwelling catheter is similar to that reported with short-term catheters, about 3% to 7% per day (5). Thus, anyone with a long-term indwelling catheter in place for longer than 30 days will be bacteriuric, and at any time the prevalence of bacteriuria in individuals with chronic catheters approaches 100%. Residents with long-term catheters are infected with a complex bacterial flora with two to five organisms present at any time (51). Proteus mirabilis, Proteus spp, Morganella morganii and P. aeruginosa are the most common organisms isolated, although many other gram-negative and gram-positive organisms also occur. Biofilm formation occurs on the catheter, primarily on the interior surface (52). This material consists of bacteria, extracellular bacterial substance, Mg2, Ca2, and Tamm-Horsfall protein from urine. It may also contain struvite if infection with a urease-producing organism is present. Biofilm contributes to catheter encrustation and obstruction (53). Bacteria growing in the biofilm are in an environment where they are relatively protected from the effect of host defenses or antimicrobials. Residents of LTCFs with chronic indwelling catheters experience increased morbidity attributable to urinary infection compared with LTCFs residents with bacteriuria who do not have an indwelling catheter. Febrile urinary infection is 10 times more frequent in these individuals (21,54), and bacteremia, primarily from a urinary source, is 40 times more frequent (46). A chronic indwelling catheter may also cause episodes of gross hematuria resulting from catheter trauma (55), and local suppurative complications including paraurethral abscesses, urethritis, epididymo-orchitis, or prostatic abscesses. Residents with indwelling catheters have a higher mortality than LTCF residents without chronic indwelling catheters, but this is attributable to underlying patient factors rather than urinary infection (50). At autopsy, residents with a long-term indwelling catheter have a higher frequency of histologic evidence for renal inflammation consistent with pyelonephritis compared with bacteriuric residents without an indwelling catheter (56,57).

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III. CLINICAL MANIFESTATIONS Urinary infection is usually asymptomatic. However, symptomatic urinary infection is an important contributor to morbidity in LTCF residents. When symptomatic infection occurs, the clinical presentation may vary across a spectrum of minor lower tract irritative symptoms to severe systemic symptoms and sepsis requiring hospitalization. Potential clinical presentations of symptomatic infection are listed in Table 4. The presentation may be similar to that in younger populations. For acute lower tract infection, or acute cystitis, frequency, dysuria, urgency, the new onset or worsening of urinary incontinence, and suprapubic discomfort may occur. Acute pyelonephritis may present with costovertebral angle pain and tenderness with fever. The clinical diagnosis, however, is often not straightforward because of chronic symptoms that interfere with assessment, difficulties in communication because of deafness, cognitive impairment, or dysarthria, and blunted clinical manifestations associated with aging, such as a decreased or absent fever response (58). Sepsis, often with bacteremia, is more frequent with obstruction or trauma to the genitourinary tract. Epididymo-orchitis may occur in male residents. Hematuria is seldom caused by urinary infection, but gross hematuria will frequently lead to secondary sepsis in the presence of infected urine (55). Chronic genitourinary symptoms are common in this population. These include chronic incontinence, nocturia, and frequency. A high proportion of residents with chronic genitourinary symptoms have positive urine cultures, but Table 4 Presentations of Symptomatic Urinary Tract Infection in Residents of LongTerm Care Facilities Symptomatic Urinary Infection Acute cystitis (frequency, dysuria, suprapubic discomfort) Acute deterioration in continence Acute pyelonephritis (costovertebral angle pain/tenderness; often with fever) Fever with hematuria Fever with no localizing findings (10% due to urinary infection) Epididymo-orchitis Additional Presentations with Indwelling Catheters Fever with catheter obstruction Urethritis Paraurethral abscess Bladder spasms with bypassing of catheter by urine Not Symptomatic Urinary Infection Chronic genitourinary symptoms Cloudy or foul-smelling urine Clinical deterioration without fever or localizing genitourinary symptoms or signs

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chronic symptoms are not attributable to urinary infection and are not improved by antimicrobial treatment of urinary infection (59,60). Thus, chronic genitourinary symptoms are not a manifestation of symptomatic urinary infection. However, acute deterioration in symptoms, such as in continence status, may be consistent with acute infection. Urinary tract infection may also present as fever without localizing findings. Fever with no apparent source is a relatively common clinical manifestation of many different infections in elderly institutionalized populations. About 50% of these episodes occur in residents with positive urine cultures because of the very high prevalence of bacteriuria in these facilities. However, only 10% of episodes of fever without localizing findings appear to be of urinary origin (20). Unfortunately, criteria to differentiate urinary infection from other potential sources of fever if localizing findings are not present have not been identified. Clinical deterioration without fever or localizing genitourinary findings is also often attributed to urinary infection. However, in the absence of fever, urinary infection is unlikely to be the cause of a nonspecific decline in resident status (61). A. Long-Term Indwelling Catheters The most common presentation of symptomatic urinary infection in the resident with a long-term indwelling catheter is fever without localizing genitourinary findings (54). Symptoms or signs localized to the genitourinary tract may include costovertebral angle pain or tenderness, suprapubic tenderness, hematuria, or catheter obstruction. Bacteremia may be present (44–46). Lower tract symptoms such as suprapubic tenderness or bypassing of the catheter because of bladder spasms may also occur, but are less common. Local suppurative complications including epididymo-orchitis, prostatic abscess, paraurethral abscesses, or urethritis occur in men. Bladder or kidney stone formation is a potential long-term complication in residents with infection with urease-producing organisms such as P. mirabilis or P. stuartii.

IV. DIAGNOSTIC APPROACH A. Microbiologic Diagnosis A diagnosis of urinary infection requires an appropriately collected and transported urine specimen that is cultured quantitatively. For a diagnosis of asymptomatic bacteriuria, two consecutive urine cultures growing 105 or more colonyforming units/ml (cfu/ml) is necessary (3). Symptomatic infection is diagnosed with only one urine culture meeting this quantitative criteria. A lower quantitative count may be consistent with a microbiologic diagnosis of symptomatic infection in some clinical settings. Individuals receiving diuretics, who have renal failure,

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or who are infected with selected fastidious organisms may have quantitative counts lower than 105 cfu/ml. If complete obstruction is present and the infection is proximal to the obstruction, urine cultures may be negative. Urine culture will also usually be negative if antimicrobial therapy is initiated before obtaining the urine specimen. Lower quantitative counts may be consistent with infection with clinical presentations in some other populations, such as acute cystitis in young women, but lower quantitative criteria have not been validated for any presentations of urinary infection in the elderly. As 10% to 25% of bacteriuric men or women in LTCFs have more than one organism isolated (9,11), urine specimens with more than one uropathogen in appropriate quantitative counts should not be dismissed as contamination. Interpretation of quantitative urine bacteriology depends on a urine specimen collected to minimize contamination with urethral and periurethral flora. For men, a clean-catch specimen collected with voiding is usually adequate and unlikely to have substantial contamination. If a male resident cannot cooperate to provide a voided specimen, collection using a freshly applied clean condom and leg bag may provide a suitable specimen (33,62). For women, a clean-catch technique also usually provides an adequate specimen (63). A clean-catch technique also has been shown to be feasible in incontinent female nursing home residents, provided the resident is cooperative and staff are properly trained (64). However, many women may not be able to cooperate with voiding for specimen collection (11). The use of pedibags, bedpans, or diapers in collecting urine specimens from women is discouraged, as these methods are subject to substantial contamination with periurethral organisms and have not been validated. When a resident is unable to cooperate and a urine culture is indicated to assist with clinical management, in and out urethral catheterization for specimen collection should be used. Any quantitative count of a potential uropathogen is diagnostic of infection in a urine specimen collected by catheterization. This procedure, however, may introduce infection in as many as 5% of catheterizations and should only be used if there is a compelling clinical indication. B. Urinalysis More than 90% of elderly residents of LTCFs with bacteriuria will have pyuria, regardless of whether infection is symptomatic or asymptomatic (38,39). In addition, 30% of residents without bacteriuria also have pyuria, presumably caused by periurethral contamination or other inflammatory conditions within the genitourinary tract. Thus, pyuria is not specific for a diagnosis of bacteriuria or for differentiating symptomatic from asymptomatic infection. However a urinalysis for determination of pyuria is useful if it is negative, as absence of pyuria has a high negative predictive value to exclude bacteriuria. The leukocyte esterase dipstick test has been evaluated for identification of pyuria in elderly institu-

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tionalized populations (6,22,39). It has a positive predictive value varying from 18% to 75% and a negative predictive value of 75% to 100% for identifying infection in this setting. Thus, it may be used as a rapid screening test to exclude urinary infection. C. Clinical Diagnosis When a resident presents with a new onset of irritative lower tract symptoms or with classic clinical findings of acute pyelonephritis, a diagnosis of symptomatic urinary infection may be straightforward. However, a diagnosis of symptomatic urinary infection is frequently problematic because of difficulties in communication and the presence of chronic symptoms associated with comorbid disease. The fever response is less marked or may be absent (58). Acute change in chronic symptoms, such as acute deterioration in continence status or increased frequency, may support a clinical diagnosis of symptomatic urinary infection. The resident with clinical deterioration without localizing genitourinary findings may present a diagnostic problem. Because a high proportion of these individuals have a positive urine culture, there is a tendency to attribute any change in clinical status for which no other explanation is apparent to urinary infection. However, urinary infection is not usually the cause for this presentation. One study reported urinary infection caused clinical deterioration without localizing findings in only 11% of such patients, and all those with urinary infection also had fever (61). In another study, fever without localizing findings was caused by urinary infection in only 10% of episodes (21). There were, however, no clinical or laboratory parameters to differentiate the 90% of episodes not linked to a urinary source from the 10% attributable to urinary infection. Thus, with a clinical presentation of fever without localizing findings in residents with a positive urine culture, some skepticism should be maintained with respect to a diagnosis of symptomatic urinary infection. Practitioners must recognize the uncertainty in attributing this clinical presentation to urinary infection. A negative urine specimen is useful to exclude urinary infection, but a positive urinary culture does not confirm symptomatic urinary infection. Careful clinical evaluation to identify localizing findings to support or exclude a genitourinary source should always be undertaken. The presence of “foul-smelling” or cloudy urine is also sometimes identified as symptomatic urinary infection and interpreted as an indication for antimicrobial therapy. Cloudy urine may be caused by crystals as well as pyuria, and even if pyuria is the cause, by itself it is not sufficient to diagnose symptomatic infection, nor is it an indication for antimicrobial therapy. An unpleasant urine odor may certainly be associated with urinary infection and is likely caused by polyamine production by infecting bacteria (65). However, not all residents with this problem have urinary infection and not all residents with urinary infection

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have an unpleasant odor. This “symptom” is more appropriately addressed through improved continence management rather than antimicrobial treatment. D. Long-Term Indwelling Catheters For microbiologic diagnosis of urinary infection in the resident with a chronic indwelling catheter, a specimen must be collected aseptically from the catheter port or by aspiration through the catheter tubing. Catheters that have been in situ for several days will have biofilm formation, primarily on the inner surface of the catheter. A urine specimen obtained from the catheter or tubing provides samples of the bacteriology of this biofilm rather than bladder urine. The microbiologic findings in a specimen obtained from the catheter differ quantitatively and qualitatively when compared with bladder urine (66,67). A higher number of bacteria and higher quantitative counts of organisms in the urine are isolated from a biofilm-laden catheter. Thus, where a urine specimen for culture is obtained to identify infecting organisms and susceptibilities, the indwelling catheter should be replaced, and a urine specimen obtained from the newly inserted catheter before antimicrobial therapy begins. The most common clinical presentation of symptomatic urinary infection in the catheterized patient is fever without localizing findings. At least 30% to 50% of such episodes in residents with an indwelling catheter have a urinary source (21). Thus, a diagnosis of symptomatic urinary infection with this clinical presentation is appropriate in the catheterized resident. Localizing findings, including hematuria, an obstructed catheter, suprapubic tenderness, or costovertebral angle pain or tenderness should be sought, as these increase the probability of a urinary source.

V. THERAPEUTIC INTERVENTIONS A. Asymptomatic Bacteriuria Asymptomatic bacteriuria in residents of LTCFs should not be treated. Prospective, randomized, comparative trials have repeatedly shown no decrease in morbidity or mortality with antimicrobial treatment of asymptomatic bacteriuria (9,11,24,68). Specifically, there is no decrease in acute episodes of symptomatic urinary infection, no change in chronic genitourinary symptoms, and no decreased mortality with treatment of asymptomatic bacteriuria (Table 5). Some studies have, in fact, reported a trend towards increased mortality with intensive antimicrobial therapy to attempt to maintain sterile urine (9,11). Treatment of asymptomatic bacteriuria does result in an increased incidence of new infection in treated residents, increased adverse effects from antimicrobial therapy, increased cost, and increased reinfection with more resistant organisms. Thus, studies are

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Table 5 Randomized Clinical Trials of Therapy and No Therapy for Management of Asymptomatic Bacteriuria in Long-Term Care Facility Residents Population

Number

Follow-up

Men (9)

36

2 years

Women (11)

50

12 months

358 191

8.5 years 3 days

35

mean 29.2 weeks

Women (23) Men and women (68) Long-term catheter (82)

Outcomes of therapy and no therapy • Similar for symptomatic episodes • Similar for mortality • ↑ infection, ↑ adverse effects, ↑ resistance with antimicrobial therapy • Similar symptomatic episodes and mortality • No difference in mortality • Treatment had no effect on chronic incontinence • No difference: bacteriuria, fever, catheter obstruction • ↑ Resistant bacteria with cephalexin

consistent in reporting no benefit with treatment of asymptomatic bacteriuria, and several harmful outcomes. It follows that routine screening of asymptomatic residents of LTCFs for the presence of asymptomatic bacteriuria is not indicated. B. Antimicrobial Treatment Antimicrobial therapy is certainly indicated for the treatment of symptomatic infection. Many different antimicrobials are effective for treatment of urinary infection (Table 6). Selection of a specific agent for treatment of an episode is directed by the known or presumed susceptibilities of the infecting organism, patient tolerance, evidence of prior efficacy of the antimicrobial in the management of urinary infection, and facility formulary. Antimicrobial selection is not altered on the basis of age alone (69). In every case, a urine specimen for culture should be obtained before instituting antimicrobial therapy. If possible, empirical treatment should be avoided. For individuals with mild lower tract symptoms or only lowgrade fever, institution of antimicrobial therapy should be delayed pending results of the urine culture. When the resident’s clinical status is severe enough to warrant empiric therapy, such as a resident with acute confusion, high fever, or hemodynamic instability, empirical antimicrobial therapy is indicated. The empirical regimen should be reassessed once the urine culture result is available, usually at 48 to 72 hours after start of treatment, and the initial clinical course and response to antimicrobial therapy can be reviewed.

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Table 6 Antimicrobials for Treatment of Urinary Tract Infection in Long-Term Care Facility Residents Regimen Oral Penicillins Ampicillin Amoxicillin Amoxicillin/clavulanic acid Piperacillin Piperacillin/tazobactam Cephalosporins Cephalexin Cefazolin Cefuroxime (axetil) Cefixime Cefotaxime Ceftriaxone Ceftazidime Aminoglycosides Gentamicin Tobramycin Amikacin Fluoroquinolones Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Gatifloxacin Moxifloxacin Other Trimethoprim Trimethoprim/sulfamethoxazole Nitrofurantoin Aztreonam Imipenem/cilastatin Meropenem Vancomycin*

Parenteral 1–2q 6h

500 mg tid 500 mg tid 3g q 4h 3.375g q 6h 500 mg qid 125–250 mg bid 400 mg od

1.0g q 8h 750 mg q 8h 1.0g q 8–12h 1.0g q 24h 1.0g q 8h 1–1.5 mg/kg q 8h or 3–4 mg/kg q 24h 1–1.5 mg/kg q 8h or 3–4 mg/kg q 24h 3–5 mg/kg q 8h or 15 mg/kg q 24h

400 mg bid 250–750 mg bid 200–400 mg bid 250–500 mg od 400 mg od 400 mg od

400 mg q 12h 500 mg od

100 mg bid 160/800 mg bid 100 mg bid 1.0g q 8h 500 mg q 6h 500 mg q 8h 1.0g q 12h

* Gram positive infections only. Abbreviations: OD, once daily; bid, twice daily; tid, three times daily; qid, four times daily.

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Few studies address the question of the optimal antimicrobial regimen for treatment of symptomatic urinary infection in residents of LTCFs. Thus, the relative efficacy of different antimicrobials and optimal duration of therapy are not known. For oral therapy, trimethoprim/sulfamethoxazole or trimethoprim alone may be preferred as initial therapy (2). If resistant organisms are known or thought to be causing infection, a quinolone antimicrobial may be appropriate, and for gram-positive infections, amoxicillin is usually preferred. Quinolone antimicrobials should be reserved for therapy when other oral options are not available, to limit emergence of resistance to this class of agents. Nitrofurantoin is useful for episodes of lower tract infection. It also has limited impact on the normal host flora and, on occasion, may be effective therapy for vancomycin-resistant enterococci. However, it is not effective for P. mirabilis infection, is not indicated for upper tract infection, and is contraindicated in patients with renal failure. When the resident’s clinical status or infection with antimicrobial-resistant organisms warrants parenteral therapy, an aminoglycoside antimicrobial such as gentamicin may be considered (2). A relatively safe and convenient dosage regimen for aminogylcosides is once-daily administration (70), which may be feasible in a long-term care setting. Gentamicin or tobramycin may be given intramuscularly or intravenously in a dose of 3 to 4 mg/kg/day every 24 to 48 hours depending on renal function of the resident (70). Aminoglycosides may be given either intravenously or intramuscularly. Aminoglycoside use avoids the extendedspectrum cephalosporins or quinolones, limiting antimicrobial pressure for emergence of extended-spectrum beta-lactamase producing Enterobacteriaceae or quinolone-resistant organisms, both of which have been identified as a concern in LTCF populations. When empirical therapy with an aminoglycoside is initiated, the clinical course and infecting organism should be reassessed after 48 to 72 hours to ensure that the aminoglycoside remains optimal therapy and that parenteral therapy is still required. In many cases, the aminoglycoside may be changed to an alternative parenteral or oral drug at this time. If a more prolonged course of aminoglycoside therapy is indicated, then aminoglycoside levels and renal function should be monitored at least twice weekly. However, in LTCFs, such regular assessments may not be feasible and alternative agents such as quinolones, extended-spectrum cephalosporin, or a carbapenen should be considered. Aminoglycosides are not an appropriate empiric choice for individuals with renal failure and in this setting, a parenteral quinolone antimicrobial or an extended-spectrum cephalosporin would be preferred. C. Duration of Treatment Few studies are available to define the optimal duration of treatment. For minor lower tract symptoms, a 7-day of course of therapy is adequate. Shorter courses of 3 to 5 days are less effective than in younger women with acute cystitis and are

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not recommended for this population. More severe clinical presentations with evidence of systemic illness should be treated for 10 to 14 days. In a few selected clinical indications, longer courses of antimicrobial therapy may be necessary. Men with symptomatic relapsing infection from a prostatic source may require 6 or 12 weeks of treatment (71,72). Residents with recurrent episodes of invasive infection and an abnormality of the genitourinary tract that promotes infection and cannot be corrected, including infection stones that cannot be removed, may benefit from long-term suppressive therapy (73). This is undertaken in only highly selected patients, and specific therapy chosen on a case by case basis. Long-term antimicrobial therapy should always be embarked on with care, as it is likely to promote emergence of resistant organisms. D. Chronic Indwelling Catheters The principles of antimicrobial selection in residents with chronic indwelling catheters are similar to those for residents without indwelling catheters. The catheter should be changed before initiating antimicrobial therapy, so the urine specimen obtained reflects the microbiology of bladder urine rather than biofilm on the catheter. Replacement of the catheter before instituting antimicrobial therapy may also lead to improved clinical outcomes, such as more rapid defervescence of fever and a decreased occurrence of symptomatic relapse (74). The optimal duration of antimicrobial therapy for treatment of a symptomatic episode in a patient with a chronic indwelling catheter is not known. However, the continuing presence of the catheter will result in recurrent urinary infection, and antimicrobial therapy promotes reinfection with organisms of increasing resistance. Thus, the duration of antimicrobial therapy should be as short as possible. In residents with a prompt clinical response and rapid defervescence of fever, a 7-day course of therapy should be sufficient.

VI. INFECTION CONTROL MEASURES A. General The goals of infection control measures in the LTCF are to prevent acquisition of infection by residents and prevent transmission of organisms between residents. The most important interventions are appropriate hand washing and glove use by staff members, use of aseptic or clean technique in patient care, and effective cleaning of equipment. A particular concern related to urinary infection in the LTCF is the cleaning and drying of leg bags for individuals using a condom or indwelling catheter (75). Surveillance for infection identifies the presence and extent of specific problems and by itself may contribute to decreasing infection rates as staff are made aware of the burden of morbidity. Because of the high prevalence and lack

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of evidence of harm of asymptomatic bacteriuria in this population, routine urine collection for screening cultures is not appropriate. Surveillance should be undertaken for symptomatic urinary infection, including bacteremia from urinary sources (75). Any surveillance strategy must have a capacity for early identification of potential outbreaks. Antimicrobial use for urinary infection should also be monitored, together with a means of assessing the appropriateness of such use. B. Long-Term Indwelling Catheters The urine from individuals with long-term indwelling catheters is a reservoir for resistant organisms within the long-term care setting. Thus, care must be taken to limit transmission of organisms, through equipment or the hands of staff, between patients with chronic catheters. Urine-measuring devices should not be shared among patients, appropriate glove and hand-washing practices by staff members in catheter care should be maintained, and policies governing catheter care in LTCF patients should be developed and updated regularly. These policies should also specify when long-term indwelling catheters should be used and how catheter use should be monitored to assist in limiting use. Surveillance of long-term indwelling catheter use should include the prevalence of catheter use, reasons for catheter use, and reasons why the catheter cannot be removed in a given individual. As all residents with chronic indwelling catheters are bacteriuric, there is no indication for routine screening for the presence of bacteriuria. However, surveillance for symptomatic urinary infection should be performed, including surveillance for episodes of catheter obstruction or trauma.

VII.

PREVENTION

A. General Measures The major factors promoting urinary tract infection in elderly residents of LTCFs are associated comorbid diseases leading to a neurogenic bladder. As these are the same comorbidities that lead to admission to the LTCF and, in most cases cannot be altered, it is not clear whether any current interventions can prevent bacteriuria. As a general approach to care, optimizing nutrition, mobility, and medical management of comorbid illnesses is desirable, but the impact of these on the occurrence of urinary infection is unknown. In fact, one clinical study reported that improving nutrition of LTCF residents did not decrease the occurrence of urinary infection (76). B. Specific Measures Several specific interventions may decrease the occurrence of urinary infection. The use of condom catheters is associated with an increased frequency of infec-

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tion, so limiting the use of these devices should decrease the occurrence of bacteriuria. Whether this would also decrease the occurrence of symptomatic infection is unknown. In many cases, however, patient care requires the use of these devices, and it is unrealistic to think use can be entirely avoided. For individuals with voiding managed with intermittent catheterization, the frequency of infection is similar using a clean or sterile catheterization technique (77). Hence, clean, intermittent catheterization is appropriate and less costly. Increased intake of cranberry juice has been suggested as an approach to decrease infection. However, increased cranberry juice did not decrease the prevalence of bacteriuria or symptomatic infection in a placebo-controlled trial (78). Topical vaginal estrogen therapy decreased the occurrence of both symptomatic and asymptomatic infection in a group of elderly, institutionalized women with a very high frequency of symptomatic infection (79) and may be an approach for some women. Finally, trauma to the mucosa in an infected genitourinary tract is associated with a high risk of bacteremia and sepsis. Prophylactic antimicrobial therapy should be given before any invasive genitourinary procedure is undertaken in a bacteriuric resident, as this is effective in preventing these severe complications (80). C. Long-Term Indwelling Catheters The most effective way to avoid urinary infection associated with a long-term catheter is, of course, not to use the catheter or to limit the duration of use to as short a time as clinically necessary. Otherwise, bacteriuria cannot currently be prevented in a patient with a long-term indwelling catheter. Several specific interventions to decrease the frequency of catheter-associated infection have been evaluated, but none have been shown to be effective. For instance, routine daily bladder irrigation with saline does not decrease the incidence of infection (81), antimicrobial treatment of asymptomatic bacteriuria does not decrease the frequency of asymptomatic or symptomatic infection (82), and different catheter materials, such as latex or silicone, do not alter the rate of infection. Silicone catheters have been reported to have fewer episodes of obstruction and may be useful in patients with a high rate of obstruction. However, they have not been shown to decrease the occurrence of symptomatic infection and, as they are more costly, are recommended only for selected patients. Other interventions, such as daily periurethral cleaning with soap and water or with a disinfectant, or placing disinfectant in the drainage bag, do not decrease the frequency of bacteriuria in patients with shortterm indwelling catheters and would also be assumed to be ineffective for longterm catheters. Because the frequency of asymptomatic bacteriuria cannot be decreased, the focus of prevention must be to minimize the occurrence of symptomatic episodes. Appropriate catheter care to limit trauma, avoiding contamination with incontinent stool (e.g., securing the catheter to the upper thigh of the resident), and

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prompt identification and replacement of an obstructed catheter will prevent some episodes of symptomatic infection. In addition, the use of prophylactic antimicrobials before an invasive genitourinary procedure will prevent postprocedure sepsis and bacteremia (80). Prophylactic antimicrobials are not indicated with catheter change, as the risk of infectious complications with this intervention is not sufficient to warrant this intervention (83,84). The problem of urinary infection in the individual with a long-term indwelling catheter is a technical issue related to ensuring adequate urinary drainage, and catheter materials to prevent bacterial growth. Further technological developments, then, are necessary to make a substantial impact on the frequency of urinary infection in residents with long-term indwelling catheters. Current studies of different drainage devices, such as intraurethral catheters, or catheter materials to prevent bacterial growth, may result in improvements in the future.

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Fierer J, Ekstrom M. An outbreak of Providencia stuartii urinary tract infections: Patients with condom catheters are a reservoir of the bacteria. JAMA 1981; 245:1553– 1555. Nicolle LE, Harding GKM, Kennedy J, McIntyre M, Aoki F, Murray D. Urine specimen collection with external devices for diagnosis of bacteriuria in elderly incontinent men. J Clin Microbiol 1988; 26:1115–1119. Muder RR, Brennen C, Goetz M, Wagener MM, Rihs JD. Association with prior flouroquinolone therapy of widespread ciprofloxacin resistance among Gram negative isolates in a Veteran’s Affairs Medical Center. Antimicrob Agents Chemother 1991; 35:256–258. Wiener J, Quinn JP, Bradford PA, Goering RV, Nathan C, Bush K, Weinstein RA. Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA 1999; 281:517–522. Suntharalingan M, Seth V, Moore-Smith B. Site of urinary tract infection in elderly women admitted to an acute geriatric assessment unit. Age Ageing 1983; 12:317– 322. Nicolle LE, Muir P, Harding GKM, Norris M. Localization of site of urinary infection in elderly institutionalized women with asymptomatic bacteriuria. J Infect Dis 1988; 157:65–70. Boscia AJ, Abrutyn E, Levison ME, Pitsakis PG, Kaye D. Pyuria and asymptomatic bacteriuria in elderly ambulatory women. Ann Intern Med 1989; 110:404–405. Rodgers K, Nicolle LE, McIntyre M, Harding GKM, Hoban D, Murray D. Pyuria in institutionalized elderly subjects. Can J Infect Dis 1991; 2:142–146. Nicolle LE, Brunka J, McIntyre M, Murray D, Harding GKM. Asymptomatic bacteriuria, urinary antibody and survival in the institutionalized elderly. J Am Geriatr Soc 1992; 40:607–613. Nicolle LE, Brunka J, Orr P, Wilkins J, Harding GKM. Urinary immunoreactive interleukin-1 alpha and interleukin-6 in bacteriuric institutionalized elderly subjects. J Urol 1993; 149:1049–1053. Nicolle LE, Brunka J. Urinary IgG and IgA antibodies in elderly institutionalized subjects with bacteriuria. Gerontology 1990; 36:345–355. Nicolle LE, Brunka J, Ujack E, Bryan L. Antibodies to major outer membrane proteins of Escherichia coli in urinary infection in the elderly. J Infect Dis 1989; 160:627–633. Muder RR, Brenmer C, Wagener MM, Goetz AM. Bacteriuria in a long term care facility: A five-year prospective study of 163 consecutive episodes. Clin Infect Dis 1992; 14:647–654. Nicolle LE, McIntyre M, Hoban D, Murray D. Bacteremia in a long term care facility. Can J Infect Dis 1994; 5:130–132. Rudman D, Hontanosas A, Cohen Z, Mattson DE. Clinical correlates of bacteremia in a Veteran’s Administration extended care facility. J Am Geriatr Soc 1988; 36:726–732. Brooks S, Warshaw G, Hasse L, Kues JR. The physician decision-making process in transferring nursing home patients to the hospital. Arch Intern Med 1994; 154:902–908. Irvine PW, van Burren N, Crossley K. Causes for hospitalization of nursing home residents: The role of infection. J Am Geriatr Soc 1984; 32:103–107.

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Nicolle Warren JL, Steinberg R, Hebel JR, Tenney J. The prevalence of urethral catheterization in Maryland nursing homes. Arch Intern Med 1989; 149:1535–1537. Kunin CM, Douthitt S, Dancing J, Anderson J, Moeschberger M. The association between the use of urinary catheters and morbidity and mortality among elderly patients in nursing homes. Am J Epidemiol 1992; 135:291–301. Warren JW, Tenney JH, Hoopes JM, Muncie HL, Anthony WC. A prospective microbiologic study of bacteriuria in patients with chronic indwelling urethral catheters. J Infect Dis 1982; 146:719–723. Cox AJ, Hukins DWL, Sulton TM. Infection of catheterized patients: Bacterial colonization of encrusted Foley catheters shown by scanning electron microscopy. Urol Res 1989; 17:349–352. Kunin CM. Blockage of urinary catheters: Role of microorganisms and constituents of the urine on formation of encrustations. J Clin Epidemiol 1989; 42:835–842. Warren JW, Damron D, Tenney JH, Hoopes JM, DeForge B, Muncie HL Jr. Fever, bacteremia, and death as complications of bacteriuria in women with long term urethral catheters. J Infect Dis 1987; 155:1151–1158. Nicolle LE, Orr P, Duckworth H, Brunka J, Kennedy J, Murray D, Harding GKM. Gross hematuria in residents in LTC. Am J Med 1993; 94:611–618. Carty M, Brocklehurst JC, Carty J. Bacteriuria and its correlates in old age. Gerontology 1981; 27:72–75. Warren JW, Muncie HL Jr, Hall-Graggs M. Acute pyelonephritis associated with bacteriuria during long-term catheterization. A prospective clinicopathological study. J Infect Dis 1988; 158:1341–1346. Bentley DW, Bradley S, High K, Schoenbaum S, Taler G, Yoshikawa TT. Guideline for evaluation of fever and infection in long-term care facilities. Clin Infect Dis 2000; 31:640–653. Brocklehurst JC, Dillane JB, Griffiths L, Fry J. The prevalence and symptomatology of urinary infection in an aged population. Geront Clin 1968; 10:242–253. Boscia JA, Kobasa WD, Abrutyn E, Levison ME, Kaplan AM, Kaye D. Lack of association between bacteriuria and symptoms in the elderly. Am J Med 1986; 81:979–982. Berman P, Hogan B, Fox RA. The atypical presentation of infection in old age. Age Ageing 1987; 16:201–207. Ouslander JG, Greengold BA, Silverblatt TJ, Garcia JP. An accurate method to obtain urine for culture in men with external catheters. Arch Intern Med 1987; 147:286–288. Ouslander JG, Schapira M, Schnelle JF. Urine specimen collection from incontinent female nursing home residents. J Am Geriatr Soc 1995; 43:279–281. Ouslander JG, Schapira M, Schnelle JF. Urine specimen collection from incontinent female nursing home residents. J Am Geriatr Soc 1995; 43:1–3. Nicolle LE. Urinary tract infections in the elderly: Symptomatic or asymptomatic? Internat J Antimicrob Agents 1999; 11:265–268. Grahn D, Norman DC, White ML, Cantrell M, Yoshikawa TT. Validity of urine catheter specimens for diagnosis of urinary tract infection in the elderly. Arch Intern Med 1985; 145:1858–1860.

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Tenney JH, Warren JW. Bacteriuria in women with long term catheters: Paired comparison of indwelling and replacement catheters. J Infect Dis 1988; 157:199–202. Ouslander JG, Shapira M, Schnelle JF, Uman G, Finegold S, Tuico E, Nigam JG. Does eradication of bacteriuria affect the severity of chronic urinary incontinence in nursing home residents? Ann Intern Med 1995; 122:749–754. Ljunberg B, Nilsson-Ehle I. Pharmacokinetics of antimicrobial agents in the elderly. Rev Infect Dis 1987; 9:250–257. Dew III RB, Susla GM. Once daily aminoglycoside treatment. Infect Dis Clin Prac 1996; 5:12–24. Gleckman R, Crowley M, Natsios GA. Therapy of recurrent invasive urinary tract infections of men. N Engl J Med 1979; 301:878–880. Smith JW, Jones SR, Reed WP, Tice AD, Deupre RH, Kaijser B. Recurrent urinary tract infections in men. Ann Intern Med 1979; 91:544–548. Nicolle LE. A practical guide to the management of complicated urinary tract infections. Drugs 1997; 53:583–592. Raz R, Schiller D, Nicolle LE. Does replacement of catheter improve the outcome of patients with a permanent urinary catheter and symptomatic bacteriuria? J Urol 2000; 164:1254–1258. Smith PW, Rusnak PG. Infection prevention and control in the long term care facility. Infect Control Hosp Epidemiol 1997; 18:831–849. Murphy S, West KP, Greenough WB, Cherot E, Katz J, Clement L. Impact of vitamin A supplementation on the incidence of infection in elderly nursing home residents: A randomized, controlled trial. Age Ageing 1992; 21:425–439. Duffy LM, Cleary J, Ahern S, Kuskowski MA, West M, Wheeler L, Mortimer JA. Clean, intermittent catheterization: Safe, cost-effective bladder management for male residents of VA nursing homes. J Am Geriatr Soc 1995; 43:865–870. Avorn J, Monane M, Gurwitz JH, Glynn RJ, Choodnovsky I, Lipsitz LA. Reduction of bacteriuria and pyuria after ingestion of cranberry juice. JAMA 1994; 271:751– 754. Raz R, Stamm W. A controlled trial of intravaginal estriol in post-menopausal women with recurrent urinary tract infections. N Engl J Med 1993; 329:753–759. Cafferkey MT, Falkiner FR, Gillespie WA, Murphy DM. Antibiotics for the prevention of septicemia in urology. J Antimicrob Chemother 1982; 9:471–477. Muncie HL, Hoopes JM, Damron DJ, Tenney JH, Warren JW. Once daily irrigation of long term urethral catheters with normal saline. Arch Intern Med 1989; 149:441– 443. Warren JW, Anthony WC, Hoopes JM, Muncie HL Jr. Cephalexin for susceptible bacteriuria in afebrile long-term catheterized patients. JAMA 1982; 248:454–458. Jewes LA, Gillespie WA, Leadbetter A, Myers B, Simpson RA, Stower MJ, Viant AC. Bacteriuria and bacteremia in patients with long-term indwelling catheters—a domiciliary study. J Med Microbiol 1988; 26:61–65. Bregenzer T, Frei R, Widmer AF, Seiler W, Probst W, Mattarelli G, Simmerli W. Low risk of bacteremia during catheter replacement in patients with long term urinary catheters. Arch Intern Med 1997; 157:521–525.

13 Influenza and Other Respiratory Viruses Ghinwa Dumyati and Ann R. Falsey University of Rochester School of Medicine, and Rochester General Hospital, Rochester, New York

I. INTRODUCTION Viral respiratory infections are extremely common during childhood but decrease in frequency with increasing age. In general, older adults experience approximately one upper respiratory infection (URI) per year (1,2). The incidence of infection is lower, but the morbidity of these respiratory viruses is significantly greater in the elderly compared with the young. The reasons for more severe disease are multifactorial and include an aging lung, the presence of comorbid conditions, and age-related immune dysfunction. In long-term care facilities (LTCFs) the rates of acute respiratory tract infection vary, depending on the season studied and the methods used for diagnosis. Several studies estimate the rate of URI to be one to three per resident per year (3–5). Acute respiratory tract infection was reported at a rate of 6.3/100 person-months in a study conducted during the winter at a 590-bed LTCF in Rochester, New York (6). Forty-two percent of these infections were proven to be caused by viruses. The devastating effect of influenza outbreaks is well defined in the nursing home population, but the impact of other viruses is less well known. More recently, respiratory syncytial virus (RSV) infection has emerged as an important pathogen causing significant morbidity and mortality approaching that of influenza infection. Less data are available, but other viruses, such as parainfluenza, coronavirus, and rhinoviruses, have also been described as pathogens in elderly adults and may contribute to increased mortality (7). Control of viral respiratory infections in LTCFs can be challenging because specific diagnosis is often difficult. Congregate settings, hands-on attention 197

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required by staff and residents, and cognitive deficits that hamper disease recognition all contribute to the spread of viruses and the development of outbreaks. In this chapter, the clinical presentation and impact of influenza, RSV, coronavirus, parainfluenza, and rhinovirus infections in residents of LTCFs will be reviewed. The mode of transmission and methods for prevention of these viruses will also be discussed.

II. INFLUENZA A. Epidemiology and Clinical Relevance 1. Viral Characteristics Influenza virus is well known to cause worldwide pandemic and epidemic disease. Three types exist: A, B, and C, which are classified based on antigenic differences between the internal proteins. Both A and B cause severe disease, whereas type C has been reported to cause milder upper respiratory tract infection. Immunity to influenza infection is both humoral and cell mediated. Protective antibodies are produced against the viral envelope proteins, haemagglutinin (H) and the neuraminidase (N). Repeated infections can occur because of yearly antigenic variations in these envelope proteins. Such variations are caused by point mutations in the envelope protein genes. This process, referred to as “antigenic drift,” leads to annual epidemics and is the reason for yearly changes in the components of the influenza vaccine. A major change due to an introduction of a completely new H or N gene, referred to as “antigenic shift,” leads to influenza pandemics. Pandemics occur because all members of the community are susceptible to infection by the new strain of influenza virus. Antigenic shift only occurs in influenza A viruses. In recent years, influenza A (H3N2 and H1N1) and influenza B have been cocirculating (8). H1N1 viruses are uncommon causes of infection in the elderly nursing home resident, possibly because of immunity acquired in younger life (9–11). 2. Attack Rate, Morbidity, and Mortality Influenza is an important viral pathogen in the elderly population, as approximately 80% to 90% of the deaths attributable to influenza occur in persons aged 65 or older. Death is caused by pneumonia or exacerbation of cardiopulmonary diseases and other underlying diseases (12–15). The estimated death rate in the United States varies between 20,000 to 40,000 deaths per season and excess hospitalizations resulting from influenza or complications average from 200 to 1,000 per 100,000 population (16). Conditions that predispose to complicated influenza include cardiovascular diseases, pulmonary diseases, and metabolic diseases, such as diabetes mellitus, renal dysfunction, anemia, and immunosuppression. The presence of any of these high-risk conditions in adults older than age 45 has

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been estimated to increase the death rate from influenza by 39-fold (15). The estimated death rates are 104 and 240 per 100,000 for persons with cardiovascular and chronic pulmonary diseases, respectively. The presence of both pulmonary and cardiovascular diseases results in the highest mortality at 870 per 100,000 deaths. In addition to causing excess mortality, influenza infection also causes significant morbidity in the elderly. Approximately 10% of older persons who are hospitalized are discharged to a higher level of care, even though many were independent before admission (17,18). Frail nursing home residents have been noted to have a decline in functional status after influenza infection (19). Influenza is an important pathogen in LTCFs because of the propensity to cause explosive outbreaks of severe illness. Attack rates vary between 20% to 40%, with a reported mortality of 15% to 30% during influenza A outbreaks and 10% during influenza B outbreaks (20–23). Risk factors for outbreaks in LTCFs include low resident and staff vaccination rates, larger homes, presence of closed wards, and common dining areas (22). Other risk factors also include crowding and poor ventilation (24). B. Clinical Manifestations After an incubation period of approximately 1 to 2 days, the classic influenza syndrome is characterized by the abrupt onset of fever, chills, headache, and myalgias, accompanied by respiratory symptoms of sore throat, nonproductive cough, and nasal congestion. Ocular symptoms, such as tearing, burning, and pain with movement of the eyes helps to distinguish influenza from other viral illnesses (8). Elderly and debilitated persons may have a less “classic” picture and present with only high fever, lassitude, or confusion and minimal respiratory symptoms. Fever typically lasts for 3 days but can persist as long as 8 days. In the nursing home population, it is difficult to clinically differentiate influenza from other respiratory viruses such as RSV because symptoms overlap and, not infrequently, viruses cocirculate. However, the presence of fever, systemic and gastrointestinal complaints suggests influenza (Table 1). C. Diagnostic Approach Viral culture from the nasopharynx is the gold standard for the diagnosis of influenza. Virus may also be recovered from sputum. A nasopharyngeal specimen is obtained by swabbing the nose and the throat separately and combining both swabs in the same viral transport media. Nasal washes are difficult to obtain from elderly, debilitated persons and nasopharyngeal swabs are preferred. Viral culture is important for epidemiological purposes and is essential for making decisions regarding the best antiviral treatment and prophylaxis. However, it takes 3 to 5 days to identify the virus by culture. Time is critical for controlling outbreaks and in-

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Table 1 Clinical Manifestation in Elderly Patients with Influenza Virus Versus RSV Infection Clinical manifestations Upper respiratory symptoms Lower respiratory symptoms Systemic (malaise, myalgias, chills) Gastrointestinal (anorexia, nausea) Temperature higher than 37.2°C (99°F)

Influenza

RSV

97% 66% 84%* 38% 90%

100% 44% 44% 0% 56%

*Statistically significant difference. Abbreviation: RSV, Respiratory syncytial virus. Source: Adapted from Ref. 56.

stituting appropriate antiviral treatment and, therefore, rapid diagnostic methods such as immunofluorescence assay (IFA) or enzyme immunoassay (EIA) have been developed. These tests detect viral antigens directly from respiratory secretions and can be used for influenza A or influenza A and B together (25,26). Results can be obtained within an hour. The sensitivity and specificity for influenza A rapid tests (Directigen Flu A®, Becton Dickinson) approaches those of viral culture under optimal conditions, with a sensitivity varying between 80% to 90% and specificity varying between 90% to 100%. For combination A and B (FLU OIA®, Biostar; QUICKVUE® Influenza Test, Quidel; ZSTATFLU®, ZymeTx) the sensitivities are approximately 60% to 70% and specificities approach 95% to 100% (27). The sensitivity of various tests depends on the quality of the specimen, with better results obtained from nasal washes and swabs compared with pharyngeal specimens alone (26,28). Other techniques include reverse transcriptionpolymerase chain reaction (RT-PCR), which although very sensitive, is not widely available. At present, PCR is expensive and requires specimens to be sent to specialized laboratories. Serology using acute and convalescent sera is not helpful for the acute management of patients but is useful in retrospective analysis of outbreaks. D. Therapeutic Interventions and Infection Control The explosive nature of influenza outbreaks suggests aerosol transmission. However, this has not been as well documented as for tuberculosis or varicella. A large amount of virus is present in the respiratory secretions of infected persons and is dispersed into the air by sneezing, coughing, and talking (29). Virus shedding begins approximately 24 hours before onset of symptoms, rapidly increases for the first 24 to 48 hours of illness, and then diminishes to low levels for up to 5 to 10 days (8). Higher rates of transmission occur in crowded and confined settings such

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as in hospitals, nursing homes, and college dormitories. Transmission may also occur through fomites and contaminated hands. Influenza virus can survive up to 24 to 48 hours on hard, nonporous surfaces and on hands for up to 5 minutes (30). 1. Treatment and Chemoprophylaxis Two classes of antiviral agents are available for prophylaxis and treatment of influenza infection. The M2 channel inhibitors, amantadine and rimantadine, and the neuraminidase inhibitors, zanamivir and oseltamivir, have both been proven efficacious. a. Amantadine and Rimantadine. Amantadine and rimantadine inhibit growth of influenza A viruses only. They act by blocking the M2 channels that span the viral membrane and result in inhibition of viral uncoating from the host cell (31). Amantadine and rimantadine have been licensed for prophylaxis and treatment of influenza A infection. Efficacy. Both amantadine and rimantadine have similar efficacy in prevention and treatment of influenza A. Most studies that have shown amantadine and rimantadine to be effective in preventing influenza have used challenge experiments in healthy adults or natural infections in the family setting. These drugs prevent 50% of laboratory-documented influenza infections and 70% to 90% of illnesses (32–34). Amantadine and rimantadine are also effective in the treatment of uncomplicated influenza. Treatment of healthy adults and children, when started within the first 2 days of illness, results in a decrease of illness duration by 1 to 2 days (33). A decrease in symptom scores and virus shedding have also been demonstrated (35). One placebo-controlled study, carried out in a nursing home population, showed more rapid reduction in fever and symptoms and less use of antibiotics, antitussives, and antipyretics in the rimantadine-treated group (36). The effectiveness of early therapy in high-risk patients with amantadine and rimantadine in reducing frequency of subsequent complications is unknown. A number of observational studies have shown that both amantadine and rimantadine are effective in controlling nursing homes outbreaks when prophylaxis and treatment have been started early (37). However, no randomized, placebo-controlled studies to assess the effectiveness of widespread chemoprophylaxis with rimantadine or amantadine have been carried out. Dosing. Amantadine and rimantadine have similar mechanisms of action; however, they differ in their pharmacokinetics. Amantadine is excreted unmetabolized in the urine. The half-life is two times longer in elderly compared with young adults and further prolonged in patients with impaired renal function. The recommended dose is 100 mg per day in persons aged 65 and older; the dose should be adjusted for creatinine clearance below 50% (33). Rimantadine is metabolized in the liver with 20% excreted by the kidney. Because a dose of 200 mg per day was associ-

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ated with high plasma levels in elderly nursing home residents, the recommended dose for rimantadine is also 100 mg per day. However, modifications are not needed for renal and liver dysfunction (38). The recommended doses of amantadine and rimantadine are summarized in Table 2. Treatment duration is 3 to 5 days. Side effects. Amantadine and rimantadine are both known to cause central nervous system (CNS) and gastrointestinal effects, but the CNS side effects are more common with amantadine and have been reported in 33% of cases (39). The CNS symptoms include nervousness, anxiety, difficulty concentrating, lightheadedness and seizures. Seizures are more common with amantadine than rimantadine and, therefore, its use is contraindicated in persons with a seizure history. A 4% to 8% increase in the frequency of falls among nursing home residents has been reported during periods of amantadine prophylaxis (40). Both drugs cause nausea and anorexia in 1% to 3% of cases. The highest incidence of adverse effects is associated with high plasma levels seen in renal failure and with the use of 200 mg of amantadine. Resistance. Resistance to both agents occurs rapidly (within 2 to 3 days) in onethird of influenza-infected patients receiving these drugs (41,42). It is recommended that treated patients be isolated from patients receiving prophylaxis. Amantadine- and rimantadine-resistant viruses do not demonstrate increased virulence, and they remain sensitive to zanamivir and oseltamivir (34). Table 2 Recommended Treatment and Prophylactic Dosage of Antiviral Drugs for Influenza, in Nursing Home Residents Drug Amantadine

Rimantadine

Zanamivir

Oseltamivir

Dose

Dose in renal failure*

Indication

Route

Prophylaxis and treatment influenza A Prophylaxis and treatment influenza A Treatment influenza A&B Influenza A&B Prophylaxis Treatment

Oral (tablet or syrup)

100 mg/day

100 mg every 48–72 hr

Oral (tablet or syrup)

100 mg/day

100 mg/day

Oral inhalation (powder)

2 inhalations of 5 mg each twice daily

No change

Oral

75 mg/day 75 mg/day 75 mg twice daily

* Creatinine clearance 50 ml/mm. Consult package insert for doses for severe renal insufficiency.

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b. Zanamivir and Oseltamivir. Zanamivir and oseltamivir are neuraminidase inhibitors of both influenza A and B viruses. Neuraminidase is an enzyme that cleaves terminal sialic acid residues from carbohydrate moieties on the surface of host cells and influenza virus envelopes. This process promotes the release of progeny viruses from infected cells, prevents the aggregation of virus, and possibly decreases viral inactivation by respiratory mucus. Inhibition of neuraminidase results in virus aggregation and a decrease in the amount of infectious virus released (43). Both agents have been approved for treatment of influenza A and B infections, but only oseltamivir has been licensed for prophylactic use. Dosing. Oseltamivir is administered orally and zanamivir by oral inhalation. Zanamivir requires a cooperative patient who can inspire effectively. Zanamivir deposits primarily in the oropharynx and throat with 20% reaching the lungs. Less than 20% is systemically absorbed. Oseltamivir is excreted unchanged in the urine, and the dose must be reduced in renal failure. The treatment duration is 5 days for both drugs. Recommended doses for both medications are summarized in Table 2. Efficacy. The efficacy of zanamivir and oseltamivir in treatment and prophylaxis of influenza has been studied primarily in healthy, young adults. Data regarding the efficacy of these drugs in high-risk patients are limited. Both drugs prevent naturally acquired influenza infection by 30% to 40% and illness by 67% to 84% (44,45). Zanamivir reduced the time to alleviation of influenza illness by 1 day in all subjects and by 3 days in those with febrile illness or those treated within 30 hours after the onset of symptoms (46). In elderly and high-risk subjects, a 2.5 day reduction in symptoms was observed (47). Nonfebrile patients or patients treated after 30 hours derive little or no benefit (46–48). Oseltamivir used in healthy adults showed a reduction in influenza symptoms by 1 to 1.5 days (49). In some studies, oseltamivir reduced the frequency of complications such as otitis media, sinusitis, bronchitis, and other infections requiring antibiotics; however, the frequency of pneumonia in these studies was too low to assess its effect on lower respiratory complications (47,49). The experience with prophylactic use of zanamivir and oseltamivir in LTCFs is limited but encouraging. One small, randomized, unblinded study in a Wisconsin nursing home population compared zanamivir to rimantadine for prophylaxis against influenza A and placebo against influenza B epidemics (50). Zanamivir was given for 2 weeks, and protection was comparable to rimantadine in influenza A epidemic. No cases of influenza B occurred in residents receiving zanamivir prophylaxis. Another randomized, doubleblind, placebo-controlled study of oseltamivir used for 6 weeks showed a statistically significant decrease of laboratory-confirmed influenza compared with placebo. The protective efficacy was 92%. This protection was in addition to that provided by influenza vaccination (51a).

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Side effects. Both zanamivir and oseltamivir are better tolerated than amantadine and rimantadine. Central nervous system side effects have been infrequently reported. Zanamivir can reduce peak expiratory flow rates and should be used cautiously in patients with chronic obstructive lung disease (43,52). Oseltamivir use is associated with nausea of mild to moderate intensity with rare vomiting. These symptoms are transient and usually occur after the first dose (45,49). Resistance. The emergence of virus resistant to zanamivir and oseltamivir is uncommon. One influenza B strain resistant to zanamivir was isolated from an immunocompromised child (53). In one study of oseltamivir treatment, only 1% of isolates recovered on day 4 to 6 post treatment were found to be resistant. There was no clinical deterioration and, unlike resistant viruses recovered during M2 channel blocker treatment, neuraminidase-resistant viruses were less virulent in animal models (51b). E. Influenza Control in Long-Term Care Facilities 1. Infection Control Recommendations for influenza control in LCTFs were recently reviewed and the recommendations of the Society for Healthcare Epidemiology of America and Centers for Disease Control and Prevention (CDC) have been published (16,54,55). All emphasize that the best method of influenza control in the nursing home is prevention of infection by yearly immunization of residents and staff. Nursing home residents continue to become infected with influenza despite vaccination because of suboptimal vaccine response, high frequency of exposure, and ease of transmission of influenza virus in closed, crowded settings. Another contributing factor is failure to immunize staff, who are frequently responsible for the introduction of influenza to the nursing home (22). The key to controlling outbreaks is to identify cases rapidly so that isolation and treatment can be initiated promptly. To achieve this goal, a surveillance program for influenza-like respiratory illnesses (ILI) should be in place during the influenza season. The CDC defines ILI as a temperature of 37.8°C (100°F) or greater accompanied by any symptoms of cough, coryza, or sore throat. However, only 70% of all elderly with influenza will have fever, so some cases will be missed. Another proposed definition includes symptoms of cough, sore throat, nasal congestion, or rhinorrhea with or without fever. However, none of these definitions have been validated in a large prospective study in nursing homes. Residents exhibiting any of the above symptoms should have a nasopharyngeal swab taken for rapid influenza detection and viral culture. Laboratory documentation of influenza infection is important because other respiratory infections have similar clinical manifestations in the elderly (56). Rapid diagnostic tests are also important for the purpose of early treatment and prophylaxis. Lower attack rates of in-

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fluenza have been demonstrated in an uncontrolled study in nursing homes that used both rapid influenza tests and culture compared with those that used culture alone (25). The CDC recommends that when institutional outbreaks occur, chemoprophylaxis should be administered to all residents regardless of their vaccine status. However, the definition of an outbreak remains controversial. Most recommend starting chemoprophylaxis when 10% of residents on a ward have ILI and influenza has been documented. Others define an outbreak as two to three cases of ILI occurring within 48 to 72 hours (57). Once prophylaxis is started, it should be continued for 2 weeks or 1 week after the last documented case of influenza (58). Other measures during an outbreak include vaccination and chemoprophylaxis of unvaccinated staff. Chemoprophylaxis should be continued for 2 weeks after vaccination of staff members when protective antibodies are generated. In epidemics where the vaccine virus does not match the circulating virus strain, staff members should receive chemoprophylaxis alone (16). The present recommendation is to use either amantadine or rimantadine in influenza A outbreaks. No recommendations have been published regarding the prophylactic use of zanamivir or oseltamivir in nursing homes. Although more expensive, rimantadine is preferable to amantadine for influenza A outbreaks because of fewer side effects. Influenza cases that develop on rimantadine prophylaxis may be treated with oseltamivir because of the possibility of rimantadine-resistant virus. For influenza B outbreaks and patients with seizure disorders, the use of zanamivir or oseltamivir should be considered. Oseltamivir is preferred because of the ease of administration and, at this time, it is the only agent approved for prophylaxis. Another measure to control outbreaks in LTCFs is isolation (Table 3). Because transmission of influenza virus can occur by aerosol and fomites, isolation of ill residents is recommended (55). Patients should be confined to their rooms and centralized activities should be decentralized or postponed. Healthcare workers should wear masks when in close contact with ill residents and should wash their hands after contact. The optimal duration of isolation is unclear, but 3 to 5 days is reasonable. The effectiveness of these isolation methods has not been proven in LTCFs but have been useful in hospital-based outbreaks. Other measures include closing the facility or ward to new admissions, restricting visitors, requesting sick personnel remain home, and restricting personnel from floating to other wards. 2. Vaccination The most effective measure to prevent influenza outbreak in nursing homes is annual administration of inactivated trivalent influenza vaccine to both staff and residents (see Chapter 20). Previous surveys of nursing homes have reported vacci-

Abbreviation: RSV, Respiratory syncytial virus. Recommended intervention. / Optional or unclear recommendation. Source: Adapted from Ref. 29.

Control measures Hand washing Gloves Masks Isolation of ill patients in their room Cohort staff Limiting group activities Closing facility or ward to new admissions Limit visitors with respiratory illness

Mode of spread

Virus

Influenza Close contact, aerosol ?Skin, fomite

/

/

RSV Close contact Skin, fomite

Table 3 Control of Nursing Home Nosocomial Viral Respiratory Infections

/

/

Parainfluenza Close contact Skin, fomite

Unknown

Coronavirus

/

Rhinovirus Close contact skin, Fomite, ?aerosol

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nation rates of residents varying between 15% to 100%. Recent surveys in 1998–1999 by the CDC, which included 1,017 homes in the United States, have shown an increased rate of nursing home resident vaccination ranging from 79% to 91% with a mean of 83% (54). This is the percentage of vaccination recommended to provide protection by herd immunity. The increase in the vaccination rate of nursing home staff has been less impressive. Low rates of staff vaccination at 7% to 10% have been previously reported during nursing homes outbreaks (22,59,60). More recent surveys report the rates to have increased to 32% to 57% of staff, with a mean of 46%. Increasing staff vaccination is important as studies have shown that immunization of staff in nursing homes is associated with a decrease in the mortality of residents living in LTCFs, irrespective of their vaccination status. Vaccination of staff is also associated with less frequent nursing home outbreaks (61,62). In healthy young adults, the inactivated trivalent vaccine has 70% to 90% protective efficacy if there is a good antigenic match between the vaccine strain and the circulating influenza virus. Few prospective studies have been conducted in the elderly population. Retrospective case-controlled studies have shown a vaccine protective efficacy of 30% to 40% (63). Protective efficacy is lower in nursing home residents, but benefit from vaccination is still derived. Hospitalization rates are reduced by 50% to 60% and mortality by 80%. Influenza vaccine also reduces the duration of illness (63–66). Because the effectiveness of vaccination is lower in individuals aged 65 and older than in younger adults, strategies to improve the level of protection against influenza infection are being studied. Higher doses of vaccine and adjuvants have been tried with mixed success (67,68). Live attenuated virus vaccines generated by genetic reassortment with cold adapted influenza A and B viruses have also been studied in children, young adults, elderly, and high-risk patients. Intranasal trivalent cold-adapted vaccine was shown to have more than 90% efficacy in preventing influenza A and influenza B in children and soon may be approved for use (69). The immune response to coldadapted influenza vaccine in elderly persons has been less than optimal when compared with younger subjects (70). Studies combining both inactivated and activated vaccines in nursing home residents indicate only modest benefit (71). The combination may provide a better protection against influenza illness, but further studies are still needed before recommendations can be made.

III. RESPIRATORY SYNCYTIAL VIRUS A. Epidemiology and Clinical Relevance Respiratory syncytial virus (RSV) is an RNA virus of the paramyxovirus family. Two antigenically distinct groups have been recognized: group A and B. Respiratory Syncytial virus is well known to cause severe disease in infants and young

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children and causes winter epidemics of bronchitis, bronchiolitis, and pneumonia in temperate climates. Reinfection occurs throughout life, as immunity is incomplete. Respiratory syncytial virus typically causes URI in young, healthy adults but is more severe in immunocompromised, frail elderly and in patients with underlying cardiopulmonary diseases (6,72–74). Respiratory syncytial virus was not appreciated as a serious pathogen in the elderly until the late 1970s after several nursing home outbreaks were described. Since 1970, 16 published reports emphasize the importance of RSV, ranking it second to influenza as a cause of respiratory infections in LTCFs (3,6,56,75–87). Respiratory syncytial virus accounts for 5% to 27% of respiratory illnesses in these facilities, and attack rates vary widely, ranging between 12% to 89% in outbreak situations and 1% to 15% in prospective studies. The severity of the disease and complications also vary, with pneumonia reported in 0 to 55% of cases and mortality in 0 to 53% (88). The highest risk of complications, as in influenza infection, occurs in patients with underlying cardiac or pulmonary diseases (74). Respiratory syncytial virus has been estimated to account for 2% to 9% of hospitalizations for lower respiratory tract disease in persons aged 65 and older. It also accounts for 2% to 9% of deaths from pneumonia in hospitalized elderly patients (89). Morbidity in the elderly is similar to influenza and results in prolonged hospitalizations averaging 2 weeks, with approximately 9% to 18% requiring intensive care admission and mechanical ventilation. In one study, more than 10% of patients experienced functional decline and required a higher level of care at discharge (18). B. Clinical Manifestations Rhinorrhea, cough, sputum production, dyspnea, and wheezing characterize RSV infections (6,90). Fever and constitutional symptoms are seen in approximately half of cases. In nursing home residents or hospitalized elderly patients, the clinical presentation of RSV infection is similar to influenza. Both infections cause overlapping upper and lower respiratory symptoms. Systemic symptoms such as malaise, myalgias, and chills are more common with influenza, as are gastrointestinal complaints or fever above 37.2°C (99.0°F) (Table 1). Rhinorrhea and wheezing are more characteristic of RSV infection (6,18,56,78). Certain features suggest influenza or RSV; however, no symptoms or signs are pathognomonic, thus the clinical distinction between the two infections is extremely difficult. In a study of patients aged 65 and older admitted to the hospital with cardiopulmonary illnesses, the only significant difference in symptoms and signs between RSV and influenza cases was the greater frequency of fever above 38.0°C (100.4°F) with influenza, which resulted in a greater number of blood cultures taken in the influenza A group (18). Because both influenza and RSV infections cause similar clinical features, it is important to perform diagnostic tests for both influenza and RSV when a cluster of respiratory infection occurs in LTCFs.

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C. Diagnostic Approach The diagnosis of RSV infection is made by viral culture of respiratory secretions. Because nasal wash is difficult in older persons, a nasopharyngeal swab is an acceptable method for specimen collection. In adults, the sensitivity of culture is poor because the titer of virus shed is low, and RSV is thermolabile and does not survive long in transit time. The reported sensitivity of culture in nursing home population is at best 50% and usually lower (91). More rapid methods to diagnose RSV rely on antigen detection from a nasopharyngeal specimen using IFA or EIA. Although useful in children, these tests are not very sensitive in older persons. In one study, only 1 out of 11 elderly patients with RSV infection proven by culture or serology was positive by IFA and none tested positive by commercial EIA (91). Reverse transcription-polymerase chain reaction is a new diagnostic technique that shows much promise for the rapid diagnosis of RSV in elderly patients. The test has been shown to be very sensitive and specific (92). However, at present, drawbacks include expense and limited commercial availability (93). Serology, using a fourfold rise of antibody in acute and convalescent specimens, is also useful but not for the immediate diagnosis of RSV infection. Detection of antibody rises by EIA appears to be about twice as sensitive as complement fixation tests (87). D. Therapeutic Interventions Treatment of RSV infection in the elderly patient is supportive, using hydration and oxygenation. Bronchospasm may be treated with bronchodilators and corticosteroids, but they are not of proven benefit. No antiviral treatment has been studied in randomized trials in adults, but aerosolized ribavirin could be considered in certain situations. The drug is approved for the treatment of severe RSV infection in high-risk infants and is usually given by inhalation for 2 to 5 days (94). It has been shown to decrease viral shedding but has no clear effect on symptoms in the treatment of experimentally infected young adults (95). Case reports using aerosolized ribavirin, mostly in adults, also suggest that its use might be beneficial in selected severe cases (96,97). In elderly volunteers with chronic obstructive pulmonary disease (COPD), the drug has been found to be safe when given for 6 or 12 hours per day for 4 days (98). If treatment is considered, it should be started within a few days of symptom onset. In the hospitalized elderly patient, a high dose of aerosolized ribavirin (60 mg/ml) administered over a short duration of 2 hours, three times per day may be better tolerated than continuous inhalation. This dosing regimen was found to be as effective in children as the recommended 20 mg/ml dose aerosolized over 18 hours (99). New antiviral compounds that inhibit the fusion protein of RSV are currently in the early stages of development and may eventually prove useful in the treatment of RSV infection (100,101).

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More data are needed before recommendations on antiviral treatment of nursing home residents can be made (102). E. Infection Control Transmission of RSV is from person to person and requires close contact (within 3 feet), suggesting large droplet or fomite spread. Respiratory syncytial virus can survive for more than 6 hours on nonporous environmental surfaces (103). Natural challenge experiments during nosocomial outbreaks on pediatric wards showed RSV spread with 70% efficacy during close contact with infected infants such as cuddling, and with 30% efficiency when only surfaces in the rooms were touched. Airborne transmission is not seen, so masks are not recommended (104). Virus inoculation is usually in the eye or nose, less commonly in the throat (105). The use of goggles that cover the eyes and nose was associated with a decrease in the rate of nosocomial infections on pediatric wards; however, these devices are not considered to be practical (29). Respiratory syncytial virus outbreaks in LTCFs are less explosive than influenza outbreaks and are characterized by a steady trickle of cases with clustering by building, floor, and hallway (6,86). Controlling outbreaks requires early diagnosis and interruption of either hand carriage or self-inoculation of the eyes and nose. Strict hand washing is the most important measure to control the spread of infection (Table 3). Because compliance with hand washing is frequently poor, some authorities have advocated the additional use of gowns and gloves. Isolating symptomatic patients in their room, cohorting staff, and closing the units to new admissions are other recommended measures (29).

IV. PARAINFLUENZA A. Epidemiology and Clinical Relevance Parainfluenza virus (PIV) is a paramyxovirus. Four serotypes have been identified: types 1–4, with type 4 having 2 subgroups (A and B). The PIV serotypes vary in their clinical presentation and seasonality. Parainfluenza virus types 1 and 2 are more common in fall and usually alternate years. Parainfluenza virus 1 and 2 primarily cause croup and bronchiolitis in children. Parainfluenza virus type 3 most frequently infects infants younger than 6 months. It occurs year-round but usually follows the influenza season in late winter and spring. By the age of 5 years, 59% to 100% of children have been infected (106). Parainfluenza virus 3 causes relatively severe disease and is second only to RSV as a cause of serious lower respiratory infection in infants and children (106). Like RSV, recurrent PIV infections are common throughout life. Parainfluenza virus 1 and PIV 3 have been most often described as the cause of serious in-

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fections in the elderly. Overall, PIV infections are not as commonly reported in older persons as influenza or RSV and account for approximately 5% to 6% of respiratory illnesses in nursing home residents and in community-dwelling elderly (3,6,90,107). Parainfluenza virus accounts for 2.5% to 3.1% of adult hospitalizations for lower respiratory tract infection (108). Several outbreaks have been described in LTCFs, with attack rates varying between 2% to 56% and associated with significant morbidity (109,110). Secondary pneumonia occurred in 0 to 36% and death in 0 to 11% of case (5,109,111). Close contact with the infected patients resulted in an attack rate of 35% in staff members compared with 11% in those without resident contact, suggesting the importance of person-to-person transmission (110). B. Clinical Manifestations The incubation period is short: 2 to 6 days. Virus can be isolated for up to 7 days or longer after onset of illness (112). In healthy adults, the symptoms of PIV infection are not distinct from the common cold. Patients typically have nasal discharge, congestion, and sneezing. Cough, generalized malaise, and fever may also occur. The most common symptoms reported from an outbreak of PIV 3 among residents of a nursing home in Canada were rhinorrhea and cough. Some residents also had wheezing, fever, and sore throat. Approximately half the residents had lower respiratory symptoms develop (5). C. Diagnostic Approach The gold standard for the diagnosis of PIV infection is viral culture of nasopharyngeal secretions, but identification may take up to 1 week. It is important to process the culture rapidly and to keep it at 4°C (39.2°F) during transport (106). Rapid tests being developed include direct detection by IFA, which is less sensitive than culture and RT-PCR. The latter, although sensitive, is not widely available (93,113). Serologic analysis can establish the diagnosis retrospectively. D. Therapeutic Interventions Treatment of PIV infection in adults is supportive. A few anecdotal reports on the use of aerosolized ribavirin in lower respiratory infections in immunocompromised children and adults with severe parainfluenza virus pneumonia are available, but no general recommendations can be made (114). E. Infection Control The exact mode of PIV transmission is not defined, but the slow transmission suggests a person-to-person spread, either through contaminated hands or droplets.

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The virus can survive at least a few hours on environmental surfaces and for a short duration on hands (115). Hand washing, disinfecting of environmental surfaces, and case isolation are all important in controlling outbreaks of PIV in institutional settings (Table 3).

V. CORONAVIRUS A. Epidemiology and Clinical Relevance Coronaviruses are single-stranded RNA viruses. Two subtypes, 229E and OC43, cause human infection. These viruses cause symptoms similar to the common cold (116). Coronavirus 229E grows in cell culture, but OC43 is more difficult to isolate and requires tracheal organ culture. Because of the difficulty with viral isolation, the overall clinical impact of coronaviruses in adults has not been well defined. Longitudinal serologic studies in different populations of children, healthy adults, and army recruits report that coronavirus infection accounts for 4% to 15% of acute respiratory disease per year (117). The percentage increases to 35% during outbreaks. Infection occurs throughout the year but has peaks in winter and early spring. Data on the impact of coronavirus infections in nursing homes are limited. One published study that used serology to test for OC43 and 229E infection in residents of 11 nursing homes in England found an 11% infection rate (76). Lower respiratory complications occurred in a quarter of the infected residents. A surveillance study in an adult day care performed over 44 months showed that coronavirus infection accounted for 8% of all respiratory tract infections (118). Infection of the staff members typically preceded infection in the elderly daycare participants. B. Clinical Manifestations The incubation period for coronaviruses is 2 to 4 days. Disease is indistinguishable from that of the common cold. In older persons in day care, the infection with coronavirus was associated with nasal congestion, cough, constitutional symptoms, and low-grade fever (118). The subjects recovered without sequelae, but illnesses were prolonged and lasted an average of 14 days. Fifty percent of subjects had lower respiratory involvement as evidenced by sputum production, shortness of breath, wheezing, or rales. No pneumonia or deaths were documented. C. Diagnostic Approach Outside of research settings, diagnosis of coronavirus infection is rarely made because of difficulty in culturing the virus and because the clinical features are in-

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distinguishable from the common cold. As with other respiratory viruses, RTPCR shows promise as a useful tool in diagnosing acute coronavirus infections (119,120). Serologic assays using complement fixation can be used for retrospective analysis, but these tests are also not available for general use. D. Therapeutic Interventions Treatment of coronavirus infections is symptomatic. One report of intranasal interferon in adults experimentally challenged with type 229E showed a reduction in severity of the clinical illness; however, no antiviral drugs are currently approved to treat coronavirus infections (121). E. Infection Control The mode of transmission of coronavirus has not been well studied, and no firm recommendations can be given for infection control. Good hand washing seems most reasonable.

VI. RHINOVIRUS A. Epidemiology and Clinical Relevance Rhinoviruses are the most frequent cause of the common cold and are recovered from approximately one-third of patients in the community with cold symptoms (122). More than 100 serotypes have been identified, accounting for the recurrence of infection throughout life. In temperate climates, rhinovirus infections tend to peak in fall and spring, although they do occur sporadically in winter (123,124). Rhinovirus infection is also common in older adults when specifically tested for using sensitive diagnostic techniques such as RT-PCR. Rhinovirus accounted for 24% of respiratory illnesses in subjects older than age 60 living in the community, according to a study from the United Kingdom (125). In frail older persons attending senior day care programs, rhinoviruses were the cause of 7% of respiratory illnesses (118). Both studies show that in the older population, the infection is more severe than in younger adults, with symptoms lasting for 14 to 16 days. There is also a greater frequency of lower airway symptoms and restriction of activities of daily living; however, serious complications such as pneumonia are uncommon (118,125). In an outbreak of rhinovirus infection in an LTCF, a high rate of lower respiratory symptoms was also noted; however, there were no deaths and only 2 of 33 infections resulted in hospitalization (126). Overall, rhinoviruses generally do not result in the significant morbidity observed with influenza or RSV infection (6,74).

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B. Clinical Manifestations The clinical symptoms of rhinovirus illness can be highly variable in older people, ranging from trivial sniffles to cough and dyspnea (118,126). Nasal congestion and scratchy throat characterize most illnesses. Fever, cough, dyspnea, and constitutional symptoms may also be observed and are more common in elderly patients than in young adults. Again, the infection cannot be clinically differentiated from other viruses that cause respiratory infections. C. Diagnostic Approach Both viral culture and RT-PCR may be used for diagnosis, but are rarely indicated. D. Therapeutic Interventions Treatment is usually symptomatic with oral decongestant, antihistamine, and nonsteroidal anti-inflammatory medications. Pleconaril, an antiviral agent with activity against picornaviruses, has been shown to be of value in decreasing symptoms of rhinovirus infection in young healthy adults, but no data are available in the elderly (127). Studies using interferon alpha 2 with ipratropium applied topically in the nose with naproxen orally have also shown modest benefits for symptom relief (128). Further studies are needed before any of these therapies can be recommended. E. Infection Control Rhinoviruses are transmitted by contact with infected secretions spread from hand to hand, followed by autoinoculation of nasal or conjunctival mucosa. Virus may also be transmitted from contaminated surfaces (129). Aerosol transmission has also been documented under experimental conditions but is not felt to be the primary mechanism of spread in nosocomial settings (130). Hand washing and avoidance of hand-to-nose or eye contact are important infection control measures. Containing infected secretions by using tissues and covering the mouth during coughing are encouraged. The use of masks to prevent the spread of infection has not been studied.

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14 Pneumonia and Bronchitis Joseph M. Mylotte University at Buffalo, State University of New York, Buffalo, New York

I. NURSING HOME-ACQUIRED PNEUMONIA Nursing home-acquired pneumonia (NHAP) is the second most common cause of infection among residents in long-term care facilities (LTCFs) (1). However, NHAP has the highest mortality of any infection occurring among residents of LTCFs (1–3), and among survivors, there is significant morbidity (4). In addition, pneumonia is a common reason for transfer from an LTCF to the hospital (5). This chapter reviews the literature on NHAP and has a particular focus on the management and prevention of this infection. The reader is also referred to other recently published reviews of NHAP (6,7). A. Epidemiology and Clinical Relevance 1. Incidence The reported incidence of NHAP has ranged from 0.3 to 2.5 episodes per 1000 resident care days (8–21). The variation in incidence may be related to several factors, including differences in incidence over time, study design, number of facilities evaluated, intensity of surveillance, or facility affiliation (Veterans Affairs versus community). Two studies (17,21) conducted prospective surveillance for NHAP. At one proprietary LTCF in 1984–1987, the incidence of NHAP was one episode per 1000 resident-care days (17). At five LTCFs in Toronto, Ontario, Canada between 1993 and 1996, the incidence of NHAP was 0.7 episodes per 1000 resident-care days (21). Therefore, it would appear reasonable to assume that the incidence of NHAP for most LTCFs is one episode per 1000 resident-care days. 223

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2. Risk Factors for NHAP Several studies have identified risk factors for NHAP (2,13–15,18,21–23), but only four have used multivariate analysis (13,14,21,22). Independent predictors of NHAP have included poor functional status (13,14), presence of a nasogastric tube (13), swallowing difficulties (14,21), an unusual event (defined as confusion, agitation, falls, or wandering) (14), chronic lung disease (22), tracheostomy (22), increasing age (21), and male sex (21). In one study (21), influenza vaccination was associated with a significantly lower risk for NHAP. In summary, these studies (13,14,21,22) identified the debilitated and poorly functional nursing home resident, especially those at high risk for aspiration, as most likely to develop pneumonia. 3. Pathogenesis Most episodes of NHAP are caused by aspiration of oropharyngeal flora into the lung and failure of host defense mechanisms to eliminate aspirated bacteria (24). The pathogenesis of aspiration among the elderly has been recently reviewed (25). So-called silent aspiration of oropharyngeal flora is said to be an important risk factor for community-acquired pneumonia in the elderly (26). Diseases of the central nervous system, such as stroke, are complicated frequently by pneumonia (27), especially in patients with dysphagia (28). Basal ganglia infarcts are associated with an especially high risk of pneumonia compared with those with infarcts involving the cerebral hemispheres (29). Infarcts of the basal ganglia may reduce production of neurotransmitter in the sensory components of the glossopharyngeal and vagal nerves, which results in impaired swallowing and cough reflexes (25). Although less common, acute aspiration of gastric contents as a cause of “pneumonia” in nursing home residents is well described (30). The chemical inflammatory response that results in the lung after gastric content aspiration may lead to symptoms and signs identical to bacterial pneumonia. However, the distinction between bacterial pneumonia and gastric content aspiration can be difficult, especially if the aspiration is not witnessed. One study (30) found that 69 (27%) of 257 patients in one LTCF had 98 aspiration events during an intensive 8-month observation period. Seventy percent of aspiration episodes were associated with fever and tachypnea, and among 53 chest X-rays obtained after an aspiration, 37 (70%) had a new infiltrate. In a multivariate analysis, a hyperextended neck (elevation of the chin above the horizontal plane with resistance to efforts to return the chin to a normal position), malnutrition, benzodiazepine use, contractures, and use of feeding tubes were independent risk factors for aspiration. Whether residents with gastric content aspiration and associated abnormal chest radiographs require antimicrobial therapy remains unclear.

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4. Etiology The etiology of NHAP has been the subject of debate for some time, especially regarding the importance of aerobic gram-negative bacilli as causative agents of this infection. A review of the literature from 1978 to 1994 on this issue assessed the value of 18 published studies based on the quality of the diagnostic testing (6). Most of these studies relied on sputum cultures to identify the etiologic agent, but not all studies assessed the adequacy of sputum samples. When strict criteria were used to evaluate the quality of sputum specimens ( 25 polymorphonuclear leukocytes and 10 epithelial cells per 100-power field) among patients with NHAP (31–34), isolation of gram-negative bacilli ranged from 0 to 12%. When less strict or no criteria were used, gram-negative bacilli were much more commonly isolated (9% to 55%) (8,10,13,15,18,23). Overall, these studies indicate that Streptococcus pneumoniae is the most common bacterial pathogen isolated among nursing home residents with pneumonia, followed by nontypeable Haemophilus influenzae, and Moraxella catarrhalis. Atypical organisms, including Legionella sp, Chlamydia pneumoniae, and Mycoplasma sp were rarely identified among the small group of studies in which these pathogens were carefully sought (21,35,36). Aerobic gram-negative bacilli were also identified infrequently as a cause of NHAP in these studies (21,35,36). 5. Mortality Mortality of NHAP treated in the hospital has tended to be higher than that treated in the nursing home setting. For residents admitted to the hospital, mortality has ranged from 13% to 41% (21,32,37–42) compared with 7% to 19% among those treated only in the nursing home (21,33,39,40,41,43). This variation in mortality is related to differences in definition of mortality, in study design (one facility versus a population of residents from multiple homes), and facility affiliation (Veterans Affairs facilities versus community nursing homes). 6. Risk Factors for Mortality Several studies have defined risk factors for mortality among residents with NHAP or lower respiratory tract infection (4,38–40,44,45). Prepneumonia functional status (low, medium, or high dependence) was an important predictor of mortality from NHAP in most of these studies (4,38,44,45). In a study of all episodes (n 378) of NHAP that occurred in 11 facilities in the Buffalo, New York region during two consecutive winter seasons, there was no significant association between prepneumonia functional status and 30-day mortality, although a definite trend was noted (P .065) (39). Other factors found to be predictive of mortality related to NHAP include dementia (4,39), increased respiratory rate (39,45), increased pulse (39), and change in mental status (39).

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Physicians have difficulty accurately assessing severity of community-acquired pneumonia (CAP) (46), and this is true for NHAP as well (47). To address this problem, a model for measuring severity of CAP has been validated in NHAP (46,48). However, the model has limited usefulness in the nursing home setting because it requires laboratory testing that is infrequently done. Therefore, a simplified severity-of-NHAP model that does not require laboratory tests and has the potential to be used by staff in the nursing home has been developed (39). In the derivation cohort, this model defined a low-risk mortality group ( 10% 30-day mortality) and a high-risk mortality group ( 35% 30-day mortality). This simplified NHAP severity model was used to further evaluate the relationship between prepneumonia functional status and mortality (39). After NHAP residents were stratified into three functional categories (low, medium, and high dependence), low- and high-risk mortality groups were identified in each of the three categories using the severity-of-NHAP model. The high-dependence category had the greatest proportion of episodes in the high-risk mortality group. Thus, residents with a high level of dependence before developing pneumonia had a high probability of severe pneumonia. B. Clinical Manifestations The dogma regarding the clinical presentation of NHAP has been that nursing home residents have an “atypical” presentation, meaning that symptoms (cough, shortness of breath, pleuritic chest pain, chills) and signs (fever, tachypnea, rales on chest examination) occur less frequently than among age-matched communitydwelling elderly or younger people (6,37). Several studies (6,18,31–33,37,38,49) have assessed the clinical manifestations of NHAP. Two (33,49) were randomized studies of treatment of NHAP, and selection bias may be an issue. For the remaining five studies (18,31,32,37,38), the clinical features involved cough in approximately 60%, dyspnea in 40%, fever in about 65%, and altered mental status in 50% to 70%. In a recent study of 378 episodes of NHAP occurring among residents of 11 LTCFs, the findings were: fever 70%; respiratory rate higher than 30 per minute 23%; pulse higher than 125 per minute 6%; cough 61%; and altered mental status 38% (39). However, all these studies are limited by retrospective design and reliance on written documentation in the nursing home record. Such documentation may be poor because of the lack of onsite evaluation by a physician, the inability of residents to provide accurate history, and the inability of nursing staff to adequately assess residents at the bedside. C. Diagnostic Approach Older studies (22,50) have suggested that infections occurring in LTCFs may not be adequately evaluated before antibacterial therapy is initiated. The lack of ade-

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quate evaluation of infections in LTCFs is caused by several factors, including lack of direct physician involvement, poor or inadequate assessment by LTCF staff, and lack of availability of laboratory facilities (51). In a study of provider practice patterns in the diagnosis and treatment of 94 episodes of NHAP, a chest X-ray was done in 85%, a sputum culture in 5%, blood cultures in 6%, and a white blood cell count in 33% (43). Recently, an expert panel developed a practice guideline for evaluation of fever and infection in LTCFs (51). This guideline clearly acknowledges the problem of obtaining adequate specimens for culture in the LTCF setting. The panel recommended the following diagnostic studies in nursing home residents with clinically suspected pneumonia: white blood cell count with differential, pulse oximetry for residents with a respiratory rate higher than 25 breaths per minute, a chest radiograph if hypoxemia is documented or suspected, and respiratory secretions for Gram stain and culture. Consideration should also be given to an assessment of the hydration status of the resident with pneumonia, for example, blood urea nitrogen determination, as dehydration commonly occurs in association with fever and infection (52). Blood cultures should not be done routinely in the diagnostic evaluation of NHAP because the yield is exceedingly low (48). There are no studies of serum C-reactive protein levels in NHAP; however, this test has been reported to be useful in diagnosis of community-acquired pneumonia and is a marker for effective treatment (53,54). The C-reactive protein test may be particularly useful in managing the resident with an equivocal chest radiograph (54). The diagnostic evaluation for suspected NHAP in the nursing home setting should include pulse oximetry while breathing room air (hypoxemia is defined as an oxygen saturation of less than 92% breathing room air), chest radiograph, white blood cell count, and serum blood urea nitrogen. The bedside assessment of residents in the LTCF by nursing staff is a critical component in managing infections, as on-site evaluation by physicians is infrequent (51). Therefore, nursing staff education regarding proper evaluation of residents with suspected infection is an important issue. The recent practice guideline for evaluation of fever and infection in LTCF (51) stresses the importance of the hierarchy of the evaluation, beginning at the level of the nursing aide and progressing to the charge nurse and, ultimately, to the physician. D. Therapeutic Interventions Once the diagnosis of NHAP is suspected or established and there are no advance directives to the contrary, four major decisions must be considered in addition to the actual choice of a specific antibacterial agent: (1) location of treatment—facility/home or hospital; (2) initial route—oral versus parenteral—of a treatment for those treated in the nursing home; (3) timing of switch to an oral agent in those

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given parenteral therapy in the nursing home or hospital; and (4) duration of treatment (47). 1. Treatment Location There is increasing evidence that most episodes of NHAP can be treated successfully in the nursing home and that hospitalization has deleterious effects for survivors. In recent studies (4,20,43,44,47), 63% to 78% of NHAP episodes were treated in the nursing home, with mortality ranging from 13% to 22%. A study that evaluated factors associated with hospitalization found, by multivariate analysis, that a respiratory rate more than 40 breaths per minute and evaluation in the evening predicted transfer to the hospital (4). In another study of the 2-month mortality and functional status of residents with NHAP treated in the nursing facility versus the hospital that stratified severe pneumonia were those with a respiratory rate 40 breaths per minute, there was no significant difference in acute mortality between those treated in the nursing facility (13%) versus the hospital (12%). However, a significantly greater proportion of survivors treated in the nursing facility had no change in functional status or had better function at 2 months of follow-up (55%) compared with those treated in the hospital initially (39%; P .005). Treatment in the hospital was confounded by having a significantly greater proportion of patients with severe pneumonia (45% versus only 7% with severe pneumonia treated in the nursing facility). When episodes were stratified by severity of pneumonia and outcomes reassessed based on treatment location, among those with severe pneumonia, only immediate death was significantly lower with treatment in the hospital (10%) versus in the nursing facility (38%; P .047). However, short-term (2-month) mortality and functional status were no different in the two groups (hospital versus nursing facility treatment). In contrast, in those with mild pneumonia, there was no difference in immediate mortality between treatment in the nursing facility versus the hospital, but death or functional decline at 2 months occurred significantly less often in those treated in the nursing facility (34%) versus the hospital (58%; P .016). Therefore, for the majority of residents with NHAP who usually have mild to moderate infection, treatment in the nursing home is preferable. 2. Initial Route of Treatment in the Nursing Home Setting In recently published studies of NHAP (4,40,43,44,47), parenteral antibiotics (usually given by intramuscular injection) were prescribed for 16% to 44% of episodes initially treated in the nursing home. No significant difference in mortality has been identified between those treated initially with an oral agent or an intramuscular agent in the nursing home (4,44,47). Moreover, it was not possible to define factors predictive of prescribing parenteral therapy initially for NHAP in the nursing home setting (47). The inability to identify factors predicting the use of initial parenteral therapy for NHAP may explain the wide variation in use of this approach in published studies, and this issue requires further evaluation.

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3. Timing of Switch to Oral Therapy Timing of the switch to oral therapy depends on the resident with NHAP reaching clinical stability, that is, improvement in symptoms and signs, afebrile for 16 hours, no other acute life-threatening complications, and ability to take oral medications (55). One study (47) has specifically addressed the issue of timing of switch to oral therapy among residents with NHAP. In that study, 75% of residents who were prescribed an intramuscular antibiotic received this therapy for 3 days or less, whereas in the hospital, the median duration of intravenous antibiotic therapy was 5 days, and 75% of patients were treated with intravenous antibiotics for 7 days. Thus, it is advisable to assess residents treated in the nursing home for clinical stability and to switch to an oral agent beginning on day 2 of therapy and for those initially treated in the hospital on day 3 of therapy (47). 4. Duration of Treatment Duration of treatment of NHAP has not been evaluated in randomized clinical trials. One study (47) has retrospectively assessed duration of therapy of NHAP. For episodes treated initially in the nursing home, there was no significant difference in mean duration of therapy between those treated with an oral agent only (9.4 days) and those treated with a parenteral agent followed by an oral agent (9.0 days; P .42). For 75% of residents, duration of therapy was 10 days for those treated in the nursing home. Thus, 7 to 10 days of therapy appeared to be the standard approach to treating NHAP in the facility (47). For episodes treated initially in the hospital, 75% of patients with NHAP received treatment (intravenous plus oral) for 14 days. 5. Choice of Antimicrobial Agent The 1993 American Thoracic Society guideline (56) for the evaluation and management of CAP and the 1998 Infectious Diseases Society of America (IDSA) CAP treatment guideline make no recommendation specifically for NHAP (57). The IDSA guideline was updated in 2000 (58) and there were no specific recommendations for NHAP. The lack of recommendations for NHAP in the American Thoracic Society guideline (56) may indicate that the expert panel did not consider this infection as a distinct clinical entity in terms of therapy (59). However, it has been emphasized that NHAP should be considered separately in terms of treatment because of the higher mortality compared with CAP in the elderly (37,59) and the impact of hospitalization on functional status of nursing home residents (41). In early 2000, the first guideline specifically for NHAP was published (47). Unlike the CAP treatment guidelines (56–58), which were based on the opinion of expert panels, the NHAP treatment guideline (47) was based on community

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practice. In the study population upon which the guideline was based (47), a wide range of oral agents was recommended for treatment in the nursing home because there was no clear consensus about this approach to therapy among practicing physicians. However, the guideline does warn against the use of a macrolide or trimethoprim/sulfamethoxazole because of increasing resistance of S. pneumoniae to these agents (60). Likewise, in the hospital setting, several different regimens were recommended. Noteworthy is that a parenteral macrolide was not recommended for NHAP treated in the hospital because of side effects and the issue of increasing resistance of S. pneumoniae. Subsequently, the Canadian Infectious Diseases Society published a separate CAP treatment guideline (61) in which there were specific recommendations for treatment of NHAP. This group recommended an oral quinolone (levofloxacin, gatifloxacin, or moxifloxacin) alone or amoxicillin/clavulanate plus a macrolide as the first choice for treatment of NHAP in the nursing home. For treatment of NHAP in the hospital, the first choice was a quinolone alone and the second choice was a second- or-third generation cephalosporin plus a macrolide. Thus, the practitioner involved in the treatment of NHAP has several guidelines (47,58,61) to follow when making a choice of antimicrobial agent(s). The antimicrobial choice should be based on the most likely potential pathogens, the potential for antibiotic resistance, and adverse effect profile of various agents. There clearly is no need to be concerned about atypical pathogens (Mycoplasma pneumoniae, C. pneumoniae, or Legionella sp) as they rarely cause NHAP. Although gram-negative aerobic bacilli are not a frequent cause of NHAP, they should be considered as a potential pathogen in NHAP (62). The primary focus of treatment should be on adequate coverage for S. pneumoniae, nontypeable H. influenzae, and M. catarrhalis. A variety of regimens will be effective (47). However, the most logical and simple approach is to use a quinolone such as levofloxacin, gatifloxacin, or moxifloxacin as initial therapy as suggested by the Canadian guideline (61). The quinolones provide excellent coverage for the common bacterial pathogens that cause NHAP, can be administered once a day, and had a low sideeffect profile. Concerns about the development of quinolone resistance among pneumococci are appropriate (63), but this caveat does not apply to the treatment of true bacterial infection. It is the unnecessary use and overuse of quinolones and macrolides, as in the treatment of viral upper respiratory tract infection in the community setting, that is increasing the resistance to these agents among pneumococci (64). Recommendations for empiric regimens for treatment of NHAP in the nursing home or hospital are listed in Table 1. One of the most provocative studies to date addressing treatment of pneumonia in the hospitalized elderly was a retrospective analysis of hospital records of 12,945 Medicare patients with pneumonia; 3,194 (25%) episodes were in nursing home residents (65). Associations between initial antimicrobial regimens and 30-day mortality were evaluated using statistical methods to control for multiple

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Table 1 Empirical Antibiotic Regimens for the Treatment of Nursing Home-Acquired Pneumonia Treatment in the Nursing Home 1. Decide on the route of administration—oral or parenteral (intramuscular). Consider the intramuscular route if the resident is unable to take oral medications and there is no alternative enteral route available. 2. Oral regimens: A. Quinolone: Gatifloxacin 400 mg once daily Levofloxacin 250–500 mg once daily Moxifloxacin 400 mg once daily B. Amoxicillin/clavulanate 875 mg PO twice daily C. Cefuroxime axetil 500 mg twice daily 3. Parenteral regimens: ceftriaxone 500–1000 mg IM once daily or cefotaxime 500 mg IM twice daily 4. If a parenteral regimen is used initially, evaluate the resident for clinical stability beginning on day 2 to identify the time to switch to an oral regimen. Clinical stability is defined as improvement in symptoms and signs, afebrile for 16 hours, no evidence of other organ compromise, and able to take oral medication 5. Duration of treatment does not need to exceed 10 days in most patients Treatment in the Hospital 1. Intravenous regimens: Gatifloxacin 400 mg once daily Levofloxacin 250–500 mg once daily Ceftriaxone 500–1000 mg once daily Cefotaxime 500 mg every 12 hours Cefuroxime 750 mg every 8 hours Ampicillin/sulbactam 1.5 g every 6–8 hours 2. Timing of switch to an oral regimen should be determined by when clinical stability is achieved, as defined above. Once it is determined that the resident can be switched to an oral regimen, there is no need to continue hospitalization unless there are extenuating circumstances 3. Oral regimens: same as for treatment in the nursing home 4. Duration of therapy does not need to exceed 10 days but should be no longer than 14 days Abbreviation: IM, intramuscular.

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confounding factors. Among the nursing home residents in this study, there was a trend toward a lower mortality with the initial use of a quinolone alone, a secondgeneration cephalosporin plus a macrolide, or a nonpseudomonal third-generation cephalosporin plus a macrolide, compared with the reference regimen (a nonpseudomonal third-generation cephalosporin alone). These findings support the recommendations of the Canadian guideline (61) and perhaps challenge the notion that atypical pathogens are uncommon among nursing home residents with pneumonia. E. Managing Volume Depletion A factor that has gotten little attention in the management of NHAP is the state of hydration of the resident with this infection. Fever and the accompanying tachypnea observed with NHAP can lead to considerable insensible water loss. In addition, oral intake of liquids may be substantially decreased with any infection, including pneumonia. These factors may lead to relatively rapid and significant volume depletion in residents with NHAP. Therefore, it is important to assess the hydration status of each resident with NHAP. However, the bedside evaluation of hydration status of the nursing home resident is a not particularly reliable method in identifying those with dehydration (66,67). An objective assessment of hydration status of the resident with pneumonia should be done, for example, by measuring the serum blood urea nitrogen. The management of volume depletion related to NHAP in the nursing home setting is also difficult, especially if the resident has decreased mentation. Ineffective hydration of the resident with pneumonia in the nursing home may be one explanation for treatment failure that leads to hospitalization, but this has not been adequately studied. Because intravenous hydration is usually not an option in the nursing home setting, alternative methods, such as clysis (68), deserve consideration for residents who are not appropriate for or do not desire hospitalization. F. Summary Management of NHAP Because of the adverse effects of hospitalization on functional status and the lack of improvement in outcome with hospitalization for treatment of NHAP, except possibly in immediate mortality among the severely ill (41), most residents with pneumonia should be treated in the nursing home. Route (oral or parenteral) of initial treatment in the nursing home should be determined after considering the severity of pneumonia (39), ability to take oral medications, mental status, and state of hydration. If intramuscular antibiotic treatment is used, the switch to the oral route should be done as quickly as clinical stability has been achieved (47), especially if the resident can take oral medications. Total duration of treatment of

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NHAP in the nursing home setting rarely needs to exceed 10 days (47). If initial treatment of NHAP takes place in the hospital, duration of treatment should not exceed 10 days usually (47); on the day treatment is switched to an oral agent, the resident should be discharged back to the nursing home to complete therapy, unless there are complicating factors. G. Prevention 1. Vaccination The burden of pneumococcal disease in terms of incidence and mortality falls on the elderly (69). As a result, pneumococcal vaccination is recommended for persons ages 65 and older (70) (see Chapter 20). However, the efficacy of pneumococcal vaccine in the elderly has been the subject of considerable debate because of the lack of prospective, randomized, controlled trials (71–73). Despite this limitation, experts recommend vaccination of all elderly people because the vaccine is safe, inexpensive, and cost-effective (70,74). There is some indirect evidence of the value of pneumococcal vaccination among nursing home residents. Several outbreaks of invasive pneumococcal disease in nursing homes in which there was little or no use of the vaccine prior to the outbreak have been reported (75,76). Unfortunately, the immunogenicity of pneumococcal vaccine decreases with age, and efficacy diminishes fairly rapidly after vaccination, especially if given for the first time at an advanced age (77). These findings argue for periodic revaccination of the elderly nursing home resident to attempt to maintain effective serum antibody levels. The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices has recommended only a one-time revaccination after 5 or more years for those 65 years or older if vaccinated before age 65 (70). Based on published retrospective studies of efficacy of pneumococcal vaccine (73) and evidence of safety of revaccination (78), vaccination probably should be repeated every 5 years thereafter. The morbidity and mortality of influenza virus infection is greatest among the elderly (79). Efficacy of influenza vaccine in the elderly in preventing acute influenza is probably no greater than 40% (79) (see Chapters 13 and 20). However, the value of influenza vaccination in the elderly lies in the reduction in the complications related to this infection. Vaccination among the elderly in LTCFs can decrease the likelihood of outbreaks (80), decrease hospitalizations by 50% to 60% (81), and decrease mortality as much as 80% (81). Influenza vaccination also significantly reduces the risk of developing NHAP. Based on these findings, influenza vaccine is strongly recommended for all LTCF residents each year, unless there is some contraindication. There is also evidence that a high level of vaccination of LTCF staff decreases the morbidity and mortality of influenza among residents, as well as the incidence of influenza among staff (82).

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2. Oral Hygiene Oral health may be related to systemic infections among nursing home residents. Overall, oral hygiene is poor in this population (83,84). Poor oral hygiene in nursing home residents may increase the rate of colonization of dental plaque and oral mucosa by potential respiratory pathogens (85). Because aspiration of oropharyngeal flora into the lung is the major route of pathogenesis of NHAP (24), colonization of dental plaque and oral mucosa represents the reservoir of potential pathogens that can reach the lung. Therefore, maintaining good oral hygiene in nursing home residents may reduce colonization with respiratory pathogens, thereby reducing the occurrence of NHAP. A recent randomized study of nursing home residents supported the hypothesis that oral care and hygiene reduces the incidence of NHAP as well as deaths related to NHAP when compared with a control group not receiving oral care. Furthermore, the oral care was feasible through family members and nursing staff assisting with brushing the teeth of the resident after each meal and dentists/hygienists providing oral care once weekly (85a). Further investigation of the link between oral hygiene and development of NHAP is warranted, as are studies of practical methods to improve oral hygiene in nursing home residents. 3. Controlling Gastroesophageal Reflux Gastroesophageal (GE) reflux is common and has been estimated to occur in one third of the elderly (86). Aspiration of material from the stomach can damage the trachea in those with GE reflux. The supine position and nasogastric tubes also promote gastric content aspiration. The simplest approach to managing GE reflux is to elevate the head of the bed and minimize the use of nasogastric tubes. Use of agents to decrease reflux should be considered, but there is no evidence that such treatment reduces the risk of gastric content aspiration or NHAP. 4. Pharmacologic Interventions A recent report described the available literature on interventions to prevent pneumonia among the elderly (25). Limited studies suggest that angiotensin-converting enzyme inhibitors, which increase the sensitivity of the cough reflex and improve the swallowing reflex in elderly prone to aspiration, decrease the risk of pneumonia (87,88). Amantadine, when given orally, may also significantly reduce pneumonia rates in stroke patients (89). These observations are provocative, but none of these interventions can be recommended at this time as these studies have not been replicated or performed in large numbers of patients in controlled, randomized trials. Efforts should also be made to minimize the use of sedative hypnotics and narcotic analgesics that may suppress the cough reflex. 5. Feeding Tubes and Gastric Content Aspiration One of the primary reasons for the use of feeding tubes has been to attempt to reduce the risk of aspiration among residents with dysphagia (90). There is now am-

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ple evidence that feeding tubes do not prevent aspiration in residents with dementia (30,91–93). In a nonrandomized study, residents with dysphagia fed orally had fewer major aspiration events than tube-fed residents (94). In addition, there is no evidence that a jejunostomy is associated with lower rates of pneumonia compared with gastrostomy (95,96). There is also no evidence that tube feeding improves quality of life or prolongs survival of nursing home residents (97). Several authors (90,97) have concluded that there is a limited role for tube feeding among residents with dysphagia and advanced dementia, and its use should be discouraged.

II. BRONCHITIS In contrast to NHAP, bronchitis or tracheobronchitis has not been extensively studied among residents of LTCF. Lower respiratory tract infection (LRTI; bronchitis or tracheobronchitis) other than pneumonia in nursing home residents has been defined as the presence of at least three of the following symptoms or signs in the absence of pneumonia on a radiograph or if a radiograph is not done: new or increased cough, new or increased sputum production, fever (38°C), pleuritic chest pain, new or increased rales, rhonchi, wheezing or bronchial breathing, or change in status of breathing (new or increased shortness or breath, respiratory rate 25 breaths per minute), or worsening mental or functional status (90). A. Epidemiology and Clinical Relevance Most published studies of infections in LTCFs have not made a distinction between pneumonia and bronchitis when reporting the incidence or prevalence of LRTI (8–16,19,22,23). However, two studies (17,21) have provided some data on incidence of bronchitis in LTCFs. A prospective study of infections in one LTCF during a 3-year period (1984–1987) found that LRTI accounted for 286 (36%) of 788 total infections identified (17). Of these 286 LRTIs, 115 (13% of the 788 infections) were identified as bronchitis, and the incidence of bronchitis was one episode per 1000 resident-care days for the 3-year study period. In a prospective study of bronchitis among 475 nursing home residents in five LTCFs in Toronto, Ontario, Canada between 1993 and 96, 89 (19%) of the 475 residents had one or more episodes of bronchitis during the surveillance period, for an incidence of 0.5 episodes per 1000 resident-care days. The cumulative incidence of bronchitis after 3 years was 24%. Univariate predictors of bronchitis were increasing age, immobility, and female sex, whereas influenza and pneumococcal vaccinations were associated with a decreased risk of bronchitis. In the multivariate analysis, only increasing age (in deciles) and immobility were predictors of bronchitis, and influenza vaccine was protective (21).

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The same study also specifically addressed the microbial etiology of bronchitis in nursing home residents. Nasopharyngeal swab cultures and paired acute and convalescent sera to identify the etiology of both pneumonia and bronchitis in their study population were used. Of 272 episodes of pneumonia and bronchitis, 166 had nasopharyngeal swabs, of which 60 (36%) grew respiratory viruses (influenza A and B [n 18], parainfluenza [n 40], and respiratory syncytial virus [n 2]). In only 15 episodes was a bacterial etiology identified, of which the most common organisms were H. influenzae (n 3), Staphylococcus aureus (n 3), and C. pneumoniae (n 3). These results indicate that respiratory viruses are the most common cause of bronchitis among nursing home residents. B. Clinical Manifestations The manifestations of bronchitis in nursing home residents have not been carefully delineated in any specific study. Studies have relied on consensus definitions (98) that have not been validated for the identification of infection in the LTCF. The best definition for the diagnosis of bronchitis includes one or more of the following: cough, pleuritic chest pain, fever of 37.77°C (100 F) or higher, or purulent sputum, plus no auscultatory findings of pneumonia (rales, rhonci, or dullness to percussion), or a chest radiograph without evidence of pneumonia (17). In contrast, another definition allows for auscultatory findings (rales, rhonci, wheezing, or bronchial breathing) as part of the definition, and this may be more indicative of pneumonia, especially in the absence of a chest radiograph (98). C. Diagnostic Approach The guideline for evaluation of fever and infection in the LTCF (51) does not specifically address the issue of the diagnosis of bronchitis. However, symptoms and signs of pneumonia and bronchitis overlap considerably (98). Therefore, the presence of symptoms and signs of LRTI should prompt an evaluation for pneumonia, as previously outlined in the section on NHAP using the guideline (51). Those who have no evidence of pneumonia on chest radiograph or with no findings on chest auscultation should be considered to have bronchitis. D. Therapeutic Interventions No studies specifically address the antimicrobial treatment of bronchitis in nursing home residents. However, one study suggests that most of these infections are caused by viruses and that treatment with antibacterial agents is usually not indicated (21). This recommendation is consistent with a recent review of the treatment of uncomplicated acute bronchitis in healthy adults (99). However, respiratory tract infections often lead to the use of antibacterial therapy in the LTCF.

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Using a methodology for monitoring antibiotic use in four LTCFs, monthly variations in occurrence of respiratory infections (upper and lower combined) explained about one third of the monthly variation in antibiotic use (100). Because almost all upper respiratory tract infections and many episodes of bronchitis are caused by viruses, there is little need for antibacterial treatment most of the time (see Chapter 13). E. Infection Control Measures and Prevention Infection control measures related to bronchitis are a function of the mechanisms of spread of respiratory viruses, for the most part. Prevention relates to the use of influenza vaccine. These topics are covered in detail in Chapter 13.

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Arden N, Monto AS, Ohmit SE. Vaccine use and the risk of outbreaks in a sample of nursing homes during an influenza epidemic. Am J Pub Health 1995; 85:399– 401. Gross PA, Hermogenes AE, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med 1995; 123:518–527. Potter J, Stott DJ, Roberts MA, Elder AG, O’Donnell B, Knight PV, Carman WF. Influenza vaccination of health care workers in long-term care hospitals reduces the mortality of elderly patients. J Infect Dis 1997; 175:1–6. Limeback H. The relationship between oral health and systemic infections among elderly residents of chronic care facilities: A review. Gerodontology 1988; 7:131– 137. Berkey DB, Berg RG, Ettinger DL, Meskin LH. Research review of oral health status and service use among institutionalized older adults in the United States and Canada. Spec Care Dent 1991; 11:131–136. Scannapieco FA, Mylotte JM. Relationships between periodontal disease and bacterial pneumonia. J Periodontol 1996; 67:1114–1122. Yoneyama T, Yoshida M, Mukaiyama H, Okamoto H, Hoshiba K, Ihara S, Yanagisawa S, Ariumi S, Morita T, Mizuno Y, Ohsawa T, Akagawa Y, Hashimoto K, Sasaki S, and members of the Oral Care Working Group. Oral care reduces pneumonia in elderly patients in nursing homes. J Am Geriatr Soc 2002; 50:(in press). Barish CF, Wu WC, Castell DO. Respiratory complications of gastroesophageal reflux. Arch Intern Med 1985; 145:1882–1888. Sekizawa, Matsui T, Nakagawa T, Nakayama K, Sasaki H. ACE inhibitor and pneumonia. Lancet 1998; 352:1069. Arai T, Yasuda Y, Toshima S, Yoshimi N, Kashiki Y. ACE inhibitors and prevention of pneumonia in elderly people. Lancet 1998; 352:1937–1938. Nakagawa T, Wada H, Sekizawa K, Arai H, Sasaki H. Amantadine and pneumonia. Lancet 1999; 353:1157. Gillick M. Rethinking the role of tube feeding in patients with advanced dementia. N Engl J Med 2000; 342:206–210. Finucane TE, Bynum JP. Use of tube feeding to prevent aspiration pneumonia. Lancet 1996; 348:1421–1424. Bourdel-Marchasson I, Dumas F, Pinganaud G, Emeriau JP, Decamps A. Audit of percutaneous endoscopic gastrostomy in long-term enteral feeding in a nursing home unit. Int J Qual Health Care 1997; 9:297–302. Langmore SE, Terpenning MS, Schork A, Chen Y, Murray JT, Lopatin D, Loesche WJ. Predictors of aspiration pneumonia: how important is dysphagia? Dysphagia 1998; 13:69–81. Feinberg MJ, Knebl J, Tully J. Prandial aspiration and pneumonia in an elderly population followed over 3 years Dysphagia 1996; 11:104–109. Lazarus BA, Murphy JB, Culpeper L. Aspiration associated with long-term gastric versus jejunal feeding: A critical analysis of the literature. Arch Phys Med Rehabil 1990; 71:46–53. Fox KA, Mularski RA, Sarfati MR, Brooks ME, Warneke JA, Hunter GC, Rappa-

81.

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port WD. Aspiration pneumonia following surgically placed feeding tubes. Am J Surg 1995; 170:564–566. Finucane TE, Christmas C, Travis K. Tube feeding in patients with advanced dementia. A review of the evidence. JAMA 1999; 282:1365–1370. McGeer A, Campbell B, Emori TB, Hierholzer WJ, Jackson MM, Nicolle LE, Peppler C, Rivera A, Schollenberger DG, Simor AE, Smith PW, Wang E. Definitions of infection for surveillance in long-term care facilities. Am J Infect Control 1991; 19:1–7. Gonzales R, Sande MA. Uncomplicated acute bronchitis. Ann Intern Med 2000; 133:981–991. Mylotte JM. Antimicrobial prescribing in long-term care facilities: Prospective evaluation of potential antimicrobial use and cost indicators. Am J Infection Control 1999; 27:10–19.

15 Tuberculosis Shobita Rajagopalan Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California

I. EPIDEMIOLOGY AND CLINICAL RELEVANCE The aging population continues to represent the largest reservoir of Mycobacterium tuberculosis (Mtb) infection in industrialized nations including the United States (1,2). Tuberculosis (TB) case rates in the United States are highest for this age group compared with other age categories (3). Older residents of long-term care facilities (LTCFs) are at a greater risk for reactivation of latent TB as well as the acquisition of new TB infection in comparison to community-dwelling elderly (4). Prevention and control of TB in such facilities is therefore of key importance (4–7). The variable and atypical clinical presentations of TB in the elderly can delay diagnosis and treatment, resulting in increased morbidity and mortality in this age group; this treatable infection can be an unfortunate autopsy finding. The Institute of Medicine report, Ending Neglect: The Elimination of TB in the U.S., sponsored by the Centers for Disease Control and Prevention (CDC) reaffirms the commitment to the goal of eliminating TB in the United States by the year 2010, defined as case rates of less than 1 case per million population per year (8). The focus of such intensive TB control efforts on all high-risk populations, including the institutionalized elderly, must be prioritized (9,10). This chapter will discuss the epidemiology, pathogenesis, and clinical features of TB in aging adults, and TB treatment, prevention, and control strategies for residents of LTCFs. A. Epidemiology A global estimate of 8 million cases and 3 million deaths had been attributed to TB in 1998 (11). In the United States, more than 17,000 new TB cases were reported 245

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in 1999 (12). In 1999, the reported case rate of TB in persons aged 65 and older was 11.7 compared with case rates of 7.3 and 8.2, respectively, in persons aged 25 to 44 and 45 to 64 (3). The 1992 resurgence of TB in the United States had been attributed to the human immunodeficiency virus (HIV) epidemic, migration from TB endemic countries, TB transmission within congregate settings, (e.g., prisons, LTCFs, and hospitals), lack of adequate TB control services, and multiple drug-resistant (MDR) TB cases. Since 1992, the downward trend of TB cases has resulted from effective TB control programs that emphasize prompt identification of cases, initiation of appropriate therapy, and monitoring of therapy completion, in addition to efforts to curb the HIV epidemic (13). The focus has shifted toward foreignborn TB cases, of which a disproportionate rise has been noted; older adults also contribute to this upward trend in TB case rates (11,14). A significant percentage (80% to 90%) of TB in the elderly occurs in community dwellers; however, there is a two to three times higher incidence of active TB in nursing home residents compared with their counterparts living in noninstitutionalized settings (15). Published data have demonstrated the heightened efficiency of TB transmission within congregate settings such as prisons, nursing facilities (nursing homes), chronic care facilities, and homeless shelters; the awareness about TB infection and disease in the institutionalized elderly has thus been stimulated (4–6,16). B. Pathogenesis The following is a concise summary of the well-integrated disease mechanisms relevant to the natural history and clinical course of TB in aging adults (17–19). Inhaled tubercle bacilli are engulfed by alveolar macrophages and transported to regional lymph nodes. Infected macrophages and circulating monocytes secrete proteolytic enzymes, generating an exudative lesion. Activated mononuclear phagocytes stimulate granuloma formation with subsequent activation of T cells, which ultimately triggers the onset of cell-mediated immune (CMI) and delayedtype hypersensitivity (DTH) responses—clinically correlated with a positive dermal reactivity to standard-dose tuberculin antigen. As the major component of the immune system affected by senescence is the T cell-mediated response, dermal reactivity to tuberculin must be interpreted cautiously (reviewed further in “Diagnostic Approach,” below) (17). The characteristic Ghon complex that ultimately develops consists of organized collections of epithelioid cells, lymphocytes, and capillaries. Tubercle bacilli are confined and their growth restrained within caseous necrosis and surrounding fibrosis with ultimate healing. Reactivation (secondary or post-primary) TB is associated with granuloma liquefaction and rupture into the bronchoalveolar and vascular systems, which promotes widespread microbial dissemination. Approximately 90% of active TB disease cases (TB disease) in the elderly are the result of reactivation of primary infection (15). Tuberculosis without ac-

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tive disease (TB infection; latent TB) may occur in 30% to 50% of aging individuals. Rarely, previously infected older persons may eventually eliminate the viable tubercle bacilli and revert to a tuberculin-negative state and a “naive” immunologic status; these individuals are at risk for new infection (reinfection) with Mtb. Thus older persons potentially at risk for TB include individuals never exposed to Mtb, those with latent and dormant primary infection that may reactivate, and others who are no longer infected and at risk for reinfection. Because animal model studies have clearly documented the association between age-related decline in T-cell responses and the enhanced risk of infections by intracellular pathogens including Mtb, immunosenescence or immune dysregulation are likely to play a role in the relapse of dormant infection in the elderly. However, other factors, including age-associated diseases (e.g., malignancy, diabetes mellitus), poor nutrition, immunosuppression, chronic renal failure, and chronic institutionalization contribute to this increased risk for TB in the elderly (9) (see Chapter 4).

II. CLINICAL MANIFESTATIONS Clinical manifestations of TB disease in the elderly can be relatively atypical. Active tuberculous lung involvement occurs in approximately 75% of elderly persons infected with Mtb; the classic clinical features of pulmonary TB, that is, cough, hemoptysis, fever, night sweats, and weight loss, may be absent (20). In addition, disseminated or miliary TB, tuberculous meningitis, skeletal and genitourinary TB increase in frequency with advancing age (2,21–29). Tuberculosis in this population may present clinically with decline in functional status (e.g., activities of daily living), chronic fatigue, cognitive impairment, anorexia, weight loss, or unexplained low-grade fever (15,22). Unrecognized TB must thus be in the differential diagnosis of prolonged, unexplained, nonspecific symptoms and signs in an elderly individual.

III. INFECTION CONTROL In this section, we will discuss diagnostic approach, therapeutic interventions, and prevention within the context of TB infection control. All LTCFs should develop and maintain appropriate TB prevention and control strategies to ensure protection of its residents and staff against this highly communicable disease (7,16). Published recommendations by the Advisory Committee for Elimination of TB (ACETB) in conjunction with the CDC staff and public health consultants are available to guide such TB control efforts (7). In large facilities, an infection control committee is usually responsible for the TB prevention and control program;

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in a system that has more than one facility providing long-term care to the elderly, a qualified individual should evaluate the overall infection control implementation at all the facilities. The four principal aspects of effective TB infection control in LTCFs include: surveillance, containment, assessment, and education. A. Surveillance Identification and reporting all cases of TB infection and TB disease in the facility among all residents and staff is referred to as surveillance. When an infectious case is documented, additional cases and new infections, as indicated by skin-test conversion (described in “Diagnostic Approach,” below) should be identified with the help of the state of local health department, and appropriate therapy should be instituted (30–32). The surveillance process is outlined as follows: All new residents on admission and all employees should receive a two-step tuberculin test. All individuals with a reaction of 10 mm or more of induration should have a follow-up chest radiograph to identify current or past tuberculous lung involvement. Skin-test-negative employees or volunteers having contact (of 10 or more hours per week) with patients should periodically have repeat skin tests, the frequency depending on the risk of tuberculous infection at that facility. Follow-up skin tests should be performed for tuberculin-negative persons after any suspected exposure to a documented case of active TB. Human immunodeficiency virus testing should be recommended for all staff and patients with TB infection or disease. Staff members suspected of having TB disease should be relieved of their work responsibilities until the diagnosis is either excluded or they are considered noninfectious as a result of effective antituberculous therapy. 1. Diagnostic Approach The tuberculin skin test is the best available screening intervention. A false-negative reaction to tuberculin increases with age, partly because of anergy (33) and the “booster phenomenon” of skin-test reactivity to antigen (34). All older persons who receive a tuberculin skin test (using 5 tuberculin units of Tween-stabilized purified protein derivative [PPD], and results read in 48 to 72 hours) should thus be retested within 2 weeks of a negative response (induration of less than 10 mm) to identify potentially false-negative reactors (35). A positive booster effect, and therefore a positive tuberculin reaction, is a skin test induration of 10 mm or more (an increase of 6 mm or more) over the first skin test reaction. Because 75% of all TB cases in the elderly occur in the respiratory tract, chest radiography is warranted after doc-

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umentation of a positive PPD skin test after the initial placement (by the booster effect or by conversion), or if the patient has clinical manifestations suggestive of TB. The majority of pulmonary TB cases in aging patients is reactivation disease; 10% to 20% of cases occur as a result of primary infection or reinfection. Clinicians must interpret radiographic diagnoses of TB in older patients judiciously, because the infection in the lung fields can often be atypical (36). All patients with pulmonary symptoms, radiographic changes compatible with TB, or both who have not been treated with anti-TB therapy should have sputum examination for Mtb by smear and culture. Elderly persons unable to produce sputum may be evaluated for a flexible fiberoptic bronchoscopy to obtain bronchial washings and bronchial biopsy to confirm the diagnosis (15). Because most LTCFs do not have the capacity to isolate residents suspected of having TB disease, these persons often merit transfer to an appropriate acute or subacute care facility for respiratory isolation and sputa collection. For suspected pulmonary TB, three fresh consecutive morning sputum specimens are recommended for routine mycobacteriologic studies that include an initial smear and culture for Mtb (31). Rapid techniques that use radiometric systems, specific DNA probes, and the polymerase chain reaction (PCR) help supplement routine mycobacterial culture methods that require up to 6 weeks for the growth of Mtb (37). The rapid diagnosis of TB is particularly important in the high-risk elderly population, as well as HIV-infected persons, other immunocompromised hosts, and patients with multiple-drug-resistant (MDR)-TB. Histological examination of tissue from various sites such as the liver, lymph nodes, bone marrow, pleura, or synovium that show the characteristic caseous necrosis with granuloma formation is also useful for the diagnosis of TB disease. B. Containment Containment ensures that transmission of TB infection is effectively halted. Persons for whom treatment of TB infection or TB disease is indicated should complete the recommended course of treatment under direct observation (see section on “Treatment”; Sec. III.B.1). Appropriate respiratory isolation and ventilation control measures should be applied in pulmonary TB disease cases. As alluded to earlier, the vast majority of LTCFs do not have the ability to initiate isolation and ventilation control measures. Residents of such LTCFs who are suspected of having TB disease will most likely require transfer to an acute care facility or a facility with the capacity to manage TB cases. Confirmed or suspected infectious TB cases do not require isolation precautions providing the following conditions are met: Three consecutive concentrated sputum smears are negative and chemotherapy is begun promptly at the time of confirmation or suspicion of diagnosis. Current and recent contacts are assessed and given appropriate therapy.

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New contacts can be prevented for a 1-to 2-week period. In the event that these conditions cannot be fulfilled, and in case of homelessness, suspected or known history of noncompliance, MDR-TB, and illicit drug use, the local health department (which should be informed of all suspected or proven TB cases) facilitates methods to achieve appropriate respiratory isolation. 1. Treatment Because of the rise of MDR-TB cases, TB treatment recommendations have been modified (Table 1) (32). Most cases of active TB in the elderly result from reactivation of a latent infection. Presumably, these persons acquired the infecting organism before the effective antituberculous chemotherapy was available. Hence, unless the older patient is from a high-prevalence country with Mtb drug-resistance, had received prior inadequate Mtb chemotherapy, or had acquired the infection from a known MDR-TB contact, most TB cases in the elderly will be highly susceptible to isoniazid and rifampin. Thus, in areas where isoniazid resistance is 4% or less, or if the population in question has a low risk for drug resistance, such as most older persons, the empirical four-drug regimen is not necessary. The more intensive, shorter duration antituberculous drug regimens can attempt to minimize treatment noncompliance and development of drug resistance, particularly when administered by directly observed therapy (DOT); however, the potential for drug toxicity limits their use in older patients. Elderly persons are at greater risk for hepatic toxicity from isoniazid, but this risk is low in frequency and mild. It is recommended that clinical assessments as well as baseline liver function tests be performed before the initiation of isoniTable 1 Treatment Regimens of Tuberculosis Option 1

Option 2

Option 3

Isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin for 8 weeks followed by isoniazid and rifampin for 16 weeks daily or 2–3 times/week (DOT)* Isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin for 2 weeks followed by 2 times/week administration of the same drugs for 6 weeks (DOT), then 2 times/week administration of isoniazid and rifampin (DOT) for 16 weeks Isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin 3 times a week (DOT) for 6 months. Consult a tuberculosis medical expert if patient is still symptomatic, or smear or culture is positive after 3 months

* DOT: Intermittent dosing should be directly observed therapy. In areas where primary isoniazid resistance is less than 4%, omit fourth drug, streptomycin is not recommended for the elderly. Source: Ref. 32.

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Table 2 Skin Test Criteria for Positive Tuberculin Reaction (MM Induration)* 5 mm* 1. HIV-positive persons 2. Recent contacts of person(s) with infectious tuberculosis 3. Persons with chest radiographs consistent with tuberculosis (e.g., fibrotic changes) 4. Patients with organ transplants and other immunosuppressed hosts receiving the equivalent of 15 mg/day prednisone for 1 month 10 mm* 1. Recent arrivals ( 5 yr) from high-prevalence countries 2. Injection drug users 3. Residents and employees of high-risk congregate settings: prisons, jails, nursing homes, other health care facilities, residential facilities for AIDS patients, and homeless shelters 4. Mycobacteriology laboratory personnel 5. High-risk clinical conditions: silicosis; gastrectomy; jejunoileal bypass; 10% below ideal body weight; chronic renal failure; diabetes mellitus; hematological malignancies (e.g., lymphomas, leukemias); other specific malignancies (carcinoma of the head or neck, and lung) (alcoholics are also considered high risk) 15 mm† 1. Persons with no risk factors for TB * Chemoprophylaxis recommended for all high-risk persons, regardless of age. † Persons considered otherwise low risk regardless of age: 15 mm induration is positive. Abbreviations: HIV, Human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome. Source: Ref. 31.

azid and rifampin (and pyrazinamide) therapy in older persons. Periodic laboratory monitoring seems a prudent practice, particularly in the frail elderly who may not be able to communicate warning symptoms of drug toxicities. A rise in serum aminotransferase (SGOT) level to five times above normal or clinical evidence of hepatitis necessitates the prompt discontinuation of isoniazid (as well as other hepatotoxic agents); these drugs may subsequently be resumed at lower doses and gradually increased to full doses as tolerated. Relapse with drug rechallenge will require trial of an alternative regimen. 2. Prevention Recently published recommendations for the treatment of latent TB infection based on tuberculin skin test induration criteria are shown in Tables 2 and 3 (31). Ideally the TB infection control program in most acute care facilities as well as LTCFs should consist of three types of control measures: administrative actions (i.e., prompt detection of suspected cases, isolation of infectious patients, and prompt institution of appropriate treatment), engineering controls (negative-pressure ventilation rooms, high efficiency particulate air [HEPA] filtration, and ul-

Twice weekly for 6 months Daily for 2 months Twice weekly for 2–3 months

Daily for 4 months

RifampinPyrazinamide (PZA)

Rifampin

In HIV persons, INH can be given with nucleoside reverse transcriptase inhibitors (PTs), (NNRTI’s) DOT must be used with twice-weekly dosing Not indicated for HIV, fibrotic lesions on CXR, or children DOT with twice-weekly dosing May also be offered to persons with INH-resistant, rifampin-susceptible TB In HIV persons, PIs or NNRTIs should generally not be administered with rifampin; rifabutin can be used with indinavir, nelfinavir, amprenavir, ritonavir, efavirenz, nevaripine, or soft gel saquinavir DOT with twice-weekly dosing Intolerance of PZA INH-resistant, rifampin-susceptible TB with intolerance of PZA

Comments

A

B C C A

C

B

B B B B

C

B

HIV

A

HIV

Rating*

*Rating: A Preferred; B Acceptable alternative; C Offer when A and B cannot be given. Abbreviations: TB, Tuberculosis; HIV, Human immunodeficiency virus; PI, Protease inhibitor; NNRTI, Nonnucleoside reverse transcriptase inhibitor; DOT, Directly observed therapy; CXR, Chest X-ray. Source: Ref. 31.

Daily for 2 months

Twice weekly for 9 months

Daily for 9 months

Isoniazid

Isoniazid (INH)

Drug

Interval and duration

Table 3 Recommended Drug Regimens for Treatment of Latent (TB) Infection in Adults (Including the Elderly)

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traviolet germicidal irradiation [UVGI]), and personal respiratory protection requirements (masks). Such measures, though, are not feasible in the majority of LTCFs because of limited staffing, resources, and diagnostic capabilities. Furthermore, the mission, goals, and clinical function of LTCFs are different from acute care facilities. While instituting such infection control measures in elderly TB patients, clinicians should be aware of the presence of concomitant chronic conditions and functional disabilities that often require more assistance and care, as well as the importance of minimizing prolonged isolation. C. Assessment Assessment refers to monitoring and evaluation of the surveillance and containment activities throughout each facility. A record-keeping system is necessary to track and assess the status of persons with TB infection and disease. Such a system should also generate data needed to assess the overall effectiveness of the TB control efforts. State and local health departments should provide support in updating policies and record-keeping systems for TB control in LTCFs in addition to expert TB medical consultation when needed. A health department representative should also be designated to provide epidemiological and management assistance to such facilities. State health departments are responsible for maintaining an updated TB registry for all persons with TB infection or disease (including LTCFs) within their jurisdiction. The health department staff should annually review the following information for each LTCF, comparing it with previous data and data from similar LTCFs: Percentage of residents and staff with positive tuberculin skin tests within the facility Percentage of tuberculin skin test conversion Description of treatment and supervision Percentage of persons who have successfully completed recommended therapy (goal is 95%) Number of persons reporting drug intolerance or adverse effects Number of persons unable to complete therapy and the reason for therapy discontinuation D. Education Providing information and imparting skills to LTCF residents, families, visitors, and employees to ensure understanding and cooperation with surveillance, containment, and assessment recommendations are all part of education. Staff from the LTCF, with the assistance of the local health department’s designee, can counsel residents, families, and visitors. Reading materials, pamphlets, videotaped demonstration, and internet access to the World Health Organization (WHO), National In-

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stitutes of Health (NIH), CDC, and other recommended web sites may also provide useful tools for TB education. The LTCF staff must have frequent in service training sessions regarding TB infection control. Because of varying levels of education, differences in cultural background, and potential language barriers, the teaching sessions should be conducted by individuals experienced in educating diverse groups. Finally, quality assurance audits should be linked to such educational efforts with continuous feedback to staff to ensure the required impact. REFERENCES 1. 2. 3. 4. 5.

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Davies PD. Tuberculosis in the elderly: An international perspective. Clin Geriatr 1997; 5:15–26. Rajagopalan S. Tuberculosis in the elderly: A global health problem. Clin Infect Dis 2001, in press. Centers for Disease Control Facts Sheets, 1999. Tuberculosis Cases and Case Rates per 100,000 Population by Age Group: United States, 1989–1999. Stead WW. Tuberculosis among elderly persons, as observed among nursing home residents. Int J Tuber Lung Dis 1998 (Suppl 1): S64–S70. Stead W, Lofgren J, Warren E, Thomas C. Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. N Eng J Med 1985; 312:1483–1487. Stead WW. Special problems in tuberculosis. Tuberculosis in the elderly and in residential homes, correctional facilities, long-term care hospitals, mental hospitals, shelters for the homeless, and jails. Clin Chest Med 1989; 10:397–405. Centers for Disease Control. Prevention and control of tuberculosis in facilities providing long-term care to the elderly. Recommendations of the Advisory Committee for Elimination of Tuberculosis. MMWR 1990; 39/RR-10:7–20. Institute of Medicine (U.S.) Committee on the Elimination of Tuberculosis in the United States. Ending Neglect: The Elimination of Tuberculosis in the United States, 2000. In: Geiter L (ed). Washington DC, National Academy Press, pp 1–257. Yoshikawa TT, Norman DC. Infection control in long-term care. Clin Geriatr Med 1995; 11:467–480. Brewer TF, Heymann SJ, Stevens JP. New approaches to preventing and eliminating tuberculosis in the United States. Infect Med 2000; 17:45–48. WHO. The World Health Report. Making a difference. Geneva World Health Organization 1999; 3:310–320. Institute of Medicine. TB Elimination Report. Washington DC, May 2000. CDC Advisory Council for the Elimination of Tuberculosis. Opportunities, and renewed commitment. MMWR 1999; 48/RR-9:1–14. Zuber PLF, McKenna MT, Binkin NJ, Onorato IM, Castro KG. Long-term risk of tuberculosis among foreign-born persons in the United States. JAMA 1997; 278:304–307. Yoshikawa TT. Tuberculosis in aging adults. J Am Geriatr Soc 1992; 40:178–187. Rajagopalan S, Yoshikawa TT. Tuberculosis in long-term care facilities. Infect Control Hosp Epidemiol 2000; 21:611–615.

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16 Infected Pressure Ulcers Nigel Livesley and Anthony W. Chow University of British Columbia, and Vancouver Hospital Health Sciences Centre, Vancouver, British Columbia, Canada

I. EPIDEMIOLOGY AND CLINICAL RELEVANCE A. Definition Pressure ulcers have been defined by the Agency for Healthcare Research and Quality (AHRQ; formerly Agency for Health Care Policy and Research) as lesions caused by prolonged exposure to pressure that lead to tissue damage (1). They represent areas of necrosis caused by compression of soft tissues between bony prominences and external surfaces. This damage can be relatively minor or may lead to massive necrosis involving deeper tissues that can cause significant morbidity and mortality. B. Incidence and Prevalence The incidence and prevalence of pressure ulcers depends on the patient population studied and the definition of pressure ulcers. There are a number of systems for classifying pressure ulcers. The National Pressure Ulcer Advisory Panel (NPUAP) (2) classifies pressure ulcers in the following way (Fig. 1): Stage I Stage II Stage III Stage IV

Nonblanchable erythema of intact skin. Partial thickness skin loss involving the epidermis or dermis; lesion presents as an abrasion, blister, or superficial ulcer. Full thickness skin loss that may extend to but not through the fascia; the ulcer may be undermined. Full thickness skin loss involving deeper structures such as muscle, bone, or joint structures. 257

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Figure 1 The National Pressure Ulcer Advisory Panel (NPUAP) Classification of pressure ulcers. (a), Stage I: nonblanchable erythema of intact skin; (b), Stage II: partial thickness skin loss involving the epidermis or dermis; (c), Stage III: full thickness skin loss that may extend to but not through the fascia; (d), Stage IV: full thickness skin loss involving deeper structures beyond the fascia. (From Shea JD. Pressure ulcers: Classification and management. Clin Orthop Rel Res 1975; 112:89–100.)

Most studies assessing the epidemiology of pressure ulcers include those ulcers that are stage II and higher. Using this definition, the prevalence of pressure ulcers in nursing homes ranges from 1.2% to 11.3% (3,4). When stage I ulcers are included, the prevalence rises to between 4% and 29.7% (3). Seventeen percent of persons admitted to nursing homes have stage II or higher pressure ulcers on arrival (4). Of these patients, 81% come from an acute care hospital, 12% from home, and 7% from another nursing home. The incidence of pressure ulcers among persons admitted to nursing homes without pressure ulcers on arrival is 13% in 1 year, and 21% by 2 years (4).

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C. Risk Factors Not all nursing home residents are at equal risk of developing pressure ulcers. Risk factors can be classified as intrinsic or extrinsic. Limited mobility (5) and poor nutrition (6) are the strongest intrinsic predictors of pressure ulcer formation. Incontinence, increased age, diabetes mellitus, white race, abnormal skin, male gender, increased temperature, and decreased blood pressure have also been implicated in at least one multivariate analysis, but have not been associated in all studies (Table 1) (3). The extrinsic risk factors for pressure ulcer development are pressure, friction, shear stress, and moisture; of these the most important is pressure. 1. Pressure The highest intracapillary pressure is 32 mm Hg (Fig. 2). External pressures that exceed intracapillary pressure lead to transudation, which increases interstitial pressure and causes edema, ischemia, and autolysis. If the pressure is removed soon enough, reperfusion can occur and irreversible damage is prevented. If pressure is sustained, necrosis occurs. There is an inverse relationship between the degree of pressure and the time required for irreversible tissue damage (Fig. 3) (7,8). Several studies indicate that the critical period of applied pressure, before irreversible tissue damage is likely to occur, is within 1 to 2 hours (9,10). A patient lying on a hospital mattress can generate pressures of 40 to 75 mm Hg over bony prominences, particularly over the sacrum, greater trochanters, ischial Table 1 Risk Factors Associated with Pressure Ulcers

Risk factors Mobility or functional limitation Incontinence Nutritional factors Altered consciousness or impaired cognition Increased age Diabetes mellitus White race Skin abnormalities Stroke Contractures Male gender Increased body temperature Decreased blood pressure Source: Ref. 3.

Studies, reporting univariate associations

Studies reporting multivariate associations

6 5 4 3 2 2 2 1 1 1 1 1 1

3 1 4 0 1 1 1 1 1 0 1 1 1

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Figure 2 Pressure in various components of the tissue microcirculation. (From Ref. 8.)

Figure 3 Inverse relationship of pressure to time in the production of pressure ulcers. (From Ref. 8.)

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Figure 4 Common locations of pressure ulcers in the prone and supine positions, corresponding to areas of the skin surfaces (stippled) where pressures equal to or greater than mean capillary of the skin surfaces are exerted. (From Reuler JB, Cooney TG. The pressure sore: Pathophysiology and management. Ann Intern Med 1981; 94:661–666.)

tuberosities, dorsal spine, and the heels. This degree of pressure is sufficient to compromise the microcirculation, and these bony prominences correspond to the locations where pressure ulcers are most commonly identified clinically (Fig. 4) (7). A patient sitting can generate pressures of 300 mm Hg over the ischial tuberosities. Pressure is highest at the bone/muscle interface (6), and fat and muscle are more susceptible to pressure-related damage than skin (11). Thus, the superficial damage visible to the caregiver often underestimates the actual degree of destruction in deeper tissue layers (Fig. 5) (6,7). 2. Friction Friction occurs when two opposing surfaces move across each other. In this case, it is the skin rubbing across sheets when a patient is dragged into a new position. This leads to damage at the surface and can compromise the skin barrier and lead to early ulceration (7).

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Figure 5 Pressure on any bony prominence is transmitted through the intervening tissues to the skin surface in a three-dimensional cone-shaped gradient, with the greatest pressure over a wide surface of bone and diminishing pressure toward the skin surface. (From Reuler JB, Cooney TG. The pressure sore: Pathophysiology and management. Ann Intern Med 1981; 94:661–666.)

3. Shearing Stress Shearing stress results from the sliding and relative displacement of adjacent structures. This occurs in patients being positioned with the head of the bed up, or from being pulled up the bed. These forces cause vessels to be crimped, increasing ischemia in surrounding tissues (7). Superficial tissues remain in place because of friction so that damage is exclusively in deep tissues. Therefore, the ulcers produced are often extremely undermined and much worse than external inspection would suggest (11). 4. Moisture Moisture, as from urinary or fecal incontinence, can increase the risk of pressure ulcers by fivefold (7). It can also be a source of bacterial contamination. D. Infection The epidemiology of infection in pressure ulcers has not been well described. A study demonstrated that infected pressure ulcers were the most common infectious problem in nursing homes, occurring in 6% of the 532 residents studied (12). The percentage of residents with pressure ulcers was not provided in this study. Another study followed up 16 long-term-care residents with pressure ulcers for 2,184 days (13). One was infected at enrollment and three developed infections during follow-up, for an incidence of 1.4 infections per 1,000 patientulcer days.

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The consequences of pressure ulcers are multiplied when they become infected. Superficial infection delays wound healing (14) and, therefore, prolongs pain and discomfort. Infections can also invade deeper tissues and cause more serious conditions, such as osteomyelitis and bacteremia. Bacteremia resulting from infected pressure ulcers accounts for 3.5 per 10,000 hospital discharges and has an inhospital mortality rate of 51% (15). Other studies have found osteomyelitis in 17% to 26% of patients with nonhealing pressure ulcers (16,17). Pressure ulcers have important implications for infection control and prevention measures taken in LTCFs. This will be addressed later in this chapter. E. Other Consequences and Cost of Pressure Ulcers Any pressure ulcer, infected or not, can cause severe or intolerable pain (18). Patients with pressure ulcers also have higher mortality rates (3), but it is unclear whether this is directly related to the ulcer or the comorbid conditions that increase the risk of pressure ulcers. Significant costs are associated with pressure ulcers. The mean cost per ulcer in a midwest LTCF in 1996 was $2,731 (19). Nearly 80% of this cost came from the 4% of patients who required hospitalization. The mean cost for 20 patients with pelvic osteomyelitis associated with pressure ulcers treated between 1994 and 1999 was $59,600 (20). The estimated cost for the treatment of all pressure ulcers in 1992 was $1.3 billion (21).

II. CLINICAL MANIFESTATIONS Superficial infections will generally manifest with erythema, warmth, and tenderness. Purulent discharge, foul odor, and crepitus may also be seen (14). Because of associated comorbid conditions and patient age, systemic signs such as fever and leukocytosis may be minimal or absent, even in grossly infected ulcers, and local signs of inflammation may not be readily apparent (14). Superficial infections can delay wound healing. This can occasionally be the only clue to the presence of infection and reflects the presence of more than 106 microorganisms per gram of tissue (14). A more serious manifestation of infection in pressure ulcers is osteomyelitis. This may manifest as a nonhealing wound with systemic toxicity, or it may be suspected on the basis of the clinical examination or radiological findings (16). It should always be considered in LTCF residents with fever, leukocytosis, or other signs of sepsis (12,22,23). Many residents will have few or no signs of infection other than a nonhealing wound. A low threshold of suspicion, therefore, is essential for recognizing infection associated with pressure ulcers (16).

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Bacteremia and sepsis, which can be secondary to superficial ulcers or osteomyelitis, are the most feared complications of pressure ulcers. Mortality rates among patients with sepsis are approximately 50% (22). Patients usually present with symptoms and signs of systemic toxicity such as fever, chills, confusion, and hypotension. III. DIAGNOSTIC APPROACH The approach to pressure ulcers requires clinical assessment and judgment, microbiological evaluation, imaging studies, and histopathologic confirmation of the diagnosis and extent of infection by deep tissue biopsies. A. Clinical Assessment Diagnosis of pressure ulcers begins with identifying the patients at risk and carefully examining for the earliest stages of pressure sore formation. The established pressure ulcer is usually easily recognized on the basis of its typical location and the clinical setting. A developing ulcer is often irregular in shape, whereas chronic ulcers tend to have regular edges with a thick fibrous ring below the surface. It must be emphasized that, because of the pressure gradient phenomenon, a very small surface defect commonly overlies a large undermining lesion. The clinical examination is critically important in identifying and locating pressure ulcers that may be an occult source of infection or sepsis; however, physical examination is less helpful in determining the extent of soft tissue infection underlying the pressure ulcer or whether there is an associated contiguous osteomyelitis. Soft tissue infections are diagnosed on the basis of purulent discharge, fever, local heat, erythema, swelling, or pain (24). The recognition of osteomyelitis underlying pressure ulcers is another matter. The clinical examination is accurate in the diagnosis of underlying osteomyelitis in only 56% of 36 patients, with a sensitivity of 33% and a specificity of 60% (16). Some authors have suggested that the presence of nonhealing ulcers is more likely associated with underlying osteomyelitis (17). This clinical finding has not distinguished infected from noninfected bone in other studies (16). Even the well-known rule suggesting that exposed bone must be infected has not been borne out in a recent study in which the incidence of osteomyelitis was only 14% among patients with exposed bone (16). B. Microbiological Evaluation All pressure ulcers will become colonized. Thus, the challenge of microbiologic evaluation is to be able to distinguish between isolates that are more likely to be associated with invasive infection (high virulence) rather than mere colonization (low virulence). Organisms isolated from blood cultures or from deep tissue

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biopsy bypassing the open wound, therefore, generally carry higher significance than those isolated from superficial swab cultures of the pressure ulcer. The relative value of superficial swabs, needle aspiration, and deep tissue biopsy for the microbiological evaluation of 72 pressure ulcers in patients aged 60 and older was assessed in one study (25). Swabs were taken using saline-moistened gauze in the ulcer bed. Aspirates were obtained by introducing a 22-gauge needle through disinfected intact skin and aspirating briskly while moving the needle in several directions. Deep tissue biopsies were obtained using sharp, sterile scalpels (26). Ninety-seven percent of cultures obtained from swabs were positive compared with 43% of aspirates and 63% of biopsies. It was concluded that the aspiration method was unreliable as it underestimated the number of isolates, compared with deep tissue biopsies. In addition to the different rates of bacterial recovery, the correlation between the species of bacteria found on deep biopsy compared with aspirates and swabs was poor. The reliability of needle aspiration compared with deep tissue biopsy in 32 patients with clinically infected pressure ulcers was determined in another study (27). Their aspiration technique involved instilling 1 mL of sterile saline into the wound margin and massaging the area before aspiration. Compared with deep tissue biopsy, the irrigation-aspiration technique had a sensitivity of 93% and specificity of 97%. A median of 4.5 bacterial species per ulcer was recovered by this method. However, aspirated samples from noninfected ulcers have also been shown to contain bacteria in 30% of cases, with the majority being usual skin contaminants (13). In a study of 23 consecutive patients, the bacteriology of pressure ulcers using both aerobic and anaerobic techniques was examined (28). Specimens were obtained either by needle aspiration, surgical drainage, or cotton swab. An average of four isolates per patient (three aerobes and one anaerobe) were recovered. Five times as many aerobes as anaerobes were isolated from the ulcers, but twice as many anaerobes as aerobes were recovered from blood among 19 bacteremic patients. The most common aerobic isolates from the ulcers included Proteus mirabilis, group D streptococci, Escherichia coli, staphylococci, and Pseudomonas sp. Anaerobic isolates included Peptostreptococcus sp, Bacteroides fragilis, and Clostridium perfringens. Among 19 (79%) patients with documented bacteremia, the predominant blood isolates were: B. fragilis (11 patients), Peptostreptococcus (7 patients), P. mirabilis (4 patients), and S. aureus (3 patients). In 10 (41%) patients, bacteremia was polymicrobial. Thus, blood cultures are clearly very important in the initial microbiologic assessment of all patients with suspected infection associated with pressure ulcers. Culture results must be interpreted with caution in cases of osteomyelitis. In a study of 36 patients with nonhealing pressure ulcers, 17% of these patients had histopathologic evidence of chronic osteomyelitis on samples taken using needle biopsy through a debrided area of the ulcer (16). In this study, cultures were not useful in making the diagnosis of osteomyelitis. All swab cultures were positive.

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Bone cultures were positive in all samples showing osteomyelitis, but 73% of cases without osteomyelitis also had positive bone cultures. The number of different organisms and the use of quantitative cultures were not predictive of the presence of osteomyelitis. Even in cases in which pure growth of the same organism was found in both the swab and bone cultures, there was sometimes no histopathologic evidence of osteomyelitis. Criticisms of this study are that there could have been sampling errors in bone biopsy (it is not as sensitive as ostectomy), so true cases could have been missed. Follow-up information regarding those patients with multiple pure cultures who were not treated as osteomyelitis was not reported. If these patients improved without specific antimicrobial therapy, it would have been stronger evidence that bone cultures obtained through debrided wounds are not predictive of osteomyelitis (29). The data regarding culture results from pressure ulcers can be summarized as follows. Firstly, superficial swab cultures are not useful and generally reflect colonization rather than infection. Secondly, needle aspirates are difficult to interpret and should either not be used or used with great caution. An exception might be the irrigation-aspiration technique that demonstrated high sensitivity and specificity compared with deep tissue biopsy results for draining pressure ulcers (27). Thirdly, the culture results themselves, even from bone or other deep tissue biopsies, should not be used as the sole criterion for evidence of infection without additional clinical or histopathologic evidence of infection. Because bacterial colonization is an almost universal phenomenon, culture results must be interpreted in the light of clinical data. Culture data may be useful to guide antimicrobial therapy, but clinical or histopathological evidence of infection is necessary before the decision to initiate antimicrobial therapy is made. C. Imaging Studies Radiologic studies play a valuable role in the investigation of infection in pressure ulcers, usually by determining the existence of osteomyelitis and in delineating the extent of the ulcer. The different modalities include plain radiography, computed tomography (CT), magnetic resonance imaging (MRI), and radionuclide scintigraphy. 1. Plain Radiography Plain films are useful for demonstrating the extent of bony damage, but it can take up to 14 days before evidence is visible radiographically (30). In cases of osteomyelitis caused by pressure ulcers, interpretation of plain films may be difficult. Even noninfected ulcers can show periosteal reactive changes and heterotopic new bone formation. Furthermore, lytic bony lesions do not develop very often (16,17). Because of these difficulties, plain radiographs have limited value

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in both establishing and excluding the diagnosis of osteomyelitis in cases of pressure ulcers, and routine use of plain films for this purpose is not recommended. The sinogram may be of value in the patient requiring surgical debridement, because this study will frequently allow the surgeon to determine the extent of the surgical procedure. Sinography may also yield unexpected findings such as excessive depth of the sinus tract, extension into neighboring joints, and abscess formation. The role of sinography in assessing pressure ulcers has probably diminished with wide availability of CT scanning. 2. Computed Tomography Computed tomographic scans have been studied in a limited way. One study found that CT had a high specificity for contiguous focus osteomyelitis, but the sensitivity was only 10% (29). Computed tomograms may be more useful in defining the size of the ulcer, the presence of fistulas, and possible joint involvement (31,32). 3. Magnetic Resonance Imaging Magnetic resonance imaging has been assessed in detecting osteomyelitis among patients with spinal cord injuries (33). Forty-two patients with clinically suspected osteomyelitis associated with pressure ulcers were assessed. The reference standard was biopsy in 32 patients and clinical follow-up in 10 patients. This study demonstrated that MRI had a sensitivity of 98% and specificity of 89% in the detection of osteomyelitis. However, the prevalence rate of osteomyelitis was extremely high in this patient series, with 47 of the 59 MRI studies demonstrating osteomyelitis. This likely inflates the positive predictive value of the test. It is unknown how the test will perform in lower prevalence groups or in older patients. 4. Radionuclide Scintigraphy Scintigraphy is another common method of investigation in cases of possible osteomyelitis. Three-phase technetium-99m (Tc-99m) diphosphate bone scans and gallium scans are useful for cases of osteomyelitis not caused by a contiguous soft tissue infection (30). In cases caused by pressure ulcers in which contiguous infection is common, however, radionuclide scintigraphy has been shown to be sensitive, but not specific (21). There have been cases with normal bone scans (34), but these are rare. The same issues exist with gallium scanning (21,34). Indiumlabeled white blood cell scanning is a more specific technique for diagnosing osteomyelitis even in the setting of a contiguous soft tissue abnormality. In a study of 41 diabetic foot ulcers, this imaging method had a specificity of 77% compared with the gold standard of bone biopsy (35). However, this technique has not been adequately studied in patients with pressure ulcers.

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In summary, the clinical examination will indicate the presence of superficial infections but is not useful for the diagnosis of underlying osteomyelitis. Microbiological data, if obtained from deep biopsy or aspiration, is useful for directing antimicrobial therapy after the clinical diagnosis of infection is made. On its own, the presence of bacteria, even from deep cultures, is not sufficient to diagnose infection. Among the radiographic investigations, CT and MRI may be of some value, but data are insufficient to recommend their general use. Scintigraphy, when used with different tests in combination, can be useful. Bone scans have good negative-predictive value, and white blood cell scans have good positivepredictive value. The bone biopsy for histopathologic diagnosis remains the gold standard for confirmation of osteomyelitis and should be used in cases of uncertainty.

IV. THERAPEUTIC INTERVENTIONS The goals of treating infected pressure ulcers are to resolve the infection and to aid in wound healing. Therapy should be directed by a multidisciplinary approach drawing from expertise in nursing, medicine, surgery, and physical rehabilitation (36). Implementation of the appropriate therapy requires an understanding of the risk factors and the pathophysiology leading to pressure ulcer formation. A. Reducing Intrinsic Risk Factors for Pressure Ulcers Most intrinsic risk factors for the development of pressure ulcers, discussed earlier, are, for the most part, not amenable to intervention; others, however, can be reduced by paying particular attention to underlying comorbid conditions. For example, both congestive heart failure and diabetes mellitus have interfered with wound healing in patients with pressure ulcers within the intensive care unit (37). It seems reasonable to extrapolate these findings to LTCF residents and to strive to improve residents’ general medical condition. Part of good general medical care is the optimization of a patient’s nutritional status. There is convincing evidence that poor nutrition is a risk factor for pressure ulcer development. Conversely, there are also data demonstrating that patients who receive higher protein diets show improved wound healing compared with those with an inadequate diet. This is independent of effects on serum albumin and other markers of nutritional status (18,38). The effects of caloric supplementation and enteral feeding are controversial. It seems intuitively obvious that if patients who are receiving more protein demonstrate better healing, then caloric supplementation or tube feeding (in those unable to feed themselves) will also lead to improved healing. However, this has yet to be demonstrated (39,40). There are

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two reasons why caloric supplementation has not been shown to be helpful. First, malnutrition can mean either that patients are underfed or that they are cachectic from underlying diseases. Caloric supplementation would be expected to help the underfed, but not those with cachexia. The second problem is that tube feeding has its own risks. The patient may become less mobile because of the tube feeding or may be tied down to prevent self-extubation. Tube feeding may also increase the risk of aspiration pneumonia (41). These possibilities can all worsen a patient’s condition and may delay wound healing. In addition to caloric and protein malnutrition, attention has been focused on zinc and vitamin C supplements. Patients deficient in these nutrients heal poorly, but supplementation in nondeficient patients has not proven beneficial (39). In general, residents with pressure ulcers should receive protein and calories appropriate for those under stress. Tube feeding should not be instituted solely for the treatment of pressure ulcers. B. Reducing Extrinsic Risk Factors for Pressure Ulcers Attention should also be paid to the extrinsic risk factors for pressure ulcer formation. Pressure relief is the cornerstone of pressure ulcer therapy. A number of devices are available for the reduction of pressure (Fig. 6). They can be classified into static and dynamic devices. Static devices such as foam- or fluid-filled products maintain constant pressure when the patient is not moving but disperse it over a greater area than standard bed mattresses. These devices are appropriate for patients who can assume different positions without bearing weight on the ulcer and without compressing the support material too much (21). For patients who cannot avoid weight-bearing on the ulcer or who do not show evidence of healing, a dynamic device may be more suitable (18,21). Dynamic devices change their support by alternating currents of air to redistribute pressure against the body. Examples are low-air-loss beds and air-fluidized beds. Low-air-loss systems maintain pressure through a constant air supply moving through a mattress of semipermeable fabric that allows some of the air to escape (54). Air-fluidized systems contain tiny silicone-coated beads suspended in strong currents of air. Manufacturers of these various dynamic devices claim that contact pressure is less than 10 mm Hg. However, evidence supporting the use of any of these devices is scant. Most authorities recommend use of dynamic beds for extensive stage III–IV pressure ulcers and for ulcers that fail to heal with standard therapy (42). C. Local Wound Care Local wound care is another fundamental part of pressure ulcer therapy. The important aspects of local care include debridement, wound dressings, adjunctive measures, and surgery.

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Figure 6 Degree of pressure reduction, in mm Hg, by pressure-relieving devices on varying anatomical locations. HOB, head of bed. (From Ref. 46.)

1. Debridement Debridement of necrotic tissue is required for optimal healing to occur. The reasons for this are not entirely clear but may be the result of decreased bacterial contamination (36), reduction of chronic inflammation (43), and improved tissue granulation (6). There are a number of techniques for debriding wounds. Sharp debridement can be performed at the bedside or in the operating room, and is recommended in cases of thick eschars or in infected wounds (21). Wound debridement can lead to transient bacteremia; systemic antimicrobial prophylaxis should be considered, especially in patients with prosthetic devices or those at risk of endocarditis (23). Mechanical debridement using saline-soaked gauze and irrigation with a 35-mL syringe and 19-gauge needle (this achieves a pressure of approximately 8 psi, enough to remove dead tissue and bacteria but not enough to damage viable tissue) is another possibility (44). The traditional wet-to-dry dressing

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can damage viable tissue and should only be used in wounds with large amounts of necrotic tissue (45). Occlusive dressings, such as hydrocolloids, hydrogels, and foams, allow tissue fluid full of phagocytes and their enzymatic products to accumulate, leading to autolytic debridement. There are also a number of enzymatic products available that may be of use in noninfected pressure ulcers. 2. Wound Dressings Dressings help to protect viable tissue, promote healing, and reduce contamination. A general rule is that dressings should keep the wound bed moist and the surrounding intact skin dry (45). Saline-soaked gauze has historically been used for pressure ulcer dressing. In superficial wounds, this can lead to excess maceration of intact skin and can impede wound healing if allowed to dry. Synthetic dressings are divided into films, hydrocolloids, foams, hydrogels, and alginates. Films are thin, semipermeable membranes appropriate for use in minimally draining stage II wounds. Hydrocolloids are adherent absorbent dressings useful for moderately draining wounds. Foams are similar but are nonadherent and need a secondary dressing. Hydrogels desiccate more easily than other dressings and are not ideal for pressure ulcers. Alginates are highly absorbable dressings derived from seaweed; they should be used in heavily draining wounds (45). Synthetic dressings should be avoided in cases of active infection, draining sinus tracts, and exposed bone or tendon (46). 3. Adjunctive Measures Some authors have advocated topical antibiotics or antiseptics to decrease bacterial contamination and promote healing (42,47). The evidence that they show benefit, however, is rather scant. Silver sulfadiazine has been shown to be of no added benefit when compared with its vehicle alone (45). Thus, the benefit seen in earlier studies may have been derived from the vehicle creams keeping the wound moist rather than the antimicrobial constituents. Antibiotics and antiseptics have also been shown to be toxic to fibroblasts in vitro (6), and there is a concern with selecting out resistant organisms. Topical antimicrobials, therefore, should not be used unless there are new data supporting their beneficial effects in the future. Adjunctive therapies such as electrical stimulation, hyperbaric oxygenation, ultrasound, and growth factors continue to be investigated, but clinical data are rather limited at this time (6,48). The use of electrical stimulation looks promising and may become a more important treatment modality in the future. 4. Surgery Surgery is the treatment of choice for difficult stage III and IV pressure ulcers. It is used to debride necrotic tissue, contour bony prominences to decrease subse-

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quent pressure loads, and close ulcer by myocutaneous flaps that fill the defect and provide adequate blood supply. Surgery should be reserved for those patients whose quality of life will improve from resolution of their pressure ulcer. There are several reviews with more information regarding the specifics of operative repair for pressure ulcers (49,50). D. Antimicrobial Therapy Treatment of infectious complications in pressure ulcers depends on both medical and surgical interventions. For the reasons mentioned above, topical antimicrobial therapy should be avoided. Systemic antibiotics have a role both in prophylaxis and treatment. Sharp debridement can lead to bacteremia. Thus, antibiotic prophylaxis should be administered 1 hour before the procedure in patients most at risk for the consequences of bacteremia (e.g., those at risk for infective endocarditis or patients with a prosthesis). Systemic antibiotics also should be used for patients with serious infections of the pressure ulcer, including those with spreading cellulitis, associated osteomyelitis, or bacteremia. Because of the high mortality associated with bacteremia, empiric antibiotics are appropriate if this is suspected. The choice of antibiotics is based on an understanding of the microbiology of infected ulcers. There are no trials assessing the superiority of one antibiotic regimen over another. Infections associated with pressure ulcers are often polymicrobial and can include a variety of gram-positive, gram-negative facultative and anaerobic bacteria (28). All of these suspected organisms should be treated. Cultures from deep aspirates can be used to guide the choice of agents and broaden the antibiotic coverage. However, because cultures from aspirates do not correlate well with tissue biopsy results, antibiotics should not be narrowed to treat only those organisms found in aspirate cultures. A variety of options are available for treating infected pressure ulcers (Table 2). Monotherapy with broad-spectrum cephalosporins, monobactams, -lactam/-lactamase inhibitor combinations, or later-generation fluoroquinolones are all appropriate choices. Combination therapies, such as a cephalosporin or fluoroquinolone for aerobic coverage plus clindamycin or metronidazole for anaerobes, would also be suitable (28). Because of poor tissue perfusion in infected pressure ulcers, antibiotic therapy should be administered by the intravenous route as initial empiric therapy in patients with signs of sepsis.

V. INFECTION CONTROL MEASURES The goals of infection control in regard to pressure ulcers are to reduce colonization and prevent infection; to reduce the spread of pathogenic organisms to other patients, staff or the environment; and to prevent selection of resistant organisms. In 1994, the AHRQ included six infection control recommendations in their treat-

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Table 2 Antibiotic Regimens for Infected Pressure Ulcers Monotherapy Cefoxitin Ceftizoxime Cefotetan Cefmetazole Ticarcillin-clavulanate Piperacillin-tazobactam Imipenem Meropenem Gatifloxacin Combination therapy Clindamycin or metronidazole plus Ciprofloxacin Ofloxacin Treatment of MRSA infection Vancomycin Quinupristin/dalfopristin (Synercid) Oxazolidinone (Linezolid)

1-2 g q6–8 h IV or IM 1-2 g q8–12 h IV 1-2 g q12–24 h IV or IM 1-2 g q12 h IV 2-4 g q4–6 h IV 2-4 g q6–8 h IV 0.5-1 g q6–8 h IV 0.5-1 g q6–8 h IV 400 mg OD IV or PO 450–600 mg q6–8 h IV or 450 mg qid PO 500 mg q6–8 h IV or 500 mg tid PO 200–400 mg q12 h IV or 500 mg bid PO 200–400 mg q12–24 h IV or 400 mg bid PO 0.5 g q6–8 h IV 7.5 mg/kg q8–12 h IV 600 mg q12 h IV

Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; OD, daily; qid, four times a day; bid, two times a day; IV, intravenous; IM, intramuscular; PO, oral.

ment guidelines for pressure ulcers (21). One of these recommendations pertains to the care of wounds at home and will not be discussed further. Of the recommendations for hospitalized patients, four are designed to reduce contamination of the wound, and one aims to reduce the spread of pathogens. Each of these recommendations was given a grade C for strength of evidence, indicating expert opinion rather than solid data from clinical trials. There are no new data allowing us to strengthen or weaken these recommendations or to add new recommendations (51). More investigation into the area is needed. A. AHRQ Recommendations to Reduce Contamination of Pressure Ulcers 1. Sterile Instruments Should Be Used to Debride Pressure Ulcers The use of sterile technique to debride wounds is entirely sensible. The act of sharp debridement changes the physiology of the wound, which renders it more susceptible to infection (43). Thus, the use of sterile technique to reduce the bac-

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terial burden in the wound is indicated in this instance. The fact that newly debrided wounds may be more susceptible to infection after exposure to smaller numbers of bacteria makes the other AHRQ recommendations for preventing contamination more difficult to apply to the general population. Newly debrided wounds and older wounds may require different precautions, a possibility that remains to be tested. 2. Clean Dressings May Be Used Instead of Sterile Dressings Sterile dressings have not been shown to lead to less contamination than clean dressings. The AHRQ, therefore, recommends that as long as clean dressings remain dry and free of heavy contamination, they are still suitable for use. The problem is that one cannot be assured that they are entirely free of any contamination. No studies could be found examining the rate of bacterial contamination of “clean” sponges; it likely varies with settings and with the length of time the dressings have been exposed to the environment. About 20% of sterile dressings will yield a few colonies of bacteria immediately upon opening the package (52). The rate of contamination increases if the dressings are saturated while placed on their wrappings over a nonsterile surface (a common practice used to avoid using another container in which to saturate the gauze), illustrating that dressings are more easily contaminated than one might expect. Dressing changes require many steps and consequently many possibilities for bacterial contamination. Using sterile dressings would help to ensure that more care is taken in each of these steps. However, this practice would add considerable cost to the healthcare system. Further research is clearly required to evaluate the cost effectiveness of the routine use of sterile dressings, especially in newly debrided wounds and in settings with endemic resistant organisms. 3. Healthcare Workers Should Use Clean Gloves for Each Patient; When Treating Multiple Ulcers on the Same Patient, the Most Contaminated Ulcer Should Be Treated Last; They Should Also Wash Their Hands Between Patients This recommendation is based on the same argument as using sterile dressings. Again, it seems prudent to use sterile gloves with newly debrided pressure ulcers, although clean gloves are likely sufficient for the care of older ulcers. A trial to assess bacterial loads, incidence of clinical infection, and impact on wound healing for pressure ulcers dressed with clean or sterile gloves would be a useful contribution to the field. In general, hand washing and the appropriate use of gloves remains an area in which there is room for improvement. A recent study found that hands were washed before an activity in 27% of cases and after an activity in 63% of cases, and that gloves were worn in only 82% of cases in which an institution’s guidelines indicated that these precautions were necessary (53). Performance in

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relation to wound care was substantially better. In all 29 assessed cases, gloves were worn and hands were washed after all observed interactions. However, hands were washed before wound care in only three of six cases. The role of hand washing in preventing nosocomial infections cannot be overstated and should continue to be emphasized. 4. Ulcers Should Be Protected from Sources of Contamination, Such as Feces This recommendation to protect pressure ulcers from fecal or other contamination also seems intuitively reasonable. Wound healing is delayed in patients with fecal incontinence. Unfortunately, it can be difficult to protect the wound entirely, but every effort to do so should be made. B. AHRQ Recommendation to Prevent Spread of Pathogenic Organisms from Pressure Ulcers Follow body substance isolation (BSI) precautions or an equivalent system when treating pressure ulcers. BSI has 6 components applicable to pressure ulcers: 1. 2. 3. 4.

Wear gloves for contact with body fluids. Change gloves and wash hands between patients. Wash hands after any type of patient contact. Wear additional barrier such as gowns, masks, or goggles when body fluids may come in contact with the clothing or skin. 5. Place soiled reusable items in securely sealed containers. 6. Place needles into designated sharps containers These recommendations apply to all patients and should also be followed in the treatment of LTCF residents with pressure ulcers. Wound dressing changes can lead to aerosolization of bacteria that can persist for up to 30 minutes (55). Masks and gowns should be worn when changing wounds heavily contaminated with resistant or highly virulent bacteria. This may be less of a problem with hydrocolloid than gauze dressings (55). The use of whirlpools to debride wounds can also be an infection control hazard. Both pseudomonas and staphylococci have been recovered, even from regularly disinfected and serviced whirlpools in nursing homes (56). Whether the benefit of whirlpools outweighs the infection control risks remains to be seen. Increasingly, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are being isolated in LTCFs (57). Antimicrobial use is an important evolutionary process selecting for these resistant strains. Improved use of antimicrobial agents, therefore, is critically important for preventing or slowing the spread of these organisms. A number of studies have

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examined antibiotic use in nursing homes, although no specific information exists regarding antibiotic utilization patterns and infection or contamination of pressure ulcers with these organisms. Thirty to 50% of LTCF residents will receive at least one course of systemic antimicrobial therapy in any given year (58–60). In reviewing the prescriptions for antimicrobial therapy, telephone orders with no evidence that a physician ever saw the patient account for approximately 50% the prescriptions (58). Recommendations have been made that clinical information regarding indications for antimicrobial therapy should be charted for each patient prescribed antibiotics and that institutions include antimicrobial utilization monitoring and review in their infection control program (59). Whether these interventions will reduce inappropriate use of antibiotics needs to be tested. The empirical use of vancomycin in LTCFs with high rates of MRSA carriage and infection is a particular concern, as this practice also leads to an increased prevalence of VRE (61). Every effort should be made to distinguish between clinical infection versus colonization before any specific antimicrobial therapy is initiated. Apart from being good medicine, the appropriate use of systemic antibiotics is also an important part of an effective infection control strategy.

VI. PREVENTION In an ideal world, the only subheading in a chapter on pressure ulcers would be prevention. All the data discussed so far should be applied to ensure that pressure ulcers are prevented. The keys to prevention are identifying patients at risk, improving general health, minimizing external forces, and educational programs informing caregivers about pressure ulcers. Individual patients or residents have different risks of developing pressure ulcers. The most important factors in predicting risk are immobility and poor nutritional status. Further risk factors include age, diabetes mellitus, incontinence, and other markers of poor general health. Risk assessment scales can be used to determine a patient’s risk of developing a pressure ulcer (62,63). The Braden scale assigns scores to six categories: sensory perception, activity, mobility, skin moisture, friction, and dietary intake. This leads to a positive predictive value of 37% to 52% (64). The Norton scale uses five categories: physical condition, mental condition, activity, mobility, and continence. The positive predictive value of the Norton scale is 0 to 37%. Movement monitoring is the most accurate way of predicting pressure ulcers with a positive predictive value of 92%, but the equipment required is not readily available. Using the Braden scale to identify patients at risk and treating them led to a 60% decrease in pressure ulcers over a 6-month period and a cost saving of $1.2 million (65). Risk assessment should be done on admission to an institution and at periodic intervals. In addition to assessing the resident’s risk of pressure ulcer development, the skin should be ex-

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amined daily for signs of breakdown so that further preventive measures can be undertaken. Signs of poor general health may predict the development of pressure ulcers, but there are little data on whether improving general health can prevent pressure ulcers. Nutrition in particular has been correlated with pressure sore development, but supplements or enteral feeds have not been shown to prevent pressure ulcers. Authorities suggest supplementation for nutritionally compromised patients (1). Feeding tubes have been associated with pressure ulcer formation and other complications, and probably should not be instituted solely to prevent pressure ulcers in malnourished patients. Care should also be taken to improve mobility by physiotherapy. Minimizing or eradicating the four extrinsic risk factors discussed earlier is also crucial. Alleviation of pressure-related tissue damage is the most important single factor. This can be achieved by proper positioning of the resident or by the use of devices to relieve pressure. The role of frequent turning is often emphasized; it appeals to common sense but has little empirical evidence behind it. It has become the standard of care since a study in the 1960s showed that patients turned every 2 to 3 hours developed fewer ulcers than historical controls (63). This practice was supported by animal models and should continue to be used in patients at risk. Positioning of residents to avoid weight-bearing on bony prominences is also important. Direct trochanteric positioning leads to increased pressure and decreased oxygen tension, and should be avoided by placing residents on their sides at 30 degrees instead of 90 degrees (65). It has also been suggested that residents at risk of developing pressure ulcers who are sitting for prolonged periods (e.g., in a wheelchair) should shift their weight every 15 minutes (21). Bony prominence massage has been suggested in the past as a useful intervention, but may actually be harmful and should not be performed (65). As discussed in the section on treatment, a number of devices are aimed at relieving pressure. Evidence that these devices protect patients from pressure ulcers compared with regular hospital mattresses is ample (64,66,67). Unfortunately, there is no evidence that one device is better than any of the others. The AHRQ also recommends the use of these devices in patients at risk of pressure ulcers. Special attention should be paid to the heels. They are extremely vulnerable to pressure and may need complete relief of pressure rather than simple reduction. Pressure relief may be attained with pillows under the calf to raise the heels off the bed. Doughnut-type devices may actually lead to increased ischemia in the center and should be avoided (21). Friction, shear, and moisture are the other extrinsic forces that play a role in pressure ulcer pathogenesis. Friction should be avoided by not dragging a resident across a surface. If the resident requires help to be repositioned, a sheet that the resident is lying on should be used to move the patient in the bed (21). Friction can also be avoided by the use of sheepskins or boots (6) or synthetic dressings (21).

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Minimizing the angle of the head of the bed can reduce shear, as can the use of undersheets to move residents. Moisture is usually the result of incontinence, which should be treated if reversible or controllable. If not controllable, moisture should be detected and removed as soon as possible, and the use of absorbent underpads or briefs should be considered (21). Barrier creams may also be helpful. Education is another key to preventing pressure ulcers and should be directed at both the residents and caregivers. The educational program should include information regarding the risk factors of pressure ulcers, skin assessment and staging techniques, pressure relief strategies and devices, wound healing, and infection control. The effects of educational programs have not been extensively studied, but there is some evidence that they reduce pressure ulcer incidence (68).

REFERENCES 1. 2. 3. 4. 5.

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Bergstrom N, Bennett MA, Carlson CE. Pressure ulcers in adults: Prediction and prevention. Guideline Report No. 3, 1992. The National Pressure Ulcer Advisory Panel. Pressure ulcers prevalence, cost, risk assessment: Consensus development conference statement. Decubitus 1989; 2:24–28. Allman RM. Pressure ulcer prevalence, incidence, risk factors, and impact. Clin Geriatr Med 1997; 13:421–437. Brandeis GH, Morris JN, Nash DJ, Lipsitz LA. The epidemiology and natural history of pressure ulcers in elderly nursing home residents. JAMA 1990; 264:2905–2909. Brandeis GH, Ooi WL, Hossain M, Morris JN, Lipsitz LA. A longitudinal study of risk factors associated with the formation of pressure ulcers in nursing homes. J Am Geriatr Soc 1994; 42:388–393. Kanj LF, Wilking SVB, Phillips TJ. Peptic ulcers. J Am Acad Dermatol 1998; 38: 517–536. Reuler JB, Cooney TG. The pressure sore: Pathophysiology and principles of management. Ann Intern Med 1981; 94:661–666. Woolsey RM, McGarry JD. The cause, prevention, and treatment of pressure sores. Neurol Clin 1991; 9:797–808. Kosiak M, Kubricek WG, Olson M. Evaluation of pressure as a factor in the production of ischial ulcers. Arch Phys Med 1958; 39:623–629. Dinsdale SM. Decubitus ulcers: Role of pressure and friction in causation. Arch Phys Med Rehabil 1974; 55:147–152. Burdge DR, Chow AW. The pressure ulcer. In: Infections in Nursing Homes and Long-term Care Facilities. Verghese A, Berk SL (eds). S. Karger, Inc., New York, 1990:143–161. Garibaldi RA, Brodine S, Matsumiya S. Infections among patients in nursing homes. N Engl J Med 1981; 305:731–735. Nicolle LE, Orr P, Duckworth H, Brunka J, Kennedy J, Murray BUD, Harding GKM. Prospective study of decubitus ulcers in two long term care facilities. Can J Infect Control 1994; 9:35–38.

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17 Herpes Zoster, Cellulitis, and Scabies Kenneth Schmader and Jack Twersky Duke University Medical Center, and Durham VA Medical Center, Durham, North Carolina

I. HERPES ZOSTER A. Epidemiology and Clinical Relevance Herpes zoster is a neurocutaneous disease caused by the reactivation of varicellazoster virus (VZV) from a latent infection of dorsal sensory or cranial nerve ganglia. Nearly all elderly adults in the United States are latently infected with VZV and at risk for zoster. The incidence of zoster increases strikingly with aging. For example, in Boston, investigators reported a zoster incidence of 1.9, 2.3, 3.1, 5.7, and 11.8 per 1000 person-years for the age groups 25 to 34, 35 to 44, 45 to 54, 55 to 64, and 65 to 75 years, respectively (1). In the Duke Established Populations for Epidemiological Studies of the Elderly (EPESE), the incidence of zoster was 7.1 per 1000 person-years among individuals aged 65 to 104 years old (2). The incidence of zoster in long-term care facilities (LTCFs) is unknown because there are no investigations of zoster in this population. In the general population, the lifetime incidence of zoster is estimated to be 10% to 20%, and as high as 50% of a cohort surviving to age 85. There are approximately 600,000 to 850,000 cases of zoster in the United States each year. Given an incidence of 7 to 11 cases of zoster per 1000 elderly persons per year and approximately 1.5 million elderly nursing home residents in the United States, one may estimate at least 10,500 to 16,500 zoster cases in U.S. nursing homes per year. Supported by the Durham VAMC GRECC and by the Duke Claude D. Pepper Older Americans Independence Center.

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Residents of LTCFs are at risk for zoster not only because of aging but also because of immunosuppression from several diseases and medications. Patients with human immunodeficiency virus (HIV) infection, lymphomas, leukemias, and systemic lupus erythematosus, as well as taking immunosuppressive medications are prone to developing zoster and may reside in LTCFs. Other potentially important risk factors for zoster include white race, psychological stress, and physical trauma (3). The most frequent and feared complication of zoster in the elderly is postherpetic neuralgia (PHN). Like zoster, the prevalence of PHN increases significantly with aging. For example, outpatients aged 50 or older had a 14.7-fold higher prevalence (95% confidence interval, 6.8–32.0) of pain 30 days after rash onset compared with outpatients younger than 50 years old in a study in Boston (4). The prevalence of PHN in older adults is about 70% 1 month from rash onset, 40% 4 months from rash onset, and 30% 6 months from rash onset (5). The prevalence of PHN in LTCFs is unknown because there are no such studies in this population. B. Clinical Manifestations The reactivation and spread of VZV in the affected sensory ganglion and peripheral sensory nerve evokes an intense cellular immune response and neuronal inflammation and destruction. These events elicit a prodrome of pain or discomfort in the affected dermatome before the rash appears. The prodrome masquerades as many other painful conditions in the elderly. The diagnosis may be particularly difficult in LTCF residents because of pre-existing pain syndromes or cognitive impairment. Clinicians should consider zoster in the differential diagnosis of any acute, unilateral, dermatomal pain syndrome. Clues to prodromal zoster include a description of typical neuropathic pain in a dermatome and very sensitive skin in the affected dermatome. The prodrome usually lasts a few days, although there are case reports of it lasting weeks to months. The diagnosis becomes apparent when VZV infects cells in the dermis and epidermis and produces the characteristic rash. The zoster rash may “hide” on the back, trunk, or buttocks of some LTCF residents when they are bed-bound or cognitively impaired and no one bothers to examine the area. The rash is unilateral, dermatomal, red, maculopapular/vesicular, and most commonly involves the T1 to L2 and V1 dermatomes. Lesions may develop in adjacent dermatomes. Typically, the vesicles crust over in 7 to 10 days. Along with the rash, most patients experience a dermatomal pain syndrome resulting from acute neuritis. The neuritis is described as burning, deep aching, tingling, itching, or stabbing and ranges from mild to severe. Complications of zoster in the elderly include PHN; ocular inflammation with impaired vision in ophthalmic zoster; stroke secondary to granulomatous arteritis of the internal carotid artery in ophthalmic zoster; focal motor paresis in muscles served by nerve roots of the corresponding affected dermatome; disordered balance, hearing, and facial paresis in cranial neuritis (Ramsay-Hunt syndrome); meningoencephalitis; and secondary bacterial infection of the rash. How-

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ever, PHN is the most debilitating aspect of zoster. The PHN patient may suffer from constant pain (“burning, aching, throbbing”), intermittent pain (“stabbing, shooting”), and stimulus-evoked pain such as allodynia (“tender”). Allodynia, the experience of pain after a nonpainful stimulus, is a particularly disabling component of the disease. Patients with allodynia suffer from severe pain after the lightest touch of the affected skin by things as trivial as a piece of clothing. These subtypes of pain may produce chronic fatigue, disordered sleep, depression, anorexia, and weight loss, all of which may have serious consequences in nursing home residents. Severe PHN may trigger events that significantly reduce quality of life or that are ultimately fatal in the nursing home resident. C. Diagnostic Approach The clinical diagnosis of zoster is sufficient when an elderly patient has the typical dermatomal vesicular rash and pain. Zosteriform herpes simplex is the main consideration in the differential diagnosis, particularly in vesicular rashes on the face or buttocks. Herpes simplex commonly recurs many times and usually does not generate chronic pain. Nonetheless, it may be very difficult to distinguish the two conditions on clinical grounds. Also, like many conditions in geriatrics, zoster may present atypically. The rash may never appear as a diagnostic guide in elderly patients with dermatomal pain alone (zoster sine herpete); acute facial palsy, hearing loss, vertigo, or dysgeusia (cranial neuritis); and fever, delirium, and meningismus (meningoencephalitis). Laboratory diagnostic testing is useful for differentiating herpes zoster from herpes simplex, for suspected organ involvement, and for atypical presentations (6). Immunofluorescence antigen (IFA) detection of VZV antigens in vesicle fluid is an excellent test because it is rapid (hours), specific, and very sensitive. Varicellazoster virus culture is slower and less sensitive but remains a standard in making the virological diagnosis. Tzanck smears may suggest VZV infection if multinucleated giant cells and intranuclear inclusions are demonstrated in stained vesicle scrapings, but the technique cannot differentiate VZV from herpes simplex virus infections. Varicella-zoster virus DNA detection using the polymerase chain reaction (PCR) is very sensitive and specific and particularly useful for unusual cases or unusual specimens (i.e., only crusts available for testing). If no rash is present (i.e., suspicion of zoster sine herpete) or specimens are inadequate, then one can pursue the diagnosis serologically using acute and convalescent VZV immunoglobulin G (IgG) titers. D. Therapeutic Interventions The main goal of the treatment of zoster in the elderly is reduction of pain. Pharmacological approaches to zoster pain include antiviral therapy, anti-inflammatory drugs, and analgesics. With the exception of complicated or severe zoster, these therapies can be delivered in the LTCF.

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1. Antiviral Therapy Acyclovir, famciclovir, and valacyclovir are guanosine analogues that are phosphorylated by viral thymidine kinase and cellular kinases to a triphosphate form that inhibits VZV DNA polymerase. Randomized, controlled trials indicate that oral acyclovir (800 mg five times a day for 7 days), famciclovir (500 mg every 8 hours for 7 days) and valacyclovir (1 g three times a day for 7 days) reduce acute pain and the duration of chronic pain in elderly zoster patients with dermatomal zoster who are treated within 72 hours of rash onset (7). It is also reasonable to treat patients with ophthalmic zoster and those forming new vesicles outside of the 72-hour window. Unfortunately, 20% to 30% of treated patients in antiviral trials had pain 6 months from zoster onset, indicating that treated patients can develop PHN. The most common adverse effects are nausea and vomiting, diarrhea, and headache in about 8% to 17% of patients. The drugs are excreted through the kidney and must be dose-adjusted for renal insufficiency. Any of the three drugs are acceptable agents. A suspension form of acyclovir is available for patients unable to swallow the pill form. Patients with complicated zoster should be transferred to the hospital for intravenous (IV) acyclovir therapy. These cases include disseminated zoster, central nervous system infection, visceral infection and severe ophthalmic zoster in any host, and multidermatomal zoster in the immunocompromised host. 2. Anti-Inflammatory Corticosteroids, with or without acyclovir, do not prevent PHN (8,9). Antiviral therapy and prednisone may accelerate time to uninterrupted sleep and return to daily life in elderly outpatients with no relative contraindications to corticosteroids such as hypertension, diabetes mellitus, or osteoporosis (9). Most LTCF residents have relative contraindications to corticosteroids, and it is unknown whether this population would experience these benefits. Corticosteroids may be useful for VZV-induced facial paralysis and cranial polyneuritis to improve motor outcomes and pain. The most common adverse effects in zoster clinical trials were gastrointestinal symptoms (dyspepsia, nausea, vomiting), edema, and granulocytosis. 3. Analgesics Clinicians should use analgesics to reduce acute zoster pain regardless of effects on chronic zoster pain. The choice of nonopiate or opiate analgesics depends on the patient’s pain severity, underlying conditions, and response to the drug. The principles of excellent pain management, such as scheduled analgesia, use of pain measures, and close follow-up, should be applied to acute zoster pain management as with any other painful condition. If pain control from antiviral agents and anal-

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gesics is inadequate, then regional or local anesthetic nerve blocks should be considered. 4. Postherpetic Neuralgia Patients and clinicians have used a large number of treatments for PHN, but few of these treatments have been carefully evaluated. Recent controlled clinical trials indicate that topical lidocaine, gabapentin, opiates, and tricyclic antidepressants can significantly reduce pain in PHN patients (10). None of these treatments has been evaluated in LTCF residents. The 10 cm 14 cm topical lidocaine patch contains 5% lidocaine base on a polyester backing (11). One or more patches are applied over the affected area for 12 hours a day. The advantages are potentially good efficacy, minimal side effects, and ease of use for the patient and staff. The disadvantages of the patch are application site reactions, such as skin redness or rash and substantial cost. If cost is a problem, one may try EMLA cream over the area under an occlusive dressing. Gabapentin was prescribed as an initial dose of 300 mg in elderly outpatients with PHN and titrated over a 4-week period to 300 mg three times a day, 600 mg three times a day, 900 mg three times a day, and 1200 mg three times a day, stopping at the effective dose or until intolerable adverse effects occurred (12). The adverse effects of gabapentin include somnolence, dizziness, and ataxia. These adverse effects may limit the use of gabapentin in LTCF residents, many of whom have falls, gait disturbance, and cognitive impairment. The above dosing regimen will probably need to be reduced in LTCF residents. Nortriptyline and desipramine are preferred tricyclic antidepressants compared with amitriptyline because they cause less sedation, cognitive impairment, orthostatic hypotension, and constipation in the elderly. Nortriptyline and amitriptyline give equivalent pain relief in PHN patients (13). A conservative dosing regimen of nortriptyline begins with 10 mg at night and the dose increases every 4 to 7 days by the same amount until reduction in pain or intolerable side effects occur. Four to 8 weeks of therapy are recommended for an adequate trial. The advantages of this therapy are potential efficacy, low cost, and relief even with small doses. The disadvantages are potential anticholinergic side effects. A subset of PHN patients will find relief with chronic opioid therapy (i.e., scheduled oxycodone) (14). Long-term care facility residents may not tolerate the constipation, nausea, or sedation associated with these agents. E. Infection Control Measures Varicella-Zoster virus may be transmitted to seronegative, susceptible individuals during the vesicular stage of a zoster rash and cause varicella. Most adults and nearly all elderly LTCF residents are latently infected and not at risk for varicella,

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including latently infected immunocompromised patients. Furthermore, there are no controlled studies indicating that exposure of a latently infected individual to zoster causes zoster or varicella (15). If the rash is only maculopapular or crusted, there is no danger of transmission. Therefore, the source of infection in LTCFs will be residents with zoster during the vesicular stage of the rash. The persons at risk for varicella include susceptible healthcare workers and staff, particularly if they are pregnant or immunocompromised. Direct contact, airborne, or droplet nuclei routes may transmit VZV, which spreads most efficiently with close contact. The incubation period of varicella is usually between 14 to 16 days with a range of 8 to 21 days. There are no studies of VZV transmission in LTCFs; however, several studies show that susceptible healthcare workers and staff may develop varicella after exposure to zoster in hospital patients. To manage zoster in LTCFs, susceptible persons should avoid contact with the person with zoster until the rash has crusted over. The optimal method to protect susceptible staff in LTCFs is not known. In hospitals, the Centers for Disease Control and Prevention (CDC) recommend a private room and contact precautions for immunocompetent hospital patients with dermatomal zoster (16). For immunocompromised patients in the hospital with localized zoster or any patient with disseminated zoster, the recommendations are a private room with special ventilation and airborne and contact precautions. These recommendations have to be modified for the more limited resources of LTCFs. Feasible measures include moving the resident to a private room and the use of contact precautions for all zoster residents. Long-term care facility staff and employees who are exposed to a resident with zoster should have an evaluation of their VZV immune status within 1 to 2 days of exposure (17). An exposure is defined as being in the same room or having face-to-face contact with the zoster patient. Employees with a history of varicella or zoster are considered immune and can return to work. Employees who do not have a prior history of varicella or who are unsure of their varicella status should have VZV antibody testing. If the antibody test is positive, they are immune and can return to work. If they are antibody negative, they may develop varicella in the next 10 to 21 days. These individuals may be candidates for varicella-zoster immune globulin (VZIG), which is recommended for exposed, susceptible individuals who are able to receive VZIG within 72 to 96 hours of exposure and are at risk for significant morbidity from varicella. Adults at increased risk who should receive VZIG include immunocompromised individuals, individuals taking systemic corticosteroids, and pregnant women. The benefit of VZIG for immunocompetent adults is less clear because it may not prevent varicella, but it is generally recommended for any susceptible adult. Alternately, the CDC recommends the varicella vaccine as postexpo-

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sure prevention, if given within 72 hours of exposure (18). Exposed, susceptible healthcare workers may be infectious in an 8- to 21-day window post exposure. They probably should not work during this period. If they develop varicella, they may benefit from acyclovir, particularly if given within 24 hours of rash onset. Varicella-zoster virus immunity among healthcare workers varies by country of origin. In general, serology studies indicate that 4% to 8% of persons in temperate climates who are older than age 20 are susceptible. The percentages are higher in countries with tropical climates. About 60% to 86% of healthcare workers report a history of varicella that correlates nearly 100% with seropositivity (17). Most workers who report a negative or uncertain history are also seropositive. Overall, studies of hospital healthcare workers show a susceptibility of 1% to 7%. Healthcare workers in LTCFs should be screened for VZV immunity at the time of their employment by the methods noted above. If they report no history of varicella or are unsure of their status and their VZV antibody test is negative, they should receive the varicella vaccine.

F. Prevention Currently, there is no known effective method for preventing herpes zoster in latently infected individuals. The varicella vaccine was licensed by the Food and Drug Administration (FDA) in the United States in 1995 to prevent varicella and is now part of the childhood immunization schedule. It is about 90% effective in preventing varicella in susceptible children and 75% effective in susceptible adults (19). Zoster can develop in vaccinated individuals but at a much lower rate than zoster after natural varicella. Whether widespread vaccination of children with the vaccine will significantly reduce zoster incidence in the elderly will not be known until the cohorts of vaccinated children become elderly. However, the vaccine virus is highly attenuated and probably less likely to reactivate and cause complications. Current LTCF residents are latently infected and at risk for zoster for the foreseeable future. Cellular immunity to VZV declines with age, so vaccination of latently infected elderly persons with the varicella-zoster vaccine may prevent zoster or PHN. Higher dose formulations of the vaccine than the currently licensed vaccine are immunogenic and well tolerated in community-dwelling elderly (20). The immunogenicity and tolerability of the vaccine in LTCF residents are unknown. A randomized, double-blind, placebo-controlled Veterans Affairs Cooperative Studies Program trial is in progress in the United States to evaluate the effects of a more potent formulation of the vaccine on zoster and PHN in the elderly.

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II. CELLULITIS A. Epidemiology and Clinical Relevance Skin and soft tissue infections are among the three most important infections, along with urinary tract infections and lower respiratory tract infections, as a cause of morbidity and hospitalizations for nursing home residents. Cellulitis is defined as a diffuse inflammation of the epidermis, dermis, subcutaneous fat, or connective tissue in which a thin, watery exudate spreads through the cleavage planes of the interstitial space. Surprisingly, the incidence, prevalence, and special features that put nursing home residents at risk and the prevention and control of cellulitis are poorly described in the medical literature. Skin infections are common among LTCF residents and occur at rates similar to that of hospitalized patients. The prevalence of skin and soft tissue infections in one nursing home was 1% to 9% and the incidence is 0.9 to 2.1 per 1000 patient days (21). Risk factors for cellulitis may be divided into predisposing factors and portals of entry. Predisposing factors include a previous history of cellulitis, being male, peripheral vascular disease, alcoholism, immune compromise by medications (particularly corticosteroids or in renal transplant recipients), and any underlying chronic disease (22–25). The best-described risk factors for cellulitis involve processes that disrupt the lymphatic or venous flow. The lymphatic and venous disruption may be a result of a previous episode of cellulitis, obesity, a history of deep venous thrombosis, breast cancer with axillary node dissection, cancer of the cervix, uterus, nasopharynx, radical pelvic surgery, lymphedema, nephrotic syndrome, right-sided congestive heart failure, saphenous vein harvesting during coronary artery bypass surgery, and hip replacement surgery (26–30). Although not described in the literature, patients who have lower extremity amputations commonly develop cellulitis. This may be the result of peripheral vascular disease compounded by disruption of the lymphatic system as a result of the amputation. A portal of entry is generally recognized in more than 60% of cases. The portal may be a surgical site, laceration, wound, pressure ulcer, insect bite, or illicit substance (23,27,31,32). A common surgical portal of entry in nursing home residents is through gastrostomy tubes. Superficial infections at the skin entry point to the gastrointestinal tract occur at a rate of 1% to 4% within 30 days of placement of the gastrostomy tube and 1% to 2% yearly thereafter (33–37). Other important portals of entry include fissured toe webs, intertrigo, and tinea pedis (38,39). The prevalence of tinea pedis is 10% in the general population, 18% in the elderly general population, and even higher among elderly in institutions (38,40). The fourth web of the foot is particularly conducive to development of tinea pedis. In one study, investigators reported that 83% of elderly patients with cellulitis of the foot and leg had concurrent tinea pedis (40). In a study of older patients who developed cellulitis in their saphenous vein graft sites after coronary

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artery bypass grafting, seven of nine had active tinea pedis and five of these seven had recurrences of the cellulitis (26). Gluteal fold intertrigo has been described as the likely portal of entry for cellulitis associated with hip replacements (29). B. Clinical Manifestations Skin infection exhibits the gamut from erysipelas to cellulitis to necrotizing fasciitis. Erysipelas, cellulitis, and necrotizing fasciitis are all more common in the elderly and share common risk factors. Their level of tissue penetration defines these conditions. Erysipelas is the most superficial infection and involves the epidermis and dermis as well as subjacent lymphatics. Erysipelas differs from cellulitis in that lymphatic involvement is prominent (streaking), and that it tends to have margins that are clearly demarcated from involved skin (41). The initial presentation is a small erythematous lesion, 80% of the time in the lower extremity, which is easily overlooked. Facial erysipelas may follow an upper respiratory tract infection. Fever is present in about one-fifth of cases and is abrupt in onset, associated with rigors, and sometimes nausea and vomiting. The clinical course is almost always benign. Local complications such as septic arthritis, skin necrosis, or necrotizing fasciitis requiring surgical intervention are rare, but recurrence is common (22,27,30). Necrotizing fasciitis is a life-threatening, deep-seated infection of the subcutaneous tissue that results in progressive destruction of the fascia and fat but may spare the skin. The initiating event is frequently trivial trauma. After 24 hours, there may be mild erythema, but the infection spreads rapidly. Untreated, the erythema darkens, changing from red to purple then to blue, and blisters and bullae form that contain clear yellow fluid. Over days, the infection progresses to gangrene and may disseminate in the form of metastatic abscesses and pneumonia (42,43). Severe pain out of proportion to physical findings should suggest this diagnosis. Cellulitis diffusely involves the epidermis, dermis and cleavage planes of interstitial and soft tissues spaces. The lesion may be brawny, edematous, or indurated (peu d’orange), particularly in the setting of venous insufficiency or chronic lymphatic obstruction, with an advancing elevated margin. The skin is hot, shiny, bright red, and frequently painful when touched. Small vesicles and, occasionally, large bullae may develop in severe disease or in cases caused by atypical organisms (23). Most cases of cellulitis occur below the waist because predisposing conditions predominate in the lower extremities (venous insufficiency, peripheral vascular disease, lymphatic obstruction). Cellulitis is often accompanied by fevers, chills, malaise, lymphangitis, and lymphadenitis (27,41,42). Cellulitis has been associated with saphenous vein donor sites for coronary artery bypass grafts (26,30) and within the flaps of the surgical incision after primary hip replacement (32). In both circumstances, the cellulitis and erythema may

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extend along the incision and produce considerable tenderness. Symptoms usually occur months after the index surgeries. Cure rates are high with antibiotics without surgical intervention, but there is a tendency for recurrence. The most common organism to cause cellulitis is Group A beta-hemolytic streptococci (44). Group C and G streptococci are also commonly reported as causative organisms. Less commonly, Staphylococcus aureus, aerobic gram-negative bacilli, Legionella sp, and Cryptococcus have been reported as causes of cellulitis (30,41,45–47). Mucormycosis has been found as the primary organism causing cellulitis in renal transplant and diabetic patients (25). In a study of cellulitis associated with gastrostomy sites in nursing home residents, bacterial cultures revealed S. aureus, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Enterococcus sp, and Escherichia coli, in that order (48). Cellulitis caused by Streptococcus pneumoniae is particularly virulent. It may be the primary infection or may occur after a case of pneumonia or otitis media. The cellulitis appears as brawny edema, is violaceous, and may form bullae. Bloodstream infections, tissue necrosis, and suppurative complications are more likely and surgical intervention is often necessary. Overall mortality is 17% (24,49). The differential diagnosis for cellulitis includes venous thrombosis, and the two conditions often occur at once. Early cases of herpes zoster, osteomyelitis particularly in the case of an open wound, necrotizing fasciitis, and varicose eczema all may look like cellulitis at some point (30,50). C. Diagnostic Approach The diagnosis of cellulitis in the nursing home is by necessity a clinical diagnosis according to the symptoms and signs described above. To establish the diagnosis, a physician, nurse practitioner, or physician assistant needs to see the skin lesion and consider the differential diagnosis carefully. Skin and soft tissue cultures are not recommended in typical cases. Skin and soft tissue cultures by fine-needle aspirates may be useful if there is a fluctuant area suggesting an abscess, unusual pathogens are suspected (i.e., immunocompromised host), or initial antimicrobial therapy has been unsuccessful (51). Blood cultures may be positive in about 5% of cases, but the organism is as likely to be a contaminant as it is causative (27,46). Aspirates of the involved skin may identify a pathogenic organism in 10% to 20% of samples, but these cultures are not very useful and not usually available to nursing home providers (30,51). Typically a red, hot, and tender area with mild systemic signs, including absent or low-grade fever, is sufficient for initiating therapy for cellulitis. Deep vein thrombosis is common enough that it should be excluded when symptoms and signs suggest it, but most cases of cellulitis can be managed in nursing homes that are able to administer intravenous therapies and have licensed nurses covering 24 hours a day and weekends.

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More virulent forms of cellulitis should be treated in the acute care setting. Vesicles, bullae, and high-grade fever would all be indications for transfer to the hospital. In these cases, cultures of the vesicles, bullae, and blood are more likely to yield the pathogen. If the clinician suspects necrotizing fasciitis, magnetic resonance imaging of the lesion and surgical consultation are indicated (42,52,53). D. Therapeutic Interventions Erysipelas and cellulitis without systemic signs can be treated by an oral first-generation cephalosporin (i.e., cephalexin 500 mg q6h). Clindamycin (150–300 mg q8h), dicloxacillin (250 mg q6h), or amoxicillin (500 mg)-clavulinic acid (1 tablet q8h) are reasonable alternatives. The cellulitis associated with gastrostomy tubes is typically mild and may also be treated in this manner (34,35,37). When cellulitis occurs with fever and systemic signs, intravenous (IV) therapy is indicated. Cefazolin (1.0 g IV q8h) or nafcillin (2.0 g IV q4h) are reasonable empirical choices. A few authors suggest treatment with clindamycin and a macrolide because of immunomodulary activity of these antibiotics. Animal models have shown that these antibiotics inhibit protein synthesis and suppress bacterial toxin production and production of penicillin-binding proteins (27,54). Cellulitis complicating saphenous vein harvests or a hip prosthesis have the same prognosis and should be managed in the same manner as other presentations for cellulitis (26,29). The experience for treating cellulitis is almost totally hospital based. No studies have examined outcomes in a long-term care setting or in using oral antibiotic therapy. Generally, most cellulitis without systemic signs can be managed in the nursing home. More severe infections needing IV therapy will most likely require transfer of the resident to an acute care facility. Local care of cellulitis includes immobilization and elevation of the extremity and cool sterile saline dressings to reduce pain. Moist heat should be applied to areas of fluctuation that suggest early abscess formation. Abscess formation is an indication for hospitalization. In a retrospective study of 101 cases of cellulitis treated in a hospital, 85 cases were well within 10 days of treatment (23). E. Infection Control Measures Outbreaks of cellulitis have been described among nursing home residents with group A streptococci (44,47). Transmission was through direct contact between staff or other residents. Based on documented risks of transmission, the CDC recommends Standard Precautions for the management of cellulitis (see Chapter 8). These standards consist of handwashing using a plain, nonantimicrobial soap after examination of the patient with cellulitis. Antimicrobial soaps or a waterless agent are indicated for control of outbreaks or hyperendemic infections. Gloves should be worn when touching skin that is not intact. The gloves should be re-

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moved promptly after use and hands should be washed. Environmental control includes cleaning and disinfecting bed rails, bedside equipment, and other frequently touched surfaces. These interventions may be problematic in a nursing home because of the personal possessions that clutter the residents’ personal space and their poor compliance with regulations owing to impaired cognitive function. This is also why complex cases may be best managed in a hospital setting. Contact isolation is indicated for open bullae with drainage and when treating a resistant organism. Most of these special circumstances are probably more appropriately managed in an acute care facility. Residents managed in the nursing home should be placed in a private room or with others who are infected with the same organism. A gown should be worn if clothing will have substantial contact with the patient (16). More aggressive attempts to control infection, such as isolation or limitation of activity, are not justified unless there is evidence that a resident is a risk to others and barriers will decrease the risk (21). Perhaps the most important control measure is good hand washing. It has been well documented that nursing staff and physicians are not compliant with proper hand-washing protocols in hospital and nursing homes (55). For example, researchers monitored hand washing in an LTCF and found that gloves were worn in 82% of indicated encounters, but they were changed when indicated only 16% of the time. Hands were washed before encounters in 27% of episodes, never during encounters, and 63% after encounters. The level of training in the staff had no influence on compliance with proper infection control. Physicians, registered nurses, licensed practical nurses, and nurses aides were all equally likely (or unlikely) to follow proper protocols (56). A problem that is rarely mentioned as a likely hindrance to appropriate hand-washing procedures is the damage done to nurses’ hands from frequent washing. A study that evaluated nurses’ hands found that one-fourth had skin damage at the time of the study and 86% had skin damage at some point in time (57). The damaged hands can be a reservoir for pathogenic organisms as well as a discouragement to proper handwashing. Alcohol-based waterless antiseptic agents may decrease damage to hands and are less time consuming (55). F. Prevention Impaired arterial, venous, and lymphatic circulation and a portal of entry are cardinal predisposing factors for cellulitis. These risks factors should be addressed in prevention efforts, particularly among nursing home residents who have had previous episodes of cellulitis. No studies address the circulatory risk factors, but venous stasis is generally undertreated and compression dressings are an effective nonpharmacologic management strategy. The portal of entry caused by tinea pedis can be addressed by topical antifungal agents as well as local skin care consisting

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of warm saline soaks (except in diabetic patients), proper foot hygiene, and avoidance of trauma. Acute infection may be treated with a short course of an oral antifungal agent (griseofulvin, terbinafine, fluconazole, ketoconazole, itraconazole). Macerated web spaces and hyperhydrosis are treated with drying agents, lamb’s wool, and cotton balls. Chronic tinea infections are treated with antifungal foot powder and disinfectant spray (e.g., Lysol®) to shoes once a week (38,39). Treatment of tinea pedis reduces recurrence of cellulitis (26). Prophylactic antibiotic therapy (i.e., intramuscular injections with benzathine penicillin) has no effect on episodes of recurrent cellulitis among subjects with predisposing factors (venous stasis, obesity, leg edema, fracture, diabetes mellitus, surgery, lymphedema)(58).

III. SCABIES A. Epidemiology and Clinical Relevance Scabies is a cutaneous ectoparasitic infestation caused by the mite, Sarcoptes scabiei (59). Itching, excoriation, and secondary bacterial infections are the main clinical problems. The clinical manifestations are caused by the adult female mite, which measures about 1/16 inch in length. The body is round without a distinct head, but there are mouth parts at one end of the body and four pairs of legs. Most of the body consists of ovaries and developing eggs. The female will copulate with a male mite on the skin, dig through the stratum corneum to the boundary with the stratum granulosum, and create a burrow. She continues to tunnel in the burrow for her lifespan of about 30 days, increasing its length a few millimeters per day. During this time, she lays a few eggs per day in the burrow. The eggs hatch into larvae. Over a 10- to 14-day period, the larvae move to the skin surface, molt into adults, and begin the reproduction process again. Scabies is endemic in most parts of the world. The mite is able to survive outside the human host for a limited time. Live mites can be recovered from the bed, furniture, and floors of nursing homes with recent scabies infestations, but fomites do not appear to be important in the transmission of scabies (60). Instead, it thrives on humans and requires human infestation to propagate. The likelihood of spread is increased with increasing amount and duration of physical contact. Overcrowding, poor hygiene, and institutional settings are associated with epidemics. Accurate data on the incidence and prevalence of scabies in nursing homes are not available, but the epidemic spread of scabies is well documented in longterm care institutions. Typically, the mite is introduced into the home by a visitor or newly admitted resident. The infected resident may have an atypical presentation or may be misdiagnosed so the infection is present for weeks or months. Contact with staff, visitors, and other residents spreads the infection within and outside the home. For example, researchers reported a nursing home outbreak in Norway

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where the index case had pruritis and rash for several months and was misdiagnosed as eczema (61). The infection spread to 13 residents and six healthcare workers before diagnosis and treatment. In an outbreak in Massachusetts, the infection spread to 111 of 313 residents (35%) and 91 staff and family members before it was recognized and controlled (62). In another nursing home epidemic, the index case had an atypical presentation on top of underlying psoriasis treated with a topical corticosteroid (63). The spread of the mite was facilitated by atypical papular and nodular lesions in other patients without psoriasis and treatment resistance among residents with malignant disease and immunosuppressive therapies. B. Clinical Manifestations The cardinal symptom of scabies is itching, which is often nocturnal and varies in severity from mild to severe. Individuals may be infested for weeks or months before itching is noted. On the physical examination, the most significant sign is the burrow, which appears as a raised, linear tunnel of skin that varies in length from a few millimeters up to 1 cm. There may be associated erythema, eczematous changes and excoriations. In immunocompetent patients, the burrows are characteristically distributed in the hands and wrists, especially in the interdigital spaces of the fingers, the palms, and flexor surface of the wrist; the posterior and medial aspects of the elbow; the feet; the anterior axilla; the waist; the buttocks; the penis and scrotum; and the nipple area in women. The typical itching, appearance, and distribution of lesions in scabies may not be present in nursing home residents (59), who often have coexisting diseases, treatments, and deficient cellular immune responses that mask scabies (59). The itching and burrows may be minimal or absent. The cutaneous manifestions may be eczema-like lesions, plaques, nodules, or papules. The face and scalp can be infested. In bed-bound patients, the lesions may be found only on the back or sides on skin in contact with bedsheets. A crusted form of scabies (Norwegian scabies) has been described in nursing home residents. It appears as a marked crusting dermatitis in the hands and feet with thick hyperkeratotic debris. Red scaling plaques on the trunk, neck, and scalp may also develop. This form of scabies is important because the parasite burden is very high and patients are highly contagious. Crusted scabies has also been described in immunosuppressed patients, including those with leukemia and acquired immunodeficiency syndrome. Left untreated, scabies persists indefinitely and causes several complications. The lesions may become extensive in the setting of poor hygiene. With repeated excoriations, patients experience an eczematous neurodermatitis. Secondary bacterial infection may follow, as manifested by impetigo, folliculitis, and cellulitis. If mistreated with topical corticosteroids, the itching and cutaneous signs may be masked for long periods. The suppression of symptoms and delay in treatment may result in extensive infestation.

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C. Diagnostic Approach The differential diagnosis includes any pruritic dermatosis, such as various forms of eczema, atopic dermatitis, contact dermatitis, insect bites, urticaria, vasculitis, and dermatitis herpetiformis. The diagnosis is straightforward when the patient has (1) typical itching, (2) visible burrows in characteristic distributions, (3) a mite demonstrated in the burrow and (4) resolution of the disease following topical scabicides (64). The mite can be demonstrated by skin scrapings of burrows. Mineral or microscope immersion oil is placed on a #15 scalpel blade and allowed to flow on the lesions. The lesion is scraped very superficially with the blade in the epidermal layer only, taking care to avoid bleeding. The skin scrapings and oil are transferred to a slide, a cover slip placed, and the specimen is examined under low power for adult mites, larvae, nymphs, eggs, egg casings, or fecal pellets. One may also demonstrate the mite by raising the closed end of the burrow with a needle and looking for the mite with a hand lens, either on the tip of the needle or in the unroofed burrow. Other techniques include epidermal shave biopsies, dermal curettage, a skin swab with adhesive tape, and punch biopsy. Even in highly suspected cases of scabies, it may be surprisingly difficult to find the organism, particularly in excoriated or inflamed areas of skin. To reduce the false-negative rate of these tests, some authorities recommend several slides from non excoriated, noninflamed sites of typical distribution. The diagnosis is even more difficult in atypical cases in nursing home residents. During the incubation period, there may be no symptoms or signs of infestation. Itching may be the first clue but the itching may be ascribed to dry skin or anxiety. In nursing home residents with unexplained itching, clinicians should perform a careful skin survey for burrows in typical and atypical locations. The lesions may be very sparse in residents who are bathed regularly. Bathing will not cure the infestation, but it will reduce the number of visible lesions. Lesions other than burrows may be the clue to scabies. These eruptions include persistent reddish pruritic nodules, papular lesions, eczematous lesions, and bullous lesions. The diagnosis should be considered in unexplained, pruritic dermatoses. D. Therapeutic Interventions Scabies can be completely eradicated by prescribing scabicides (59). Permethrin 5% cream is effective, safe, and well tolerated. The cream is applied to all areas of the body and washed off after 8 to 14 hours. In one case series of 195 patients with scabies, including nursing home residents, 46.7% had clearing of the infection with one application, 39.5% after two applications, and 11.8% after three applications for a total cure rate of 98% (62). Resistance has not been a problem with permethrin. Lindane (gamma benzene hexachloride) 1% cream or lotion is effective, easy to use, and generally safe in nursing home residents. One ounce of lotion or

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30 g of cream is applied to all areas of the body and washed off after 8 hours. Investigators have reported treatment failures and possible resistance in U.S. nursing homes. Seizures have been reported in individuals who used lindane after a hot bath or on skin with extensive dermatitis. Benzyl benzoate lotion or crotamiton cream/lotion are also effective topical scabicides, but the CDC considers permethrin or lindane to be the scabicides of choice. Ivermectin is an effective, safe, inexpensive, convenient, oral pill for scabies. In the United States, it has not yet been approved for human use by the Food and Drug Administration. In small case series, cure rates approaching 100% have been reported after two doses (65,66). In one trial in outpatients, nursing home residents, and hospitalized patients in Argentina, patients received either a single oral dose of ivermectin (150 to 200 mcg/kg body weight) or topical application of 1% lindane. Treatment was repeated after 15 days if clinical cure had not occurred. At day 15, 14 of 19 (74%) of the group treated with ivermectin were cured compared with 13 of 24 (54%) of the lindane-treated patients. At day 29, 18 of 19 (95%) of invermectin patients were cured compared with 23 of 24 (96%) of lindane-treated patients. Adverse effects were mild, few, and transient. (67). It is well tolerated, but investigators have not shown that ivermectin is superior to topical treatment. However, it can be useful for scabies outbreaks in nursing homes. In a large group of nursing home residents, topical scabicides may be difficult to apply properly or may be poorly tolerated because of burning or other skin reactions. Itching often persists after therapy. If itching persists for 1 to 2 weeks, a diagnostic examination should be done again. The differential diagnosis includes hypersensitivity to scabies, cutaneous irritation, contact dermatitis to the scabicide, a recurrence of scabies, an unrelated skin disease, or delusions of parasitosis. Hypersensitivity and contact dermatitis can be treated with topical corticosteroids, provided it is certain that the itching does not represent scabies. Some experts recommend a scabicide retreatment for patients who are symptomatic regardless of whether live mites are demonstrated, whereas other experts recommend treatment only if live mites are observed. Recurrent scabies requires headto-toe application of a scabicide or a dose of ivermectin with treatment of all contacts as before. Several relapses raise the issue of resistance, which can be addressed by using a different scabicide. E. Infection Control Measures The CDC recommends Contact Precautions for persons with scabies (see Chapter 8). These precautions include gloves upon entering the room, removal of gloves before leaving the room, and washing hands immediately with an antimicrobial agent. A gown is recommended if clothing could have contact with the infested resident. Ideally, the resident should be placed in a private room or cohorted with another resident with scabies. However, a private room for a resident with scabies

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may not be feasible. Skin-to-skin contact should be avoided until after scabicide treatment. The duration of the precautions is 24 hours after the initiation of treatment. Resident transport should be limited during this time. All staff, relatives, and other residents with prolonged skin-to-skin contact with the resident should be identified and treated prophylactically with a scabicide regardless of whether they have symptoms. In addition, close household contacts of employees undergoing treatment should be offered prophylactic treatment. Staff can return to work the day after completing treatment. Staff should remove and decontaminate bedding and clothing by machine washing at 60°C. Fumigation of living areas is unnecessary. If clinicians suspect an outbreak of several cases in the institution, it is important to have parasitological diagnostic confirmation because a full-scale infection control program is costly in time and personnel (68). When an outbreak is confirmed, the infection control team in the facility should be assembled to manage the epidemic. The entire population at risk—patients, staff, visitors—should be treated. Some time may have passed before the scabies was diagnosed so many people may have been exposed. Recurrent epidemics of scabies have been reported in nursing homes when all residents were not treated during an outbreak. Furthermore, some exposed staff or residents may have gone to other institutions and need to be treated. It is useful to have an inservice training seminar where everyone is educated about scabies and understands the rationale for measures in control program. Staff commonly lack knowledge about parasite transmission, diagnosis, and clinical manifestations, as well as the methods for confirming the existence of an outbreak. F. Prevention Residents and staff would prefer to prevent an outbreak rather than spend the time and energy controlling one (68). Prevention includes the following steps: (1) Staff education. A very important step is educating staff and raising consciousness about scabies. Everyone should be aware that any nursing home is at risk for infestation. (2) Screening for index cases. New residents should be screened for scabies in their admission history and physical examination. New employees should be queried for new rashes or pruritis. Any suspect infestations should be evaluated. (3) Early detection of infested patients or staff. Clinicians and staff need to have a high index of suspicion for scabies in any case of undiagnosed itching or rash. (4) Accurate early diagnosis. The index case in many nursing home outbreaks had long-standing scabies that was misdiagnosed. Clinicians need to think about the possibility of scabies and develop competency in skin scraping procedures. In unclear or difficult cases, consultation with dermatology subspecialists is useful. (5) Patient care procedures to end skin-to-skin contact once a case is identified. These procedures include standard precautions with protective gloves,

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clothing and hand washing. Although simple, many of these steps are difficult to implement in the nursing home because the incidence of scabies is low and the staff and clinicians are occupied with other problems.

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18 Infectious Diarrhea Abbasi J. Akhtar Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California

I. EPIDEMIOLOGY AND CLINICAL RELEVANCE Diarrhea, one of the most common gastrointestinal complaints, is also one of the four most common infections in elderly residents of long-term care facilities (LTCFs). Nonspecific diarrhea is the most common type of diarrhea in the United States; however, it is anticipated that an increase in the number of specific infectious causes of diarrhea will be diagnosed with the development of newer diagnostic techniques (1). Physiological protective mechanisms against invasion of pathogenic organisms, such as gastric acidity, forward propulsive gut motility, and normal intestinal flora, may be compromised in the elderly, because of the aging process alone, a combination of comorbid conditions, or various medications. These factors, along with weakened immune system and other defense mechanisms, make the elderly more susceptible and vulnerable to infectious diarrhea as compared with the younger population (2,3). Moreover, after acquiring a diarrheal disease, elderly patients tolerate it less well and suffer more frequently from complications than their younger counterparts with the same disorder. Infectious diarrhea in LTCF residents may be associated with significant morbidity and mortality, even in developed countries. Mortality from diarrhea is much higher in older (older than age 75) LTCF residents. About one-third of all deaths resulting from diarrheal disease in the United States occur in the elderly residents in LTCFs, probably because of their lack of tolerance to resulting volume depletion (4). Early recognition and prompt treatment of diarrheal disease are, therefore, essential in preventing serious complications of dehydration and electrolyte disturbance that may result in multiple organ system disease and even death. 305

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The risk of exposure to pathogens that cause diarrhea is enhanced in LTCF residents because of shared bathroom and dining facilities, liberal social and physical mixing of residents, and suboptimal infection control measures. The most common cause of infectious diarrhea in LTCF residents is viral infection. The exact epidemiology of viral diarrhea is difficult to determine because of lack of precise diagnostic measures in many viral illnesses. However, Norwalk virus and Norwalk-like virus, rotavirus, are the most common pathogens. Moreover, acute diarrhea may occur as a component of a general viral syndrome caused by viruses such as influenza. Viral diarrhea may occur as sporadic cases or as an outbreak of diarrheal disease in LTCFs. Usually, viral diarrhea is a self-limited condition. However, some frail residents may develop complications from dehydration and electrolyte imbalance. Any microorganism that causes diarrhea in the general population can also cause diarrhea in LTCF residents. However, a definitive laboratory diagnosis of the culprit microorganism is made in no more than half of all patients with diarrhea (5,6). Common bacterial causes of diarrhea in LTCFs include Clostridium difficile, Escherichia coli (0157:H7, enterotoxigenic, enteropathogenic, and enteroinvasive), Salmonella spp, Shigella spp, Campylobacter spp, Vibrio cholera, and other Vibrio spp, and Yersinia enterocolitica. Some cases of acute diarrhea resulting from food poisoning may be caused by Clostridium perfringens, Bacillus cereus, Staphylococcus aureus, or Listeria monocytogenes (Table 1). Table 1 Etiology of Diarrhea in LTCF Residents Infectious causes Viruses Norwalk virus Rotavirus Calcivirus Bacteria Clostridium difficile Clostridium perfringens Campylobacter spp Escherichia coli Salmonella spp Shigella spp Staphylococcus aureus Vibrio spp Parasites Giardia lamblia Entamoeba histolytica Cryptosporidium spp Cyclospora spp

Noninfectious causes Dietary Hyperosmolar formula High-sorbitol foods High-lactose foods Medications Antibiotics Antacids Laxatives Miscellaneous Gut disorders Inflammatory bowel disease Ischemic bowel Systemic diseases Urosepsis Renal failure Thyrotoxicosis Diabetes mellitus

Abbreviation: LTCF, Long-term care facility.

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Clostridium difficile, a nosocomial pathogen, is an important cause of diarrheal illness in LTCF residents, and because of its spore-forming capacity, the organism may persist and cause protracted diarrhea. The incidence of asymptomatic carrier state of C. difficile may rise from 2% in healthy adults to 9% of LTCF residents; however, antibiotic use and hospitalization may increase the incidence to 16% to 56% (7). The clinical spectrum of infection with C. difficile may include asypmtomatic carrier state, trivial or serious diarrheal disease, toxic megacolon and its complications, fever of undetermined origin, and protein-losing enteropathy. Clostridium difficile spores may be resistant to commonly used soaps, and stronger chemicals may be required for adequate disinfection; this may be one possible explanation of recurrent/relapsing cases of C. difficile-associated pseudomembranous colitis. Among the parasitic causes of diarrhea, Giardia lamblia, occasionally Cryptosporidium, and Microsporidium may be found, although other parasites, such as Entamoeba histolytica, may be responsible for some cases in LTCFs, depending on underlying disease and exposure.

II. CLINICAL MANIFESTATIONS Diarrhea may occur sporadically in one or more residents or as an outbreak in multiple residents. The clinical spectrum of infectious diarrhea may vary from a few loose stools to a potentially life-threatening condition. Most patients in the general population suffering from infectious diarrhea will complain of one or more of the following symptoms: crampy lower abdominal pain, anorexia, nausea, fever, malaise, and watery or bloody diarrhea. Elderly residents in LTCFs with diarrhea, however, may not complain of diarrhea, and thus the condition may not be noticed by the nursing or paramedical staff. Sometimes a complication such as dehydration or altered mental status may prompt the discovery of diarrhea. Infectious diarrhea in elderly residents may or may not be accompanied by fever; occasionally, these residents may have hypothermia. Severe constipation and fecal impaction may be present as overflow diarrhea. Clostridium difficile-associated pseudomembranous colitis, which usually is accompanied by low-grade fever and watery diarrhea, may sometimes occur with little or no diarrhea and appear as an acute abdomen and, if unrecognized, may lead to unnecessary surgery, increased morbidity, and even mortality (8).

III. DIAGNOSTIC APPROACH A. History In the evaluation of infectious diarrhea, noninfectious causes of diarrhea must be considered in the differential diagnosis. Attempts should be made to distinguish

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fecal incontinence and constipation from fecal impaction and overflow diarrhea from true diarrhea. A careful history should be obtained from the resident, if possible, or from the nursing staff. Duration of diarrhea may give useful clues to the diagnosis. In general, acute diarrhea of less than 2 weeks, duration is more likely to be of infectious origin. Diarrhea caused by food poisoning may have its onset in less than 12 hours after ingestion of contaminated food. There may be a clue to etiology of the diarrhea in the type of food ingested, for example, Vibrio cholera from eating raw sea food, salmonellosis from improperly cooked eggs and poultry, E. coli from improperly cooked meat, and listeriosis from contaminated milk products. Salmonella, Campylobacter, and Yersinia have been reported to cause diarrheal disease after consumption of raw milk or unpasteurized milk products. Antibiotic-associated diarrhea usually occurs 4 to 7 days after initiation of antibiotic therapy, although it may occur even more than 1 month after stopping the antibiotics. Some cases of antibiotic-associated diarrhea in frail elderly residents may be caused by Candida, and this should be considered if diarrhea persists and repeated assays for C. difficile toxin assay in stools are negative (9). A careful drug history should be obtained. Besides antibiotic-associated diarrhea and C. difficile colitis, many drugs, such as magnesium-containing antacids, may cause diarrhea. Excessive ingestion of sorbitol-containing foods such as grapes, candies, etc. may also result in diarrhea, as does milk or milk products ingestion in residents with lactose intolerance. Diarrhea may be a side effect of many medications; therefore, a careful review of all medications (both prescription and nonprescription), including herbal remedies, is of importance. In residents receiving enteral feeding, the formulation of feeding solution and rate of administration should be carefully reviewed, as rapid administration of hyperosmolar formulas may cause diarrhea. An uncommon but very clinically important scenario is when elderly persons with underlying inflammatory bowel disease (ulcerative colitis or Crohn’s disease), develop infectious diarrhea (10). If the diarrhea episode is mistakenly considered an exacerbation of the underlying inflammatory bowel disease and corticosteroids are administered, catastrophic complications such as hyperinfection syndrome may develop, leading to significant morbidity and even death. B. Physical Examination A meticulous physical examination is always necessary in every sick patient and more so in elderly LTCF residents, who may not complain or be able to communicate adequately. Attempts to identify early clinical evidence of presence and severity of dehydration and electrolyte disturbance in elderly sick residents with diarrhea are more important than determining the etiology of diarrhea. Vital signs, including measurement for orthostatic hypotension and change in body tempera-

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ture, should be checked. A gentle digital rectal examination will provide useful information about sphincter weakness caused by neuropathy or muscle injury and presence of hard fecal masses or blood, as well as finding of perianal skin tag, fissures, fistulas, and abscesses that may be a clue for possible diagnosis of Crohn’s disease. Bloody diarrhea or blood in stools—usually a sign of infection associated with inflammation, microbial invasion of mucosa, or tissue damage—may occur in E. coli 0157-H7, Yersinia, shigella, or Salmonella infections. This should be differentiated from noninfectious causes of diarrhea, such as inflammatory bowel disease (ulcerative colitis and Crohn’s disease), diverticulosis, or ischemic colitis. C. Laboratory Tests After consideration of noninfectious causes of diarrhea, stools should be examined for ova, parasites, and fecal leukocytes and appropriate cultures should be obtained. Close collaboration of laboratory staff is crucial for rapid and precise diagnosis. A complete blood count, serum electrolytes, and renal functions tests should be obtained in most elderly residents with significant diarrhea who appear ill, are febrile, or have rapid decline in function. Unexplained leukocytosis, more than 15,000/mm, may be a potential clue to C. difficile-associated diarrhea or colitis; likewise, fever, cramps, and hypoalbuminemia (probably caused by proteinlosing enteropathy) may act as surrogate markers of C. difficile-infection or other enteric infectious agents (11). If the diagnosis is still unclear and the resident is febrile, tachycardic, or hypotensive, transfer to an acute unit should be considered for further evaluation and aggressive management. A flexible sigmoidoscopic examination may also be justified. This examination should be done without any cleansing enemas or oral laxatives, as the cleansing solutions may act as mucosal irritants, causing hyperemia and excess mucus that mimic inflammatory changes. In most cases, a limited examination is enough to make a diagnosis. Sigmoidoscopy may reveal evidence of colonic ischemia or uniformly congested and ulcerated mucosa, suggestive of acute infectious colitis or idiopathic ulcerative colitis. Pseudomembranous colitis can also be diagnosed by sigmoidoscopy. However, some cases may have evidence of pseudomembrane formation limited to the right colon and may only be diagnosed by full colonoscopy. Colonoscopy will also facilitate diagnosis of ulcerative colitis, Crohn’s disease, and colorectal neoplastic lesions such as villous adenoma or carcinoma. Of note is that the decision for acute unit transfer for more extensive evaluation and therapy should be in accordance with residents’ advanced directives or wishes of the healthcare proxy. However, because diarrhea is often acute, self-limited, and easily treated, care-limiting advance directives may not be relevant.

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IV. THERAPEUTIC INTERVENTION Most cases of infectious diarrhea, especially those of viral etiology, are usually self-limiting, and symptomatic supportive therapy with fluid and electrolyte replacement is all that is required. Principles of general resuscitation are basically the same irrespective of exact etiology of diarrhea and include adequate hydration and maintaining electrolyte balance. The oral route should be used whenever possible. Oral fluids (water, juices, electrolyte-containing drinks) should be encouraged, as tolerated. Milk and milk products, with the exception of plain yogurt, should be avoided, at least in the initial phase of diarrheal illness. Any of the commercially available oral rehydration solutions (ORS) may be used (12). Most such solutions contain balanced amount of electrolytes and glucose, the latter facilitating fluid absorption by the glucose pathway. Maintenance rehydration solutions with a modest sodium content (45–50 mEq/L) should be administered rather than acute rehydrating solutions with higher sodium content (75 mEq/L) to avoid hypernatremia. If the resident shows signs of significant dehydration (poor skin turgor, dry skin, altered level of consciousness, hypotension, or orthostasis), then intravenous administration of fluids and electrolyte solutions may be required and the resident may need a transfer to an acute care facility. Particular care should be exercised in rapid intravenous replacement of fluids and electrolytes, as elderly, frail patients may have limited tolerance of fluid overload and may rapidly develop pulmonary edema and electrolyte imbalance because of underlying renal and cardiovascular diseases. Specific therapy with appropriate antibiotics, such as metronidazole or vancomycin, may be required in symptomatic patients with C. difficile-associated pseudomembranous colitis (Table 2). In general, antidiarrhea medications with antiperistaltic property should be avoided in acute stages of illness, particularly before an exact diagnosis is made because of the risk of developing toxic megacolon. Bismuth subsalicylate may be used in some patients who are not toxic.

V. INFECTION CONTROL MEASURES It should be determined whether the case of diarrhea is sporadic, occurring in an individual resident, or in a group of residents in the LTCF. As the mode of transmission of most enteric pathogens is the fecal-oral route, enteric precautions (hand washing with chlorhexidine and wearing gloves by visitors and LTCF staff, entering residents’ room) should be observed (see Chapter 8). Appropriate infection control and administrative authorities should be informed promptly so that diagnosis and effective treatment of index case, as well as adequate sterilization of bed

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Table 2 Antibiotic Therapy of Common Pathogens Causing Infectious Diarrhea in the Elderly Clostridium difficile Campylobacter jejuni Salmonella typhi/paratyphi Shigella spp Vibrio cholerae Giardia lamblia

Entamoeba histolytica

Metronidazole 500 mg or vancomycin 125 mg orally four times a day for 10 days Erythromycin 250 mg orally four times a day for 5 days or azithromycin 500 mg orally daily for 3 days Ofloxacin or norfloxacin 400 mg twice daily for 7 days Trimethoprim-sulfamethoxazole 160/800 mg or ofloxacin 400 mg orally twice daily for 5 days Tetracycline 500 mg orally four times daily for 3 days Metronidazole 250 mg orally three times daily for 5 days or furazolidone 100 mg orally four times daily for 7 days Metronidazole 750 mg orally three times daily for 10 days, followed by cyst eradication with iodoquinol 650 mg orally three times daily for 20 days

linen, towels, and clothing of patients can be instituted without delay. Such measures are necessary to control infection and to prevent outbreak of disease (see Chapter 9).

VI. PREVENTION Food handlers in particular, and all staff of LTCFs in general, should be screened for absence of enteric pathogens, especially after a history of travel to high-risk areas. Food and water supply should be supervised and checked repeatedly for absence of any possible contamination. Health education should be provided to all relevant persons and updates provided continuously. Hand washing and sanitary hygiene should be strictly recommended and supervised. Avoiding medications such as antibiotics, laxatives, and magnesium-containing antacids may also decrease incidence of diarrheal disease in this setting. Development of vaccines against enteral pathogens may prevent significant morbidity and mortality from diarrhea in the elderly, especially in LTCF residents (13).

REFERENCES 1.

DuPont HL. Guidelines on acute infectious diarrhea in adults. The practice parameters committee of American College of Gastroenterology. Am J Gastroenterol 1997; 92(11):1962–1975.

312 2. 3. 4.

5. 6. 7. 8. 9. 10. 11.

12. 13.

Akhtar Altman DF. Changes in gastrointestinal, pancreatic, biliary and hepatic function with aging. Gastroenterol Clin North Am 1990; 19(2):227–234. Schmucker DL, Daniels CK. Aging, gastrointestinal infections, and mucosal immunity. J Am Geriatr Soc 1986; 34(5):377–384. Lew JF, Glass RI, Gangarosa RE, Cohen IP, Bern C, Moe CL. Diarrheal deaths in the United States, 1979 through 1987. A special problem for the elderly. JAMA 1991; 265(24):3280–3284. Pentland B, Pennington CR. Acute diarrhea in the elderly. Age Ageing 1980; 9(2): 90–92. Bennett RG. Diarrhea among residents of long-term facilities. Infect Control Hosp Epidemiol 1993; 14(7):397–404. Bentley DW. Clostridium difficile-associated disease in long-term care facilities. Infect Control Hosp Epidemiol 1990; 1(8):434–438. Klipfel AA, Schein M, Fahoum B, Wise L. Acute abdomen and clostridium difficile colitis: Still a lethal combination. Digest Surg 2000; 17(2):160–163. Danna PL, Urban C, Bellin E, Rahal, JJ. Role of Candida in pathogenesis of antibiotic-associated diarrhoea in elderly inpatients. Lancet 1991; 337:511–514. Akerkar GA, Peppercorn MA. Inflammatory bowel disease in the elderly. Practical treatment guidelines. Drugs Aging 1997; 10(3):199–208. Bulusu M, Narayan S, Shetler K, Triadafilopoulos G. Leukocytosis as a harbinger and surrogate marker of Clostridium difficile infection in hospitalized patients with diarrhea. Am J Gastroenterol 2000; 95(11):3137–3141. Swerdlow DL, Ries AA. Cholera in the Americas. Guidelines for the clinician. JAMA 1992; 267(11):1495–1499. Rajagopalan S. Infectious diarrheas in older adults. Infect Dis Clin Pract 1997; 6:313–316.

19 Hepatitis Darrell W. Harrington and Peter V. Barrett Harbor–UCLA Medical Center, Torrance, California

I. INTRODUCTION Clinical disease in the context of a long-term care facility (LTCF) presents problems for the healthcare professional that differ considerably from those found in the ambulatory setting or in acute care hospitals. This chapter will focus on the acute and chronic forms of the most common types of viral hepatitis as may occur in a long-term care setting, as well as on the challenges to infection control that they represent. Numerous viral agents may involve the liver, but the following discussion will focus on the three major types, hepatitis virus A, B, and C, with additional comments on the less common varieties, hepatitis virus D, E, and G (Table 1). Advances in technology during the past 2 decades have provided healthcare professionals with enormous amounts of new information about the biology and pathogenesis of these viruses, and as a result, great strides have been made in both the treatment and prevention of disease.

II. EPIDEMIOLOGY, CLINICAL RELEVANCE, AND DIAGNOSTIC APPROACH A. Hepatitis A Virus Hepatitis A virus (HAV) was historically known as “infectious hepatitis.” It is prevalent worldwide and is transmitted predominantly by the fecal-oral route through person-to-person contact or by contaminated food or water. Transmission is rarely reported after contact with blood or body fluids other than feces. In countries where HAV is endemic, most of the population becomes exposed in child313

DNA hepadnavirus

RNA picornavirus

15–60 days No Uncommon Unrelated

Incubation period Chronicity Fulminant disease Hepatocellular carcinoma Mortality Vaccine

Bloodborne, sexual, perinatal 45–160 days 15%–30% Common Strong association 1%–2% Yes 1%–2% No

14–180 days 50%–80% Rare Strong association

2%–20% No (vaccinate against HBV)

42–180 days 70%–80% Common Strong association

Bloodborne and Bloodborne, sexual sexual, perinatal

1%–2% No

15–60 days No No Unrelated

Not significant No

Unknown Yes No Unknown

No reported cases Unknown in U.S. Primarily occurs Estimated in developing antibodies countries present in 1%–2% of Americans Fecal-oral Bloodborne

RNA F1avivirus

RNA calicivirus

Defective RNA virus Unknown

G

E

D

Antibodies present HDV present in 10%–20% with in 1.5% of chronic HBV American

38,000/y

RNA flavivirus

C

Abbreviations: HDV, Hepatitis D virus; HBV, Hepatitis B virus. Source: Data compiled from National Notifiable Diseases Surveillance System, Centers for Disease Control and Prevention.

Yes

1%

Fecal-oral

125,000 to 140,000 to 200,000/yr 320,000/yr Antibodies present 1–1.25 million in 33% of chronically Americans infected

B

A

Mode of transmission

Prevalence

Epidemiology Incidence

Type and family

Viral agent

Table 1 Viral Characteristics and Epidemiology

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hood and life-long immunity to the virus is conferred. However, in industrialized societies, improved sanitation has decreased the frequency of infection, thereby producing a decrease in the proportion of the population that is immune to the virus. In the United States, the highest rates of natural immunity can be found in Native Americans and Hispanics; the rate for Native Americans is more than tenfold higher and the rate for Hispanics is more than twofold higher than for other ethnic groups. During an epidemic, secondary cases of hepatitis A occur 2 to 6 weeks after the index case. Infected individuals are most infectious in the late incubation period, a time when they are asymptomatic; they are usually no longer contagious by the time jaundice appears. The vast majority of infected individuals recover completely from acute infection. Fulminant hepatitis and death are rare complications, and the virus virtually never persists as a chronic infection. Groups at risk for HAV infection include household or sexual contacts of infected individuals, international travelers, and persons living in endemic areas. During outbreaks, day care center employees or attendees, homosexually active men, and injecting drug users are at risk. However, in nearly one-half of patients with hepatitis A, no known risk factor can be found. It is likely that asymptomatic infections, particularly in children, play an important role. The incidence of hepatitis A varies cyclically, with an interepidemic period of 7 to 10 years. The most recent increase began in 1993 and continued through 1995 with a total of more than 31,000 cases reported in the United States (1). The incidence of hepatitis A also varies regionally with rates in the West that are two to five times higher than in the rest of the nation. The prevalence of hepatitis A in the elderly population has been well documented. In population-based surveys, such as the National Health and Nutritional Examination Survey (NHANES) (2,3), the frequency of serologic evidence of past infection increases steadily with age, ranging from 10% in people younger than age 5 to three-fourths of people aged 50 and older. This age-associated increase is seen in both men and women and in all racial and ethnic groups. An inverse relationship exists between personal income and the prevalence of antiHAV antibodies. Studies have shown that closed communities (4) and small food-related outbreaks (5) are potential sites of outbreaks. No documented outbreaks of HAV in nursing homes have been reported (6). The latter observation is reassuring, but complacency must be avoided because as improved sanitation conditions become widespread, HAV infection will become progressively less frequent in childhood or adolescence, and as a corollary, the proportion of the adult population that will be susceptible to HAV infection will grow. This is especially important because acute HAV infection is more severe in the aged (7,8). The diagnosis of HAV infection is not difficult. Viral cultures are not practical for clinical purposes, but serological testing can allow the clinician to distinguish between acute infection and remote infections. The detection of HAV IgM immunoglobulins in serum indicates present or recent infection and may persist

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for several months. There is no chronic infection associated with HAV infection. Antibodies of the IgG class appear after complete resolution of infection and remain throughout life, thus conferring protection from reinfection (Fig. 1). The composition of the virus’s antigenic map is preserved throughout the world and, thus, global protection is conferred by the administration of immune globulin or by vaccination with a vaccine. B. Hepatitis B Virus Between 140,000 and 320,000 persons become infected with hepatitis B virus (HBV) every year, but more than half remain asymptomatic. As shown in Figure 2, the overall incidence of HBV increased steadily from 1966 to 1985, but has declined more than 60% since that time. Evidence from the Centers for Disease Control and Prevention (CDC) indicates that there are 1.0 to 1.25 million persons in the United States with chronic infection, and almost 6,000 people will die each year from cirrhosis or hepatocellular carcinoma as consequences of the infection. The peak age of infection is 20 to 39 years. Interestingly, the risk of developing symptomatic disease is directly related to age, whereas the risk of persistent infection is inversely related. The incidence of hepatitis has been decreasing in the United States in recent decades, coincident with recognition of the acquired immunodeficiency syndrome (AIDS) epidemic and subsequent decline in high-risk behavior. Hepatitis B virus was known as “serum hepatitis” a generation ago be-

Figure 1 Clinical course of acute viral hepatitis A. (From Ref. 43.)

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Figure 2 Hepatitis B by year, United States, 1966–1995. (From Ref. 1.)

cause it was shown to be transmitted to recipients of blood transfusion and serum products; however, it may be transmitted by any parenteral route, and is also transmitted by sexual contact and perinatally. Currently, the most common mode of transmission is high-risk heterosexual contact with an infected individual, followed in frequency by injected drug use and homosexual contact. All of these activities are poorly represented among the elderly population, making acute infection with HBV in the setting of an LTCF unlikely. The best information regarding the prevalence of hepatitis B infection in LTCFs and in the elderly may be found in the NHANES II and III surveys (2,3). For persons 65 to 74 years of age, hepatitis B surface antigen (HbsAg) was found less often than in the general population, with a frequency of 0.2% in white subjects and 0.9% in black subjects. A small number of reports have been published describing outbreaks of hepatitis B infection among nursing home residents. These infections were considered to have been spread by sharing bath brushes (9), through sexual contact with an infected nursing aide (10), or through the reuse of nondisposable syringes and shavers (11). Two outbreaks of nosocomial hepatitis B virus infection were reported from nursing homes in Ohio and New York (12). The infections were traced to the use of fingerstick devices, and in both reports personnel failed to restrict the use of the device to individual residents and to discard used parts. Failure to comply with universal precautions and the Food and Drug Administration (FDA) recommendations regarding the use of such devices will provide a continuing risk of exposure to patients requiring multiple percutaneous exposures.

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Figure 3 Clinical course of acute viral hepatitis B. (From Ref. 43.)

Two nucleocapsid antigens, hepatitis B core antigen (HBcAg) and hepatitis B e-antigen (HBeAg) and a surface marker, HBsAg, are important components of this complex virion. The incubation period is long, ranging from 45 to 160 days (average 120). Hepatitis B surface antigen is the first marker detected in serum and appears as early as 6 weeks after exposure. In acute resolving disease, this antigen becomes undetectable 6 to 8 weeks after the resolution of clinical symptoms. Hepatitis B e-antigen appears in the serum shortly after HBsAg and is a qualitative marker of viral replication. In the normal host, after HBsAg disappears, antibody to HBsAg becomes detectable in serum and remains detectable indefinitely, conferring immunity to reinfection (Fig. 3). In chronic HBV infection, HBsAg and HBV DNA persist indefinitely in the serum as manifestations of chronic active infection and viral replication. C. Hepatitis C Virus In the 1980s, hepatitis C virus (HCV) was shown to be the infectious agent responsible for most “non-A, non-B hepatitis” that occurred after transfusion or accidental needlestick. The incubation period for HCV infection has been reported to average 6 to 7 weeks. Although sexual and perinatal transmission occurs, percutaneous exposure to infected blood and transplantation of organs from infectious donors remain the most efficient modes of transmission. However, since the development of serological markers such as anti-HCV antibodies and the institu-

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tion of mandated testing in 1992, the incidence of transfusion-associated or organ transplant-associated HCV infection has declined rapidly (Fig. 4). In contrast to HBV, HCV circulates at very low titers in infected serum, and this observation may explain why transmission via sexual contact is less common. Vertical transmission perinatally may occur, but there is no evidence to support transmission during breastfeeding. In almost half of HCV seropositive persons, no definitive risk factor can be identified. In contrast to both HAV and HBV, the risk of chronic liver disease in patients infected with HCV is extremely high. Three-fourths of infected individuals will develop chronic infection and at least one-fourth of these will develop cirrhosis (13). The prevalence of anti-HCV varies in the U.S. population depending on various risk factors, but the interpretation of the results from commonly used screening assays (enzyme immunoassays) is limited by several factors: (1) these assays do not detect anti-HCV in approximately 10% of people infected with HCV; (2) these assays do not distinguish between acute and chronic or past infection; (3) in the acute phase of hepatitis C, there may be a prolonged interval between onset of illness and seroconversion; and (4) in populations with a low prevalence of infection, the rate of false-positive tests for anti-HCV is high. Hepatitis C virus is the most frequent cause of acute viral hepatitis in older people. In a series of cases of acute viral hepatitis in older patients in the United

Figure 4 Estimated incidence of acute hepatitis C, United States, 1982–1995. (From Ref. 1.)

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States, non-A, non-B hepatitis accounted for 74% (14–16). In most studies, the major risk factor for hepatitis C infection in older people is a history of blood transfusion. Because mandatory screening programs have been in effect for less than a decade, the elderly have had a longer period of possible exposure to the virus. Today, rather than infection from blood transmission, the main mode of transmission for this virus is intracommunity from unknown sources (17). Several studies have suggested that the prevalence of anti-HCV in older patients is similar to that of the general population (18–20). In a study evaluating 315 institutionalized elderly people in Italy, anti-HCV was present in 2.2% (18). Conversely, in a recent study of 199 residents in nursing homes, anti-HCV was present in 4.5% (21). These results were obtained with screening methodology for anti-HCV that is not as reliable as assays for HCV RNA. In another study of 273 patients in an Israeli geriatric hospital, only five (1.8%) were found to have antibodies to HCV, and HCV RNA was found in only one of those five patients, suggesting a low prevalence in older patients (22). It is also likely that residents of LTCFs will have minimal additional exposure to HCV because of the context of their living arrangements. In a study of 208 elderly subjects living at home compared with 288 elderly subjects living in a nursing home, no difference in the prevalence of antiHCV was detected (23). Hepatitis C is a single-stranded RNA virus similar to flaviviruses, and it accounts for the majority of non-A, non-B hepatitis. No commercial test is available to detect HCV antigen, but infection with HCV can be detected with antibody to HCV or with testing for HCV-RNA. Hepatitis C virus-RNA may be detected in infected serum as early as 1 to 2 weeks after exposure. Unlike HAV and HBV, antibodies to HCV are detected in the serum of patients during both the acute and chronic phases of infection, and their presence does not confer immunity. D. Hepatitis D Virus Hepatitis D virus (HDV) has an unusual replication cycle. Infection can be acquired either as a coinfection with HBV or as a superinfection of chronic HBV carriers. People with HBV-HDV coinfection may have more severe acute disease and a higher risk of fulminant hepatitis than those infected with HBV alone. Chronic HBV carriers who acquire HDV superinfection usually contract chronic HDV infection. In long-term studies of people with HDV superinfection, 70% to 80% had evidence of chronic liver disease with cirrhosis, compared with 15% to 30% of patients with chronic HBV infection alone. The actual incidence of HDV is uncertain because this disease is not reportable in the United States, but the CDC has estimated that there are approximately 7,500 infections annually. The prevalence of HDV infection among persons positive for HBsAg is low in the general population (1.4% to 8.0%) and has been found to be highest in those with repeated percutaneous exposure, such as injection drug users (20% to 53%) and

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hemophilia patients (48% to 80%). Infection with HDV is virtually absent from populations with HBV infection acquired during infancy or childhood. The percutaneous route is the most efficient mode of transmission for HDV infection, but it may also be transmitted through sexual intercourse. No data are available to document the prevalence of HDV infection in the aged, and no outbreaks have been described in LTCFs. Testing for HDV infection is rarely indicated. Coinfection is diagnosed by the presence of immunoglobulin M (IgM) antibodies to the delta agent (anti-HDV) together with antibody to hepatitis B core antigen IgM anti-HBc. Tests for immunoglobulin G (IgG) anti-HDV are commercially available in the United States but HDV antigen and HDV RNA are only available in research laboratories. E. Hepatitis E Virus Hepatitis E virus (HEV) is the major etiologic agent of enterically transmitted non-A, non-B hepatitis worldwide, but in the United States it has been reported primarily in returning travelers. Unlike HAV, which is also transmitted by the fecal-oral route, person-to-person transmission of HEV appears to be uncommon. There is no evidence of chronic infection with this viral subtype. To date there are no data regarding the prevalence of this infection in nursing home residents in the United States or abroad. However, like hepatitis A, data from endemic areas suggest that the prevalence of anti-HEV antibodies increases with age and probably represents the cumulative chance of being infected by the virus. No serologic tests are commercially available in the United States to detect HEV infection. F. Hepatitis G Virus The hepatitis G virus (HGV) is a newly identified, bloodborne viral agent that often results in chronic infection. As much as 10% of posttransfusion hepatitis and community-acquired hepatitis that cannot be explained by known types of viral hepatitis may result from HGV. Importantly, HGV infection does not seem to be associated with symptoms or with clinically significant liver disease. The role of HGV in the elderly is not well understood, but in two large series of elderly patients, 11% to 24% were found to have antibodies to HGV, and three individuals were found to be viremic (21,24). In addition, 40% of anti-HGV-positive subjects in one study had evidence of anti-HCV antibodies (24). It appears that in most cases, HGV infection is silent, self-limiting, and clinically unimportant. Polymerase chain reaction testing has been used in research studies to detect HGV virus in the serum of infected individuals, but this methodology is not generally available for clinical purposes.

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III. CLINICAL MANIFESTATIONS AND TREATMENT OF VIRAL HEPATITIS The liver has a great reserve capacity, and the decline in function that usually occurs with aging has little clinical relevance except for altered drug metabolism. Conventional liver function tests, such as serum bilirubin, the transaminases, alkaline phosphatase, and gamma glutamyl transpeptidase, do not change with age, and abnormal values should be taken seriously. However, older patients often have chronic medical conditions requiring complicated medical regimens, and abnormal liver function tests should be evaluated in the context of symptoms and potential effects of medication. The clinical manifestations of many diseases have been abundantly described in young and middle-aged subjects, but less is known about the presentation of the same illnesses in the elderly. This is also true regarding viral hepatitis. Generally, the accepted “classic” symptoms and signs are not reliable in the elderly. Furthermore, changes in both immunological and endocrinological function, as well as the presence of comorbidities such as neurological disease may have a significant impact on the clinical presentation of disease in the elderly. The elderly population is at risk for all clinical forms and consequences of viral hepatitis including acute hepatitis, chronic active hepatitis, cirrhosis, hepatocellular carcinoma, and even death. A. Acute Hepatitis The most common presenting complaints of acute hepatitis are anorexia, nausea, fatigue, and myalgia, which usually develop 7 to 14 days before the onset of jaundice. In addition, infected persons may complain of headache, right upper quadrant pain, and arthralgias. These symptoms are virtually identical for all forms of viral hepatitis. In general, elderly patients have milder clinical disease and may present with a simple flulike illness and complain only of malaise. Cholestasis rather than hepatocellular inflammation dominate the pathophysiological changes. Clinical recovery and clearance of the virus is usually slower in the aged compared with the younger individual. Jaundice can usually be observed when the bilirubin rises to 3.0 mg/dl or greater and is most easily observed in the sclerae, soft palate, or under the tongue. However, it is important to remember that the absence of jaundice does not exclude the diagnosis of viral hepatitis. These vague symptoms may go unnoticed in the setting of an LTCF as the prevalence of other comorbidities such as depression, congestive heart failure, and pulmonary disease may exist concurrently with the onset of an acute viral infection. Conversely, many elderly with acute infection may be completely asymptomatic. Other physical findings may include hepatomegaly or splenomegaly. The presence of lymphadenopathy or fever should alert the examiner to other viral syndromes or to the

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Table 2 Diagnostic Approach to Patients with Acute Viral Hepatitis Serological Test of Patient’s Serum IgM antiHAV

IgM antiHBc

Anti-HCV

Diagnostic interpretation

– –

– –

– – –

– –

–

– – –

–

–

–

–

–

–

Acute hepatitis B Chronic hepatitis B Acute hepatitis A superimposed on chronic B Acute hepatitis A and B Acute hepatitis A Acute hepatitis A and B (HBsAg below detection threshold) Acute hepatitis B (HBsAg below detection threshold) Acute hepatitis C

HBsAg

Abbreviations: HbsAg, Hepatitis B surface antigen; IgM, Immunoglobulin M; HAV, Hepatitis A virus; HBc, Hepatitis B core; HCV, Hepatitis C virus. Source: Adapted from Ref. 44.

possibility of malignancy such as lymphoproliferative disease. Diagnosis of acute viral hepatitis may be confirmed by the presence of serological markers (Table 2). One of the most feared complications of acute viral hepatitis is fulminant hepatitis, an illness characterized by rapid prolongation of prothrombin time, hyperbilirubinemia, encephalopathy, and occasionally death. The clinical features of this rare manifestation of hepatitis are seen almost exclusively in patients infected with HBV, HDV, and HEV and less commonly in HAV and HCV. However, the case-fatality rate is disproportionately high in the elderly. Accordingly, the ratio of deaths from hepatitis A to the total number of patients reported increased from 0.07% in the age group 15 to 24 years to 4% in those aged 65 and older (8,25). Hepatitis B is the most common viral infection leading to fulminant viral hepatitis and accounts for 35% to 70% of all virus-related cases. In a multivariate analysis of risk factors for fulminant hepatitis, age was an independent predictor of mortality in patients with both HBV and HCV (26,27). B. Chronic Hepatitis Chronic hepatitis is primarily a feature of HBV, HCV, and HDV. Approximately 10% of persons infected with HBV will develop chronic hepatitis, but 80% to 85% of persons infected with HCV and HDV will develop chronic hepatitis. In contrast

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to the low chronic carrier state in young adults, up to 60% of older people infected with HBV become chronic carriers. The higher frequency of chronicity may be the result of the decline in cellular immunity and decreased viral clearance that have been demonstrated in the older population. Clinical symptoms associated with chronic hepatitis range from patients who are asymptomatic to those with varying degrees of constitutional symptoms (fatigue, anorexia, and nausea), or to cirrhosis and its complications. Up to 25% of persons with chronic infection will be found to have normal aminotransferases. In older patients with chronic hepatitis B, HBsAg and anti-HBc antibodies can be detected in their serum. However, evidence of active viral replication, such as the presence of HBeAg or HBV DNA in the serum, is usually slight or absent (28). It is likely that most hepatitis B carriers in the elderly are individuals with long-standing infection who acquired their disease many years earlier. There is little evidence of viral replication in such patients, but they may still be highly infective to others. Chronic infection with HCV may also occur in the elderly and is a very common sequel to acute infection. It is well established that older patients with chronic HCV have significantly higher HCV RNA titers than their younger counterparts (29). This observation may represent a decreased ability of the immune system in the aged to clear the infection. In addition, it should be noted that genotype 1b is overrepresented in the older population and that patients infected with this genotype have higher levels of HCV RNA in the serum compared with those infected by other hepatitis virus genotypes (30). A study of the natural history of chronic HCV infection in patients with transfusion-associated hepatitis C found that among patients who were aged 50 and older at the time of transfusion, the average time from the transfusion to the development of chronic active hepatitis, cirrhosis, and hepatocellular carcinoma was 10.7, 9.8, and 14.7 years, respectively (31). Among patients who received transfusion before the age of 50, the average time to the development of these diseases was 20.4, 23.6, and 31.5 years, respectively. It is possible that the significantly shorter duration from transfusion to symptomatic disease in older subjects may be caused by more rapid progression of disease. Older patients with chronic hepatitis C may present for the first time with complications of cirrhosis or hepatocellular carcinoma. Histological stage correlates directly with prognosis in HBV and HDV, but is of little value in the natural history of HCV. Ultimately, morbidity and mortality are associated with the development of end-stage liver disease and cirrhosis. C. Hepatocellular Carcinoma Primary hepatocellular carcinoma (HCC) is highly associated with underlying cirrhosis and is overrepresented in the elderly, with more than 40% of cases occurring

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in persons older than age 70. Among the known viral hepatitis agents, only HBV, HDV, and HCV are important in the pathogenesis of HCC. The incidence of HCC associated with hepatitis B and C has been observed to increase with age (32–34). For example, in a study of Chinese government employees infected with hepatitis B, the incidence of HCC increased from 197 to 927 cases per 100,000 carrier-years in age groups 30 to 39 and 60 to 90, respectively (35). The length of time during which an individual has had cirrhosis is an important factor contributing to the development of HCC, thus conferring an increased risk among the elderly. Of note, the mean age of detection of HCC is significantly older in patients with HCV compared with HBV infection, probably because HCV infection is more often acquired later in life than the HBV infection. In addition, HCV is usually associated with more advanced liver disease and cirrhosis at the time of HCC presentation compared with individuals infected with HBV. Prognosis is, to a large extent, dependent on the size of the tumor at the time of diagnosis. Therefore, screening of all patients with known cirrhosis for the development of HCC is recommended. It has been reported that the median survival of HCC in persons aged 65 and older was 10.5 weeks (36).

IV. THERAPEUTIC INTERVENTIONS A. Acute Hepatitis Treatment for acute viral hepatitis remains supportive. Moreover, many older patients will often have mild nonspecific symptoms or may be completely asymptomatic. Acute hepatitis in the elderly only occasionally warrants hospitalization in an acute care facility. It is common to prescribe bedrest; however, forced and prolonged bedrest should be avoided because the associated deconditioning may be difficult to reverse in older patients. Anorexia and nausea may be present, but patients should be encouraged to try to maintain fluid and caloric intake. Drugs that require metabolism by the liver and those with potential for hepatotoxicity should be avoided if possible. Treatment with corticosteroids is not efficacious. Clinical trials of interferon in patients with acute HBV and HCV have shown some efficacy, but many of these patients recover spontaneously. Accordingly, treatment in the acute phase of infection would unnecessarily expose large numbers of patients to the potentially harmful effects of this drug. Furthermore, observational studies strongly suggest that acute icteric disease resolves spontaneously at a significantly higher rate than silent or asymptomatic acute disease. Therefore, interferon is not recommended for acute, symptomatic hepatitis B or hepatitis C. B. Chronic Hepatitis Both HBV and HCV may have significant chronic infectious stages that lead to profound clinical sequelae, including cirrhosis and hepatocellular carcinoma. Un-

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fortunately, little information exists about treatment efficacy of the available chemotherapeutic regimens in patients older than age 60. It is likely that they have been excluded from the various clinical studies because of concern about the increased frequency of side effects that may be seen in the elderly population with many drugs. In fact, the National Institutes of Health (NIH) consensus statement published in 1997 recommends treating patients older than age 60 only in the context of a clinical trial (37). Given the growing number of older patients in our society, clinically significant complications from chronic hepatitis will become increasingly common, and the decision to treat or withhold therapy for chronic hepatitis infection must be made while balancing the potential risks and benefits of treatment for an individual patient. All potential candidates for therapy should be referred to a hepatologist. 1. Patient Selection The minimal criteria recommended by the NIH for candidates who may benefit from interferon-based therapy include the following: Elevated liver function tests for at least 6 months The presence of viral genetic material in the serum Portal fibrosis or moderate to severe liver inflammation on liver biopsy Compensated liver disease Exclusion criteria are listed in Table 3. The most important factors in assessing the elderly for potential treatment are the patient’s motivation and the presence of comorbid disease. A comorbid chronic disease, such as severe chronic obstructive pulmonary disease, coronary artery disease, or malignancy that likely will limit lifespan, would make treatment for chronic hepatitis a secondary issue. Likewise, patient motivation is critical in managing treatment side effects as well Table 3 Exclusion Criteria for the Use of Interferon-Based Therapy Patients with a history of drug or alcohol abuse without abstinence 6 months to a year History of hepatic encephalopathy, variceal bleeding, ascites, or other signs of hepatic decompensation History of other causes of chronic hepatitis, including alcoholic liver disease, hemocbromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, hepatotoxic drug injury, or autoimmune hepatitis History of significant cardiovascular disease such as unstable angina pectoris or congestive heart failure; pulmonary diseases including chronic obstructive pulmonary disease; uncontrolled diabetes mellitus and other comorbid conditions that would limit treatment History of previous psychiatric illness such as severe depression and psychosis Patients taking other antiviral medications

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as the administration of injections. Age, independent of physiological function or comorbidities, has not been shown to influence response rates. Therefore, it is likely that therapy will benefit only the healthy segment of the aged population with additional life expectancy of more than 10 to 15 years. 2. Chronic Hepatitis B Interferon-alfa therapy is the treatment of choice for chronic hepatitis B infection. It is administered as an injection of 5 to 20 million units three times a week for 12 weeks. Response to interferon is highest (40% to 50%) in patients with infection acquired during adulthood, with inflammatory liver disease consistent with chronic active infection who are not immunocompromised. Additional promising treatments include famciclovir and lamivudine. 3. Chronic Hepatitis C Combination therapy with interferon and ribavirin has proved to be more effective than interferon therapy alone. Studies using combination therapy for chronic HCV infection have demonstrated sustained response rates up to 40% to 50% compared with 15% to 25% seen with interferon alone. Patients with genotypes 2 or 3 typically have favorable response rates to chemotherapy. However, patients with genotype 1, the most common genotype found in the United States, have significantly lower response rates. Combination therapy should not be used in patients with anemia, renal insufficiency, coronary artery disease, cerebral vascular disease, or gouty arthropathy. Because of these limitations, it is clear that many elderly patients may not be candidates for combination therapy. The recommended dose of interferon-alfa is 3 million units three times a week and ribavirin 1,000 to 1,200 mg/day for 24 or 48 weeks, based on the viral genotype and the serum HCV RNA level measured at week 24.

V. INFECTION CONTROL AND PREVENTION Infection control in any specific setting must reflect the nature of the healthcare activities and the biology of potential pathogens. It is obvious that there will be differences in emphasis on certain measures necessary for control of infection in LTCFs compared with those for acute care or for the operating theater. Nevertheless, there are requisite conditions at all sites for successful transmission: in each instance it is necessary to have an infectious agent, a transmission vector, and a susceptible host. Infection control has become more complex in recent decades and is subject to regulation by various federal and state government agencies. Each LTCF is required to have coordinated infection control policies and procedures that address

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sick employees, hand washing, and surveillance, as well as other infection control issues. Isolation practice guidelines are fundamental components of infection control, and CDC has formulated one that calls for a two-tiered system. The first, Standard Precautions, are recommended for all patients and was previously known as universal precautions. These guidelines emphasize hand washing and use of gloves. Avoidance of needlestick and other “sharps” injuries are also emphasized. Transmission-Based Precautions, that is airborne, droplet, and contact precautions, the second type of isolation practice, is recommended for patients with suspected contagious pathogens (38) (see Chapters 8 and 9). The work of numerous investigators has identified the most common pathogens that afflict residents in LTCFs, as well as the epidemiology of these agents. Urinary tract infections, respiratory infections, tuberculosis, and skin infections have comprised the greatest number of clinical problems in recent decades, but diarrheal illness and antibiotic-resistant bacteria have also posed challenges to physicians. In comparison, viral hepatitis is much less common. However, because of the serious nature of the disease, and because individuals may harbor inapparent infections, it deserves close attention. The biology of the three major types of viral hepatitis has been described in previous sections. For the purposes of discussion, infection control measures for viral hepatitis can be divided into those that address agents involving transmission predominantly by the oral route (e.g., hepatitis A virus) or by the parenteral route (e.g., hepatitis B or hepatitis C virus). A. Hepatitis A 1. Frequency of HAV Infection in LTCFs In recent decades, the occurrence of HAV infection in LTCFs has been rare. Clearly, the potential remains for transmission from infected food handlers to residents, residents to healthcare workers (HCWs) (e.g., fecal incontinence), and even from resident to resident by the classic fecal-finger-oral route. However, current food preparation systems and a significant prevalence of host immunity in patients and HCWs seem to have been sufficient to minimize this threat. In patients older than age 70 in the United States, more than 75% have been found to have antibody to HAV, testifying to previous infection or vaccination (39,40). Before dismissing HAV as a potential problem, however, we must acknowledge the uncertain impact of ongoing economic pressures on regulatory compliance of LTCFs, with the resulting potential for a relaxing of current infection control standards. 2. Screening for HAV Acute hepatitis from HAV in older adults is unusual, and no testing for it is indicated in asymptomatic patients admitted to an LTCF. Furthermore, in contrast to

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HBV and HCV, HAV does not produce a chronic, infectious form of disease that could serve as a rationale for testing. 3. Vaccination Clinical guidelines have been developed to identify patients who should receive vaccination against HAV as primary prevention (Table 4). It has been recommended that patients with chronic liver disease should be vaccinated to prevent

Table 4 Hepatitis A Vaccine: Indications and Schedule Persons who should receive hepatitis A vaccine 1. Persons traveling to or working in countries outside of the U.S. (except for Northern and Western Europe, New Zealand, Australia, Canada, and Japan) 2. Children (younger than 2 years) in communities that have high rates of hepatitis A and periodic hepatitis A outbreaks 3. Men who have sex with men 4. Illegal drug users (injecting and noninjecting) 5. Persons who have occupational risk for infection 6. Persons who have chronic liver disease 7. Persons who have clotting factor disorders 8. Food handlers where health authorities or private employers determine vaccination to be cost-effective Vaccination schedule Two doses are required The minimal interval between doses is 6 months Recommended dosages of HAVRIX® (Merck) Vaccinee’s age (years) 2–18 18

Dose (EL.U.)

Volume (ml)

No. doses

Schedule (months)

720 1,440

0.5 1.0

2 2

0,6–12 0,6–12

Recommended dosages of VAQTA® (Merck) Vaccinee’s age (years) 2–17 17 Source: Ref. 39.

Dose (EL.U.)

Volume (ml)

No. doses

Schedule (mos)

25 50

0.5 1.0

2 2

0,6–18 0,6

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possible infection with HAV that could produce diagnostic confusion and result in a poor outcome because of diminished hepatic reserve. It may be difficult to make a definitive diagnosis of chronic liver disease in the setting of an LTCF, given the many causes of minor liver function test abnormalities. In some clinical situations, additional testing may be unwarranted, and physicians may wish to proceed with vaccination without additional interventions and X-rays. Consideration should also be given to vaccination of food handlers who work in LTCFs. However, in one investigation, rates of hepatitis A among food handlers were found to be similar to rates among the general population, and in general, the frequency of outbreaks in hospitals, institutions, and schools is not high enough to warrant routine hepatitis A vaccination of persons specifically because they are in these settings (39,40). 4. Postexposure Protection In the rare instance in which an active case of hepatitis A is identified in an LTCF, use of immune globulin (IG) and vaccination with hepatitis A vaccine is recommended for susceptible persons who are in close contact with infected patients. Persons identified as candidates for postexposure management should receive a single intramuscular dose of IG (0.02 ml/kg) as soon as possible, and not later than 2 weeks after exposure. Hepatitis A vaccination should also be given, with the first vaccination administered as early as possible after exposure, and a second and final vaccination 6 to 12 months later. B. Hepatitis B Transmission of bloodborne pathogens presents a more complicated picture than orally transmitted infections. Generally, blood transfusions are not an important infection control issue in LTCFs because they are given infrequently in this setting, and because current blood-banking practices have been very effective in eliminating this source of hepatitis B virus and hepatitis C virus. Infection control measures must address issues that affect HCWs, such as injuries from sharps, as well as patient-to-patient transmission caused by contaminated instruments. Several examples of the latter have been reported over the past several years in diabetics who have contracted viral hepatitis from contaminated lancets used for fingerstick glucose monitoring (12). A highly effective vaccine against HBV has been available for more than 20 years, however, this infection remains a threat to both HCWs and patients. Federal regulations require all hospitals and LTCFs to offer vaccination to employees at no cost, yet a determined few decline and remain at risk for infection, whereas the majority of residents in LTCFs are also susceptible. Infection control measures must be in place to minimize risk for HBV transmission in these two populations.

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1. Frequency of HBV Infection in LTCF The frequency of HBV infection in LTCFs varies greatly, according to the cultural and socioeconomic background of the population in the facility. The likelihood that residents will be chronic carriers of HBV will vary from less than 1% for healthy, American-born individuals to 5% to 15% for recent immigrants, dialysis patients, and users of illicit parenteral drugs. 2. Screening for HBV Screening for HBV infection in residents admitted to LTCFs is not indicated on a routine basis but should be part of an evaluation of residents with acute and chronic liver disease or abnormal liver function tests. The critical issue to resolve, both for the individual and for the LTCFs, is whether the individual is an infectious carrier of HBV. Of the many serologic tests available in the laboratory, only the detection of the HBsAg and anti-HBc provides useful information about an individual’s infectious status. Screening HCWs in LTCFs for HBV infection or immunity is not routinely necessary because vaccination during professional training or at the time of employment is almost universal. 3. Vaccination Healthcare workers should be encouraged to undergo vaccination for HBV as early as possible in their professional training. Published guidelines recommend that all HCWs who perform tasks involving contact with blood, blood-contaminated body fluids, other body fluids, or sharps should be vaccinated (Table 5). Prevaccination serological screening for previous infection is not indicated for persons being vaccinated because of occupational risk (41). For residents or patients, those with chronic liver disease or unexplained abnormal liver function tests should be vaccinated to prevent a possible infection with HBV that could produce diagnostic confusion and have a poor outcome because of diminished hepatic reserve. 4. Postexposure Protection Prophylaxis should be considered for HCWs for any percutaneous, ocular, or mucous membrane exposure to blood, which is determined by the HBsAg status of the source person and vaccination status of the exposed individual. Treatment of an unvaccinated HCW after an exposure will include hepatitis B immune globulin (HBIG) and the initiation of an HBV vaccine series if the source person is unknown or has evidence of infection with HBV. (The reader is referred to CDC guidelines for more details [42]).

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Table 5 Hepatitis B Vaccination: Indications and Schedule Persons who should receive hepatitis B vaccine 1. 2. 3. 4.

All babies at birth Persons at occupational risk for exposure to blood All adolescents High-risk adults including the following conditions or behaviors: Household contacts and sex partners of HBsAg-positive persons Users of injectable drugs Heterosexuals with more than one sex partner in 6 months Men who have sex with men People with recently diagnosed sexually transmitted disease Patients receiving or likely to receive hemodialysis Recipients of certain blood products Healthcare workers and public safety workers who are exposed to blood Inmates of long-term correctional facilities Clients and staff of institutions for the developmentally disabled

Vaccination schedule Three doses are needed on a 0, 1, 6 months schedule Alternative timing options for vaccination include 0, 2, 4 months 0, 1, 4 months There must be 4 weeks between doses 1 and 2, and 8 weeks between doses 2 and 3. Overall there must be at least 4 months between doses 1 and 3 Recommendations Vaccination Recombivax® HB Group Infants of HbsAg-negative mothers and children aged 11 or younger Infants of HbsAg-positive mothers; prevention of perinatal infection Children and adolescents aged 11–19 Adults aged 19 or older Dialysis patients and other immunocompromised persons

Engerix® HB

Dose (g)

(ml)

Dose (g)

(ml)

2.5

(0.5)

10.0

(0.5)

5.0

(0.5)

10.0

(0.5)

5.0 10.0 40.0

(0.5) (1.0) (1.0)

20.0 20.0 40.0

(1.0) (1.0) (2.0)

Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR, 1991. Abbreviations: HBsAg, Hepatitis B surface antigen; HB, Hepatitis B. Source: Ref. 41.

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C. Hepatitis C Most of the principles and practices described above for HBV may be applied to infection control strategies for HCV. Unhappily, and in contrast to HBV, the prevalence of HCV is greater than HBV, immunization is not available, and postexposure treatment is unsatisfactory. Hepatitis C virus is the most common chronic bloodborne infection in the United States, and in general, transmission patterns and population risk groups are similar to those for HBV. The frequency of HCV found among residents of LTCFs has ranged from 1% to 3% (42). 1. Screening Policies concerning screening for HCV infection in persons admitted to LTCFs are similar to those given in the previous section for HBV. Thus, screening is not indicated on a routine basis but should be part of an evaluation of residents with acute and chronic liver disease or abnormal liver function tests. Residents considered at high risk for HCV should also be tested; this would include individuals who ever injected illegal drugs, those who received clotting factor concentrates, those requiring long-term hemodialysis, and recipients of organ transplants and transfusions before 1992. It is not necessary to screen HCWs for HCV because of the rarity of transmission of HCV infection from HCWs to patients or residents. 2. Vaccination No vaccination is available for HCV. 3. Postexposure Protection Healthcare workers should be tested routinely for HCV infection after needlesticks, sharps injury, or mucosal exposure to HCV-positive blood. However, prophylaxis after HCV exposure with immunoglobulin or antiviral treatment has not been shown to be effective and is not recommended. For the 2% to 10% of HCWs who will have anti-HCV seroconversion after exposure to an HCV-positive source, combination treatment with interferon and another anti-viral drug should be considered.

VI. CONCLUSION Knowledge of the epidemiology and biology of the various types of viral hepatitis is essential for primary prevention and optimal management of residents exposed to infection in LTCFs. It is encouraging to consider that effective vaccines are now available for two of the three major types of viral hepatitis, and numerous, specific serological tests facilitate diagnosis of these infections. It is hoped

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that the information and clinical approach to patient care contained in this chapter will be helpful to healthcare professionals in LTCFs who face a myriad of complex management issues concerning viral hepatitis.

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20 Vaccinations Stefan Gravenstein Eastern Virginia Medical School, Norfolk, Virginia

I. INFECTION, AGING, AND IMMUNE RESPONSE Probably the most profound effect of immunosenescence in old age is the increase in infectious morbidity and mortality. The impact of a number of infections increase with age, including influenza, pneumonia, Clostridium difficile diarrhea, nosocomial infections, and recrudescent latent infections such as herpes zoster (1). Unfortunately, the use and abuse of antimicrobial agents selects for subsequent resistant and often unusual microorganisms that may spread from the primary source patient. This is particularly true for methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pneumoniae. The latter is becoming increasingly resistant to standard antimicrobial therapy, is a leading cause of morbidity and mortality, and stands out among resistant organisms in that the most important of the pathogenic strains are vaccine preventable. Immunosenescence also results in atypical presentations of infections in old age, potentially obscuring the diagnoses of influenza and pneumococcal pneumonia (2). Infections also occur more frequently and are longer in duration in elderly people (3). It is likely, largely due to immunosenescence, that old individuals, particularly the very old, may fail to respond as efficiently to therapy for infection such as C. difficile or influenza, may develop infections by unusual pathogens such as Listeria monocytogenes, or experience reactivation of quiescent diseases such as shingles. The level of integrity of the immune and inflammatory response to infection is the principle driver of many of the resulting symptoms and the impaired response. Typical signs of infection can be absent and a keen index of suspicion is necessary for an adequately inclusive differential diagnosis in old age. Elderly patients may not develop the spiking fevers, leucocytosis, or prominent inflam337

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matory infiltrates on chest X-ray as younger patients with pneumonia. Lower baseline temperatures may require monitoring the change in temperature, rather than the absolute temperature in old age (4). The need for efficacious vaccinations for elderly patients is pressing, and immunization is one of the few tools to cost effectively defend against infections, especially in settings where transmissibility may contribute to the impact of the disease. A second consideration for vaccine use is for employees of long-term care facilities (LTCFs). Part of good facility management includes protecting residents and employees from infections (e.g., influenza) potentially introduced by employees and transmitted by residents (e.g., hepatitis, influenza). A. Vaccine Utilization in Long-Term Care Facilities Despite the overwhelming evidence of risk for vaccine-preventable illnesses and their morbidity and mortality in LTCF residents, vaccination rates remain suboptimal. A survey of Minnesota LTCFs in 1993 observed 12-month resident immunization rates for influenza (flu), pneumococcal, and tetanus/diphtheria vaccines of 84%, 11.9%, and 2.9%, respectively (5). One-third of the nursing homes surveyed failed to offer influenza vaccines to residents admitted during flu season. Written policies for influenza vaccine were present in 69% of the survey respondents, but only one-third had policies for pneumococcal vaccine, and less than 20% had policies for tetanus/diphtheria administration. In an evaluation of policies and procedures and vaccination rates in 1,270 LTCFs in Canada, pneumococcal vaccination rates of less than 10% were observed in almost half the facilities surveyed, even if the province agreed to pay for the vaccine (6). B. Efforts to Increase Vaccine Utilization One of the most important steps to improve vaccine utilization in an institutional setting is through the implementation of standing orders for routine vaccination in a sustainable immunization program. Policy statements and manuals have been written to aid in the development of such policies (7). It is also important that there is a consensus among staff members, the infection control professional, medical director, administration, and others about the importance of vaccination in this setting. Creating a vaccination program team with defined roles and responsibilities and setting a specific measurable vaccination goal can help create that consensus. Other methods that have been found to increase utilization include having a written and well-defined program and plan. The plan should include assessing the immunization status of newly admitted or transferred residents, offering vaccination to new and current residents on the basis of standing order protocols, and

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conducting an annual vaccination campaign each year, such as in conjunction with annual influenza vaccination. Immunization programs should also include annual inservice of staff members, personal physicians, and medical directors. The inservice can provide an overview of the facility’s vaccination policy, vaccine effectiveness, recommendations, record-keeping requirements, infection control, and indications for and contraindications to vaccination. An often-overlooked component of programs is evaluation. Improving future vaccination utilization may depend on successes and failures of past vaccination programs. Periodically reviewing current resident and employee vaccination status and comparing that with the baseline or prior status, assessing efficiency of administration schedules, evaluating the number of residents and staff not appropriately vaccinated and the reason why, and other measurements can help the program team identify areas for improvement.

II. INFLUENZA Older adults, considered those aged 65 and older, currently account for more than 90% of the deaths attributed to pneumonia and influenza (8). In an evaluation of influenza-related deaths from 19 epidemics occurring from 1972 to 1973 through 1994 to 1995, the influenza-related death rate ranged from 30 to more than 150 per 100,000 persons aged 65 and older (9). Influenza-related illness costs more healthcare dollars and lives lost than any other viral illness in the United States. National hospital discharge data indicate an average of 114,000 excess hospitalizations annually related to influenza. Since 1968, the greatest number of hospitalizations have occurred during epidemics caused by type A (H3N2) viruses, where an estimated 142,000 influenza-related hospitalizations occurred per year, and more than 40% of those were in individuals aged 65 and older (10) (see Chapter 13). Outbreaks of influenza are related to two phenomena: antigenic drift and antigenic shift. Because the influenza virus genome is segmented so that different combinations of segments yield a phenotypically different virus, when recombination of the genetic segments occurs, antigenic shift is possible. Antigenic drift resulting from single nucleic acid substitutions of the genome also occurs. These phenomena enable the influenza virus to escape immune recognition and allow annual epidemics (with antigenic drift) or pandemics (with antigenic shift) to occur. In the 1997/1998 season, for example, a mismatch between the vaccine component and the most prevalent epidemic influenza A virus was identified in the Netherlands and caused the influenza epidemic related to antigenic drift, and this strain circulated worldwide, causing significant morbidity and mortality for the ensuing three seasons (11). Elderly persons are at increased risk for influenza complications related to secondary bacterial infection, and they are more likely to require hospitalization

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and experience a higher mortality rate. In LTCFs, up to 70% of the residents may contract influenza-like illnesses during an outbreak; during nonepidemic years an attack rate of 5% to 20% is the norm. The case fatality ratio during an outbreak may be as high as 30% (12). Because individuals older than age 80 are the fastest growing segment of the U.S. population (13), the impact of influenza will continue to intensify unless we attain better control of the disease. A. Vaccine Effectiveness The cornerstone of influenza prevention remains vaccination. Vaccination is far more cost-effective than the alternative intervention, that is chemoprophylaxis with amantadine or other antivirals (14). A well-matched vaccine is effective in reducing the incidence and severity of influenza illness, but even a poorly matched vaccine can provide benefit. Vaccination can reduce the number of influenza-related hospitalizations, radiologically diagnosed cases of pneumonia, and deaths (14–16). Despite high resident vaccination rates in LTCFs, outbreaks of influenza occur annually (17). The influenza vaccine can fail to provide the intended protection because of several factors, including immune senescence, weak vaccine immunogenicity, lack of herd immunity, antigenic drift, or antigenic shift. Because of advanced age and underlying disease, not all healthy elderly (18) and only about half of LTCF residents develop “protective” vaccine-induced antibody titers compared with 70% to 90% of young healthy adults; even fewer elderly develop substantial cellular immunity (19,20). Supplemental vaccination and vaccines with higher concentrations of antigen have not consistently demonstrated increased antibody response in elderly persons, but they have demonstrated more side effects (21). Nevertheless, elderly persons may benefit from vaccination despite low antibody titers; the influenza illness may be less severe and the risk of complications, hospitalization, and death may be reduced. Results from retrospective vaccine efficacy studies vary from 30% to 80% (16). However, one prospective study suggested that the Centers for Disease Control and Prevention (CDC) case definition for influenza may only be 61% sensitive and 63% specific for detecting laboratory-confirmed H3N2 influenza (22). The low sensitivity and specificity of this case definition (i.e., oral temperature 100° F accompanied by either sore throat, cough, or coryza) may occur because the clinical features of an influenza illness are largely indistinguishable from other viral illnesses that occur primarily during the influenza season. Additionally, the sensitivity of the case definition for influenza may be reduced because elderly persons are less likely to have a fever in response to infection and, therefore, do not meet the temperature requirement of the case definition (23). Clinical influenza may also be attenuated in previously vaccinated individuals,

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further compromising the case definition’s sensitivity. Thus, retrospective studies reporting vaccine efficacy relying on clinical symptoms for case detection may underestimate the ability of the vaccine to prevent infection. Nevertheless, when infection occurs in vaccinated individuals, the vaccine is effective in preventing serious morbidity and death (14). Reduction of influenza-associated hospitalization and death has been reported in both community and LTCF settings (14,15). B. Indications Annual influenza vaccination is recommended for high-risk individuals and their caregivers, including physicians. High-risk individuals include residents of LTCFs, persons aged 50 and older, those with chronic disorders of the pulmonary or cardiovascular system, and those requiring regular medical follow-up or hospitalization during the preceding year because of chronic metabolic disorders, renal dysfunction, hemoglobinopathies, or immunosuppression (8). Annual influenza vaccination rates in LTCFs across the United States range from 0 to 100%, but are now estimated to exceed an average of 80% nationwide (12,16,24). The proportion of vaccinated LTCF staff is frequently less than 30% (16). The rate of vaccination of LTCF residents and staff depends on the energy and enthusiasm of the medical director, director of nursing, and infection control practitioner, as well as implementation of LTCF educational programs and vaccination policies. One purpose of influenza immunization programs in LTCFs is to induce herd immunity, thereby reducing the probability of virus transmission within a population (25). The ambitious vaccination rate of 80% for residents and staff is calculated to generate herd immunity and is a minimum goal that LTCFs should set. C. Administration and Revaccination An intramuscular injection of 0.5 ml of the trivalent influenza vaccine through a 1-inch needle is recommended in the United States. Half-inch needles may fail to reach the muscle of older individuals because of changes in body composition (i.e., reduced lean muscle mass, increased fat). Subcutaneous and intradermal routes have been used, but their efficacy has not been adequately compared. Annual vaccination is necessary, as the protective response to current influenza vaccines is short-lived and the virus’ rapid antigenic change reduces the previous year’s vaccine effectiveness. The question of optimum timing of the influenza vaccine is important and not easily answered. If vaccination takes place too early, protective antibody titers may no longer be present when the virus circulates, whereas late vaccination per-

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mits viral exposure before protective antibody develops. Because it may take 4 to 6 weeks for elderly individuals to develop optimum antibody titers, it is advisable to vaccinate 4 to 6 weeks before the influenza season is expected (26). In most states, vaccination during November is reasonable, whereas vaccination during August and September is usually premature. Influenza typically circulates from December to March, justifying vaccination of new staff and residents in January or later. When an influenza outbreak is identified, unvaccinated staff and residents should be reoffered the vaccine. Those accepting the vaccine during an influenza A outbreak should also be offered adjunctive therapy with an antiviral agent (amantadine, rimantadine, zanamivir, or oseltamivir) for the 2-week interim after vaccination to allow time to develop vaccine-induced immunity. Neuraminidase inhibitors (zanamavir and oseltamivir) also are effective in reducing influenza B illness (27–29). At the very least, unvaccinated persons should be offered chemoprophylaxis with amantadine (if at low risk for side effects), rimantadine, or a neuraminidase inhibitor for the duration of the influenza A outbreak. Most outbreaks are associated with influenza A; however, if influenza B is identified, amantadine or rimantadine is ineffective because of lack of activity against influenza B, and a neuraminidase inhibitor is the acceptable prophylaxis option. Dosing information is presented in Table 1. Clinical trials with new vaccines have met with variable success. Approaches to enhance immunogenicity have included use of biological response

Table 1 Daily Dosage of Influenza Antiviral Medications for Prophylaxis in LTCF Residents During an Outbreak Daily dose Antiviral agent Amantadine (Influenza A only) Rimantadine (Influenza A only) Zanamivir ‡‡ Oseltamivir‡‡

65 yrs 100 mg twice daily* 100 mg twice daily† 10 mg/day 75 mg/day

65 yrs 100 mg/day 100 mg/day 10 mg/day 75 mg/day

Duration** 14 days 14 days 14 days 14 days

* Consult the drug package insert for dosage recommendations for administering amantadine to persons with creatinine clearance 50 ml/min/1 .73m2. ** 14 days is the recommended duration of prophylaxis for influenza outbreak control. For prophylaxis of a roommate, 7 to 10 days should be a sufficient duration of drug administration. † A reduction in dosage to 100 mg/day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance of 10 ml/mm. Other persons with less severe hepatic or renal dysfunction taking 100 mg/day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. ‡‡ Neither zanamivir nor oseltamivir are approved for prophylaxis. Abbreviation: LTCFs, Long-term care facilities.

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modifiers (30,31), adjuvants (32), protein conjugates (33), and cold-adapted (34) vaccine constructs. Several of these have provided evidence of improved immunogenicity and even clinical efficacy in ambulatory or long-term care settings, yet none has demonstrated an advantage sufficient for the manufacturers to bring them to market in the United States. D. Safety A presumption of adverse effects to influenza vaccine, particularly influenza illness, has impacted the rate of influenza vaccine uptake by individuals (35). The current, commercially available vaccine, because of its noninfectious particles, is incapable of causing influenza infection. Respiratory illness occurring temporally after vaccination is merely coincidental. About 30% of recipients complain of injection site tenderness for 1 to 2 days after administration. Fever, malaise, or myalgia occurs in less than 10% of individuals and most often in persons naïve to the influenza vaccine. The rate of systemic reactions in elderly persons is similar to that in saline placebo recipients (36). Although rare, hypersensitivity reactions to vaccine components, residual egg proteins, or preservatives is possible. The influenza vaccine is contraindicated in individuals with anaphylactic hypersensitivity to eggs. Only the 1976 influenza vaccine was significantly associated with the Guillain-Barre syndrome, and although this relationship appears to be real, its impact should be small ( 1/1,000,000 vaccinated) (37).

III. PNEUMOCOCCAL VACCINE A. Microbiology and Clinical Disease of Pneumococci Reduced immunocompetence because of age, disease, or drug therapy should be considered when assessing risk for pneumococcal disease. Streptococcus pneumoniae, a gram-positive bacterium, also referred to as pneumococcus and Diplococcus pneumoniae, is a normal inhabitant of the nasopharynx. Before the widespread availability and use of antibiotics, S. pneumoniae could frequently be isolated from the nasopharynx of individuals (up to 70%); however, the rate of colonization is believed to be much lower today (i.e., 40%) (38). Microbiologically, pneumococci are gram-positive, nonsporulating, encapsulated, lancet-shaped diplococci, although they may also grow in chains. The capsule is the antigenic determinant in the current pneumococcal vaccine. Historically, pneumococci have been exquisitely sensitive to penicillin antibiotics. However, the prevalence of penicillin-resistant pneumococci is on the rise worldwide, including the United States (39). This poses interesting implica-

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tions for future antimicrobial treatment of these infections and reinforces the need for prevention as a primary management strategy for pneumococcal disease. The presence of S. pneumoniae in the nasopharynx is usually without sequelae, as it resides without inducing an inflammatory response. In individuals with a fully competent immune system, infection is usually avoided. However, when the bacterium makes its way into the lung, an inflammatory response (i.e., pneumonitis) follows, which progresses to pneumonia. Risk factors for pneumococcal infections include conditions that predispose an individual to aspiration of pneumococci into the lung. These factors include: dementia, stupor, other conditions, such as stroke, with abnormal swallowing, chronic obstructive pulmonary disease, alcoholism, and seizure disorders. Nasogastric tubes, which contribute to aspiration, regardless of their specific placement in the gastrointestinal tract, should be considered in assessing aspiration risk. Alterations of sensorium and sedation associated with antipsychotic and anxiolytic therapy, are another concern. Many of these conditions are common in nursing facilities, placing this population at considerable risk for pneumococcal infections. Reduced immunocompetence because of age, disease, or drug therapy should be considered when assessing the risk for pneumococcal disease. One study found the incidence of pneumococcal disease to be 70 cases per 100,000 in individuals older than age 70 compared with five cases per 100,000 in younger adults (40). Prevention of pneumococcal disease holds great promise for affecting the incidence of disease in the elderly and immunocompromised populations. Pneumonia is the most prevalent expression of infection with S. pneumoniae. Other infections associated with pneumococcus include otitis media, sinusitis, meningitis, septic arthritis, pericarditis, endocarditis, peritonitis, cellulitis, glomerulonephritis, and sepsis (especially postsplenectomy). B. Pneumococcal Vaccine The first use of pneumococcal vaccination dates back to the early 1900s when a crude, monovalent vaccine was used to prevent pneumonia in South African diamond miners. A vaccine containing 14 different strains of S. pneumoniae was first licensed for use in the United States in 1977. Numerous studies have documented the efficacy of the first 14-valent and the current 23-valent vaccine in preventing pneumococcal pneumonia and bacteremia in elderly persons. However, underutilization of pneumococcal vaccine has resulted in outbreaks in nursing facilities, underscoring the need for appropriate utilization of the vaccine (41–43). Studies have shown the vaccine to be cost effective. Still, the public health benefits of this vaccine have been received with little enthusiasm. The Advisory Committee on Immunization Practices of the CDC recommends pneumococcal vaccine for the

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individuals at risk for pneumococcal disease (Table 2) (44). In addition, revaccination is recommended for persons aged 65 and older if they received the vaccine 5 or more years previously and were younger than age 65 at time of vaccination. The pneumococcal vaccines available today, Pneumovax® 23 (Merck and Company) and Pnu-Immune® 23 (Wyeth-Lederle Laboratories), contain 25 mcg of capsular polysaccharide antigen for each of the 23 most prevalent and pathogenic S. pneumoniae serotypes in a 0.5-ml dose. The current vaccine was licensed in 1983 as a replacement for the 14-valent vaccine that contained 50 mcg of each serotype and had been available since 1977. The new vaccine was developed to provide a broader spectrum of coverage of S. pneumoniae serotypes implicated in pneumococcal disease. The composition of the current vaccine was recently compared against the respiratory isolates obtained in a national surveillance study conducted from 1987 to 1988 (45). The most common pneumococcal serotype encountered was type 3 (13.1%), followed by 19F, 23F, 6B, 14, 4, and 6A. All of these serotypes, which comprised 74.9% of the respiratory isolates in the study, were included in the current 23-valent pneumococcal vaccine. When cross-reactive serotypes (i.e., when antibody specific for one serotype or pneumococcal strain will cross-react with or also bind another serotype or pneumococcal strain) were considered, 89% of the respiratory disease isolates were included in the protective spectrum of the current vaccine. These data were more recently confirmed, with 93% of serotypes implicated in infections in the population being represented in the 23-valent vaccine (46). Theoretically, the 23-valent pneumococcal vaccine should provide an individual with the ability to develop immunity against the S. pneumoniae strains most commonly implicated in disease. The clinical experience with this vaccine has generated considerable controversy regarding its efficacy and cost effectiveness. C. Efficacy Efficacy has been measured in clinical and serologic terms (see antibody response below). Numerous clinical trials on pneumococcal vaccine efficacy have been conducted in the United States. The clinical efficacy has varied considerably between trials ranging from negligible to effective in three-fourths of patients. The Department of Veterans Affairs Cooperative Study was one of the few randomized controlled trials of pneumococcal vaccine efficacy; however, it has been criticized because it was underpowered and had too few pneumonia cases observed to draw generalizable conclusions (47). Out of a study population of 2,295, there was one proven case of pneumococcal infection among 1,175 vaccine recipients. A total of 43 infections of proven and probable cause were identified. In two other trials conducted in individuals older than age 50, efficacy was 69% and 70%, respectively (48,49). A recent randomized trial in Finland comparing pneumococcal and influenza vaccination to influenza vaccine alone demonstrated a protective

• All residents and staff who have direct contact with residents. • Adults who are age 50 or older • Adults age 50 yrs with medical problems such as heart disease, lung disease, diabetes, renal dysfunction, hemoglobinopathies, immunosuppression, and/or those living in chronic care facilities • People working or living with at-risk people • All healthcare workers and those who provide key community services. • Adults who are age 65 or older • Adults age 65 y who have chronic illness or other risk factors including chronic cardiac or pulmonary diseases, chronic liver disease, alcoholism, diabetes mellitus, CSF leaks, as well as persons living in special environments or social settings (including Alaska natives and certain American Indian populations). Those at highest risk of fatal pneumococcal infection are persons with anatomical or functional asplenia, sickle cell disease, immunocompromised persons including those with HIV infection, leukemia, lymphoma, Hodgkin’s disease, multiple myeloma, generalized malignancy, chronic renal failure, or nephrotic syndrome, those receiving immunosuppressive chemotherapy (including corticosteroids), and those who received an organ or bone marrow transplant.

Pneumococcal polysaccharide Give IM or SQ

For whom it is recommended

Influenza Give IM

Vaccine name and route

Table 2 Recommendations for Adult Immunization in LTCFs

• Given every year • October through November is the optimal time to receive an annual flu shot to maximize protection, but the vaccine may be given at any time during the influenza season (typically December through March) or at other times when the risk of influenza exists. • May be given anytime during the influenza season • May be given with all other vaccines but at a separate site • Routinely given as a one-time dose; administer if previous vaccination history is unknown, • One-time revaccination is recommended 5 years later for people at highest risk of fatal pneumococcal infection or rapid antibody loss (e.g., renal disease) and for people age 65 and older if the 1st dose was given prior to age 65 and 5 years have elapsed since previous dose. • May be given with all other vaccines but at a separate site.

Schedule

• Previous anaphylactic reaction to this vaccine or to any of its components. • Moderate or severe acute illness.

• Previous anaphylactic reaction to this vaccine, to any of its components, or to eggs. • Moderate or severe acute illness.

Contraindications and precautions (mild illness is not a contraindication)

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• All susceptible adults and adolescents should be vaccinated. Make special efforts to vaccinate suspectible persons who have close contact with persons at high risk for serious complications (e.g., healthcare workers and family contacts of immunocompromised persons) and susceptible persons who are at high risk of exposure (e.g., teachers of young children, day care employees, residents and staff in institutional settings such as colleges and correctional institutions, military personnel, adolescents and adults living with children, nonpregnant women of childbearing age, and international travelers who do not have evidence of immunity). Note: People with reliable histories of chickenpox (such as self or parental report of disease) can be assumed to be immune. For adults who have no reliable history, serological testing may be cost effective as most adults with a negative or uncertain history of varicella are immune.

Varicella Give SQ

Give IM

• All adolescents and adults • After the primary series has been completed, a booster dose is recommended every 10 years. Determine if patients have received a primary series of 3 doses. • A booster dose as early as 5 years later may be needed for the purpose of wound management, such as pressure sores.

Td (Tetanus, diphtheria) • Booster dose every 10 years after completion of the primary series of 3 doses • For those who have fallen behind: The primary series is 3 doses: • Give dose #2 four weeks after #1. • #3 is given 6–12 months after #2. • May be given with all other vaccines but at a separate site. • Two doses are needed. • Dose #2 is given 4–8 weeks after dose #1. • May be given with all other vaccines but at a separate site. • If the second dose is delayed, do not repeat dose #1. Just give dose #2. • Previous anaphylactic reaction to this vaccine or to any of its components. • Pregnancy, or possibility of pregnancy within 1 month. • Immunocompromised persons because of mallgnancies and primary or acquired cellular immunodeficiency including HIV/AIDS. Note: For those on high-dose immunosuppressive therapy, consult ACIP recommendations regarding delay time. (continued)

• Previous anaphylactic or neurological reaction to this vaccine or to any of its components. • Moderate or severe acute illness.

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Unlabeled use: Prevention of herpes zoster and post herpetic neuralgia in the elderly.

For whom it is recommended

Schedule

• If blood products or immune globulin have been administered during the past 5 months, consult the ACIP recommendations regarding time to wait before vaccinating. • Moderate or severe acute illness. Note: Manufacturer recommends that salicylates be avoided for 6 weeks after receiving varicella vaccine because of a theoretical risk of Reyes syndrome.

Contraindications and precautions (mild illness is not a contraindication)

Adapted from the Advisory Committee on Immunization Practices (ACIP) by the Immunization Action Coalition with review by ad hoc team, October 2000. Abbreviation: LTCFs, Long-term care facilities; IM, Intramuscular1y; SQ, Subcutaneous1y; CSF, Cerebrospinal fluid; HIV, Human immunodeficiency virus; AIDS, Acquired immunodeficiency syndrome.

Varicella (Continued)

Vaccine name and route

Table 2 (Continued)

348 Gravenstein

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efficacy for pneumonia of 71% in individuals older than age 70 with an additional risk (other than age alone) for contracting pneumonia (i.e., those also with heart disease, lung disease, bronchial asthma, alcoholism, or who were institutionalized or permanently bedridden) (50). The study was conducted in a population-based cohort using data from 1982 to 1985. Generalizability of the study is also limited because vaccine efficacy in one population does not necessarily imply efficacy in another. Individuals with acquired immunodeficiency syndrome, young adults, children, and the elderly may all respond differently to the vaccine and require individual study to demonstrate efficacy. D. Antibody Response Another method of evaluating the efficacy of vaccination is by assessing the antibody response to vaccination. It is assumed that if an individual develops antibody to the vaccine antigen, they will be protected from infection on future exposure. Most healthy adults are able to generate a satisfactory antibody response to the serotypes in the pneumococcal vaccine (51). In the populations at risk, however, the antibody response is inconsistent. In immunocompetent adults who are at increased risk of pneumococcal disease or its complications, or who are age 65 or older, antibody responses have been variable. In the healthy elderly patient, a lower antibody response has been observed compared with younger healthy adults (52–54). This would not have been predicted because pneumococcal vaccine is composed of polysaccharide antigens that should generate a T-cell independent Bcell response, and B-cell responses are less affected by advancing age. However, T-dependent B-cell responses do decline with age, such as for peptides and glycoproteins (e.g., influenza vaccine) suggesting there may be a T-cell-dependent component to pneumococcal vaccine response. Objective measurements of health status and consideration of nutritional status, presence of malignancy, or known immunodeficiency, administration of immunosuppressant therapies, and anergy status may assist in identifying residents most likely to respond to pneumococcal vaccine. The currently available pneumococcal vaccines are composed of purified capsular polysaccharide antigens. Polysaccharide vaccines are less immunogenic than other vaccines that are composed primarily of protein antigens (i.e., live or killed bacteria, viruses, or toxoids). A pneumococcal conjugate vaccine has recently been approved for use in children (Prevnar® by Wyeth-Lederle Laboratories), but is not appropriate for use in adults. Several advances in the knowledge of protein conjugate technology, immunobiologics, and antigenic determinants that relate to protection by pneumococcal vaccines are in various stages of development and promise to improve pneumococcal vaccine efficacy. As noted before, current protein conjugates are already in the marketplace, but these vaccines have not been appropriate for use

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in adult populations. However, combining cytokines with the existing or conjugated vaccines (55) may provide a targeted approach relevant to immunosenescence. Selecting different cross-reactive epitopes by using a protein rather than polysaccharide-based antigen, such as with pneumococcal specific protein A, may allow a trivalent to pentavalent formulation to generate protection against the majority of serotypes rather than just 25% as is the case for the 23-valent polysaccharide formulation (56). These latter approaches hold the greatest promise for vaccines to address the challenge of antibiotic-resistant carriage and invasive disease in old and immune compromised populations. E. Cost Effectiveness Physicians and other clinical decision-makers are becoming more conditioned to consider the cost of a therapeutic intervention before accepting it into their general practice. Pneumococcal vaccine has undergone this scrutiny and negative perceptions may partially explain the low utilization of the vaccine. Until recently, population-specific efficacy data have been equivocal, and high-risk populations have a more variable antibody response, compromising measures of efficacy. Healthcare practitioners, therefore, may not consider pneumococcal vaccination a therapeutic priority based on the available data. Contributing to the confusion regarding vaccine use was the Immunization Practices Advisory Committee’s (ACIP) recommendation. The recommendation was equivocal until 1984, 7 years after the 14-valent vaccine was licensed for use (57). Several studies addressing the cost savings potential of the vaccine have since been published and support its use. The cost savings of the vaccine were evaluated in a retrospective study of Blue Cross/Blue Shield recipients in Minnesota using medical and pharmaceutical claims information (49). In persons at risk for developing pneumonia who are older than age 50, the cost savings associated with use of the vaccine was $141 per person or a total observed cost savings of $141,098 for each 1,000 persons vaccinated. Using a Markov decision-tree model in two hypothetical cohorts, one vaccinated with pneumococcal vaccine and the other unvaccinated, a cost-effectiveness analysis for elderly individuals aged 65 and older was conducted (58). A net savings of $8.27 and a gain of 1.21 quality-adjusted days of life per person vaccinated were identified at an estimated savings of $194 million dollars and 78,000 years of healthy life for the 23 million elderly people unvaccinated using 1993 data. In an analysis assuming an 8-year duration of immunity, the cost to Medicare in treating pneumonia would be the same as the cost of the vaccine (59). F. Safety The currently available pneumococcal vaccines are safe. The reactions to initial administration have been characterized as follows: erythema and pain at the in-

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jection site in 50% or more of persons; fever, myalgia, and severe local reactions in less than 1% of persons vaccinated (44); and anaphylactoid reactions that are reported to occur in approximately 5 cases per million (57). Neurological complications of immunization, which have been reported to occur with vaccines derived from whole, killed organisms or live-attenuated organisms, have not been associated with pneumococcal vaccine (60). The product information for the two pneumococcal vaccines currently available mentions a temporal association of use with neurological disorders such as paresthesias and acute radiculoneuropathy, including Guillain-Barrè syndrome. However, there are no case reports in the medical literature to support this observation, a presumed but unproven adverse effect of administration of some other vaccines (60). Revaccination with the pneumococcal vaccine has been reported to result in more severe local reactions when the administration time between the primary and secondary doses was less than or equal to 13 months, but low in individuals who could not recall when prior vaccination occurred (61,62). The incidence of adverse effects is similar for revaccination and primary immunization when revaccination occurs more than 4 years after the initial dose of vaccine. As noted in Table 2, revaccination should be considered for those individuals at highest risk for pneumococcal disease and/or complications. G. Drug Interactions Administration of pneumococcal vaccine and influenza vaccine in separate intramuscular sites has not resulted in an increase in adverse effects or change in immunogenicity and is accepted by the CDC when necessary to administer two or more vaccines concurrently. Corticosteroids and other immunosuppressant drugs (e.g., alkylating agents, antimetabolites, antithymocyte antibodies, cyclosporine, and radioisotopes) may interfere with the antibody response to vaccines. Vaccine administration should be delayed for 3 to 12 months after discontinuing immunosuppressant therapy.

IV. TETANUS AND DIPHTHERIA VACCINES A. Tetanus Tetanus is one of the oldest diseases known to man. National surveillance began in the United States in 1947 when the incidence was 0.39 per 100,000 personyears. The incidence has declined to a current rate of 0.02 per 100,000 personyears (based on 1997 data; 48 reported cases) (63). The risk of tetanus, however, is twofold higher in individuals aged 60 and older compared with those aged 20 to 59 and more than 12-fold that of persons age 5 to 19.

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Tetanus is a disease caused by Clostridium tetani, a spore-forming, grampositive, anaerobic bacillus. It is widely distributed in soil that has been fecally contaminated by humans and animals and is considered part of the indigenous intestinal microbial flora of humans and animals (64). The disease caused by C. tetani toxin results in prolonged muscular spasms of both the flexor and extensor muscle groups. Advanced tetanus shows generalized flexion contractures with prolonged spasm of the masseter muscle (lockjaw). Respiratory failure, caused by involvement of the muscles of respiration, may also occur and result in death. The risk for tetanus and its associated mortality increases with age (Fig. 1). The case-fatality ratio for the elderly, based on CDC data from 1995 to 1997, is 18%. Elderly persons are more prone to this disease principally because protective antitoxin levels decline with age, at least in frail populations. Healthy, independently living elderly have been shown to retain vaccine immune responses similar to younger populations (65). Pressure ulcers, vascular ulcers, and surgical wounds are also more common in older people, placing hospitalized and institutionalized elderly persons at risk for tetanus. Fecal incontinence, a common problem for many frail elderly, further makes pressure ulcers high-risk lesions for potential contamination with C. tetani. In a population-based serologic survey of immunity to tetanus in the United States, the prevalence of tetanus immunity was

Figure 1 Reported number of tetanus cases, average and annual incidence rates, and survival status of patients, by age group—United States, 1995–1997. Source: Centers for Disease Control and Prevention, Ref. 63.

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28% among persons aged 70 and older compared with 80% among younger individuals (66). In LTCF residents, studies in individuals with an average age of approximately 80 years have found protective antitetanus antibodies in 29% to 51% of individuals (67,68). Protective antibody titers decline with age, especially in elderly women, whereas elderly men with previous military service show better immunity to tetanus (69). Besides immunization, more attention to appropriate care of wounds has contributed to the reduced incidence of tetanus in this country. However, individuals lacking a primary series of vaccination, particularly elderly women, occasionally are identified. In these individuals, if a contaminated wound is found, tetanus immune globulin should be given. A booster alone is appropriate if the patient completed a primary series but has not received tetanus toxoid within the preceding 5 years. A thorough attempt should be made to determine the primary immunization status of all LTCF residents. Patients with unknown or uncertain previous immunization histories should be considered to have no previous tetanus toxoid doses. Persons who had military service since 1941 can be considered to have received at least one dose, although most may have completed a primary series. However, this cannot be assumed for everyone. The number of people at risk for tetanus will increase unless elderly persons are more conscientiously given tetanus toxoid vaccines. B. Diphtheria First described in 1821 by Pierre Brettonneau, illness with Cornyebacterium diphtheriae is now extremely rare in the United States with only a few cases reported each year, primarily in nonimmunized elderly individuals (70). The pathogenesis of diphtheria begins with C. diphtheriae mucosal colonization of the nose or mouth. Toxin elaboration causes tissue necrosis and local inflammation followed by absorption of the toxin, which has particular topism for cardiac, neural, and renal cells. Clinical manifestations appear after tissue fixation of toxin with myocarditis appearing 10 to 14 days and peripheral neuritis 3 to 7 weeks after onset of disease. Tonsillar and pharyngeal diphtheria is characterized by anorexia, malaise, low-grade fever, and sore throat (71). Severe cases are associated with increasing toxemia, resulting in myocarditis, arrhythmias, congestive heart failure, stupor, coma, and death with 6 to 10 days. Cutaneous diphtheria is an indolent skin infection that often occurs at sites of burns or other wounds and is more common in warmer climates and conditions of poverty, overcrowding, and poor hygiene (72). Widespread use of diphtheria toxoid in the United States has limited the annual occurrence of the disease to practically nil, with one case reported to the CDC in 1999 (70). More than 90% of diphtheria cases occur in adults, virtually all of whom are unprotected. Adult susceptibility to diphtheria reflects reduced lifetime

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exposure (to C. diphtheriae) and failure to administer the primary series of the vaccine and decadal boosters throughout life. 1. Effectiveness Tetanus-diphtheria toxoids (Td) are among the most immunogenic of vaccines indicated for older adults, and they are virtually 100% effective in immunocompetent adults who have kept their vaccination status up to date. Naturally acquired immunity to tetanus toxin does not occur, and natural immunity to diphtheria occurs in only 50% of individuals who acquire the disease. Evidence indicates that complete primary immunization with tetanus toxoid provides 10 or more years of protection. Appropriately timed boosters are needed to maintain antitoxin titers. Recent outbreaks of diphtheria in other countries highlight the risk of outbreaks of diphtheria (73–76). After a 23-year period without reported cases of diphtheria, the disease re-emerged in Sweden. Ninety-five percent to 99% of the children were vaccinated and 81% of the population younger than age 20 had protective immunity, but only 19% of women and 44% of men older than age 60 had protective immunity (77). All those individuals who died or had neurological complications had low levels of antibodies, whereas 33 of 36 symptomfree carriers of the same strain had protective antibody titers. In an evaluation of 676 cases of hospitalized diphtheria cases in Khrgyzstan in 1995, the case fatality ratio was 3% (76). In the United States, the number of older adults with protective antibody to both tetanus and diphtheria is similarly low, making an experience similar to the one in Sweden likely if we are unable to better vaccinate our population (78). 2. Indications All elderly persons should be actively immunized against both tetanus and diphtheria through the initial primary series and then revaccinated every 10 years. Anyone who has not received the complete primary series should complete it with the combined Td vaccine, although earlier doses need not be repeated if the schedule is delayed. A booster dose even 30 years after primary vaccination results in rapid protection for both tetanus and diphtheria. Getting the series up to date is especially relevant if travel to developing countries is anticipated. Tetanus-diphtheria prophylaxis is recommended with clean, minor wounds if the primary series is incomplete or the last booster vaccination was more than 10 years ago. More serious wounds require both active and passive immunization with tetanus immune globulin. The cost effectiveness of tetanus immunization, specifically booster doses, has been questioned (79). Because tetanus is rare, the cost of each case prevented and its associated year of life gained is high, therefore, some experts have recom-

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mended targeting high-risk adults, such as those with vascular ulcers or those seen at time of injury, for revaccination (80). 3. Administration and Revaccination Tetanus toxoid (TT) is produced singly or in combination with Td with or without whole-cell or acellular pertussis vaccine. In elderly LTCF residents, Td is the recommended preparation. The primary series used for adults consists of two 0.5-ml doses of Td given intramuscularly 1 to 2 months apart, followed by a third 0.5-ml dose 6 to 12 months later. The Td vaccine contains only 10% of the diphtheria toxoid contained in the pediatric diphtheria-tetanus-pertussis (DTP) vaccine, making it much less reactogenic. 4. Adverse Reactions Present vaccines have been well tolerated with minimal reactions. The high reactogenicity of childhood DTP vaccines has been largely attributed to the pertussis component, and that has been minimized with the transition to an acellular formulation of pertussis antigen. The only contraindication to tetanus and diphtheria toxoid is a history of a neurological or severe hypersensitivity reaction after a previous dose, or sensitivity to the preservative. In previously immunized adults, the local reaction rate is 40% to 50%. Less than 10% of vaccines develop an area of redness or swelling larger than 5 cm (81). Potential side effects include local reactions, fever, chills, hypersensitivity, arthralgia, rash, and encephalopathy. Reactions may be related to high antitoxin titers or mediated by hypersensitivity to the mercury preservative.

V. VARICELLA VACCINE As noted in Table 2, varicella immunization is recommended for all individuals in LTCFs, including residents and staff, who have no history of primary varicella infection (chicken pox). It has been suggested, as naturally occurring varicella incidence declines because of increasing use of varicella vaccine in children, that the rate of herpes zoster will increase (82,83). Herpes zoster is a prevalent condition in LTCF residents, with a high prevalence of complications, most notably postherpetic neuralgia (see Chapter 17). Varicella vaccine has been shown to boost cell-mediated immunity to varicella zoster virus in elderly individuals (84). It is hoped that this boost will result in a decreased incidence of herpes zoster in the elderly. Large scale clinical trials are currently underway at the National Institutes of Health to study this issue extensively. Interested readers are referred to published reviews of this issue (85–87).

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VI. VACCINATION OF HEALTHCARE WORKERS IN LTCFs Immunization of healthcare workers is recommended by a number of organizations to prevent the spread of infection to the frail elderly residing in LTCFs, and the recommended vaccine uptake for providers having direct contact with residents is also at 80%. The rate of immunization among LTCF staff remains low, despite these recommendations (6). The effect of vaccinating healthcare workers in geriatric long-term care hospitals on the incidence of influenza, lower respiratory tract infections, and death has been evaluated (88). In the hospitals where healthcare workers were vaccinated, influenza-like illness occurred in 7.7% of unvaccinated patients compared with 0.9% of vaccinated patients. Fewer patients died in hospitals where healthcare workers were vaccinated than in hospitals where healthcare workers were not vaccinated (10% vs 17%, respectively). Clinical data regarding the efficacy of vaccination of healthcare workers with respect to benefit to the resident population is primarily on influenza vaccination; however, it is reasonable to encourage pneumococcal vaccination, in addition to annual influenza vaccination to reduce carriage of pathogenic and antibiotic-resistant strains and hepatitis vaccination to protect staff from infected residents. For maximum compliance, vaccinations should ideally be offered free to employees, and vaccine status should be reviewed upon employment and annually at the time influenza vaccination is reoffered. A formal policy regarding vaccination status review, and inclusion annual education regarding the importance of vaccination to employees and residents will help build compliance. Also, policy review and enforcement should be assigned to the infection control practitioner, backed with authority consistent with local, state, and federal statutes.

VII.

SUMMARY

Infectious diseases are an important underlying cause of much of the morbidity and mortality experienced in long-term care settings. This risk is in part the result of the nature of a closed setting, close living environment affecting disease transmissibility, and the susceptibility of the resident population owing to both the nature of the underlying diseases and age-related immune decline. Vaccination is an important part of the overall infection control program for LTCFs. The currently available vaccines that should be part of the standing orders at the time of admission to the facility are pneumococcal, tetanus/diphtheria, and influenza vaccines. Standing orders or policy driving the standing order should include review procedure for past vaccination, timing for initial and repeat vaccination, and review of contraindications for vaccinations. For healthcare staff, these three vaccines, in addition to the hepatitis vaccine, should be placed in the facility’s infection con-

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trol policy and ideally be readily available and included in employee benefits to improve compliance. Newer vaccines are currently under development that may provide significantly better safety profiles and immunogenicity. Shingles from herpes zoster may prove to be a vaccine-preventable disease. Although not discussed here, the role of vaccines is expanding from a current preventive strategy to likely include treatment modalities for various diseases, including, for example, osteoporosis and Alzheimer disease in the next decades. The LTCF practitioner will be challenged but wise to stay abreast of developments of vaccine benefits, policy, and strategies to maximize uptake of both residents and staff.

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21 Pathogenesis and Molecular Mechanisms of Antibiotic Resistance Robert A. Bonomo Case Western Reserve University, Cleveland, Ohio

I. INTRODUCTION The infectious disease challenges facing clinicians committed to the care of the growing number of elderly will be great (1). It is estimated that the incidence of infection in long-term care facilities (LTCFs) in the United States ranges between 1 to 10 per 1000 days of care (2,3). Surveys of medication use in nursing homes indicate that antibiotics account for nearly 40% of all medications prescribed in LTCFs (4,5). Most of the antibiotic use is empiric, without the benefit of accurate culture data or information regarding susceptibility to guide clinicians. This intense antibiotic usage creates selective pressure for the emergence of resistance. Because elderly patients are mobile between acute care settings, LTCFs, and the community, the movement of the elderly in the healthcare system has played a major role in the evolution of antibiotic resistance in this population.

II. ANTIBIOTIC RESISTANCE IN LTCFs In the past decade, the increasing prevalence of antibiotic-resistant pathogens in LTCFs has emerged as a major concern (6–11). In many publications, LTCFs are regarded as “reservoirs of resistant pathogens.” In LTCFs, resistance to -lactam antibiotics (especially third-generation cephalosporins), -lactam -lactamase inhibitor combinations, macrolides, trimethoprim-sulfamethoxazole (TMP-SMX), 363

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fluoroquinolones, aminoglycosides, vancomycin, and linezolid are becoming major fears for clinicians prescribing antibiotics in LTCFs. Understanding how these resistant pathogens emerge in the setting of antibiotic use remains a critical tool in the design of strategies aimed to stem this problem (10,12,13). A. The Emergence of Resistant Pathogens in LTCFs Long-term care facilities are prime settings for the emergence of resistant bacteria for several reasons. The principal explanation may be that patients colonized with resistant pathogens are transported between acute care facilities and LTCFs: this can facilitate the spread of antibiotic-resistant pathogens from the endemic environment (hospital) to a nonendemic one (LTCF). The best-studied example of this is the spread of methicillin-resistant Staphylococcus aureus (MRSA) (14,15) (see Chapter 22). Many LTCF residents also suffer from conditions, such as malnutrition or skin and soft tissue breakdown, that place them at risk for colonization and infection by resistant bacteria. Moreover, the frequent presence of indwelling foreign material, such as percutaneous endoscopic gastrostomy (PEG) tubes and indwelling bladder catheters, have been identified as risk factors for colonization and infection by multiresistant bacteria (16). Many of these devices are placed in the acute care setting and become colonized with resistant pathogens prevalent in the hospital. Ultimately, these pathogens become endemic in LTCFs as patients undergo convalescence. Another major factor in the establishment of resistant pathogens in LTCFs may be related to lapses in infection control procedures (hand washing) (2). When resources are limited and the number of patients cared for increases, hand washing becomes increasingly difficult. Lastly, excessive use of antimicrobial agents can easily select for resistant pathogens. This has been the major cause for the emergence of ceftazidime-resistant gram-negative bacilli (acquisition of point mutants that confer novel hydrolytic properties to these -lactamases) (17,18). Not only are individual resistance determinants evolving, but so are the plasmids encoding these genes. Many ceftazidime-resistance genes are encoded on large plasmids containing multiple resistance determinants (17). Why are antibiotics used so readily in LTCFs? The uncertainties of diagnosis of infection inherent in caring for the elderly drive empirical use. The diagnosis of infection may be extraordinarily difficult in the elderly population in LTCFs (19), where functional decline may be a more important clue to the presence of infection than fever. Furthermore, the fear of fatal clinical failure (unrecognized sepsis) often influences antibiotic choices, making it difficult to resist using broad-spectrum agents to cover all clinical possibilities (even if infection is not a likely cause). Retrospective studies demonstrate that in more than one-third of cases, the evidence to start an antibiotic is inadequate (20–23). Unfortunately, this inappropriate use of antibiotics impacts the LTCF-resistant microflora of the nursing home.

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B. Pathogenesis of Infections in the Elderly and the Impact of Antibiotic Resistance The most vulnerable older adults are more likely to be exposed to a larger number of infectious agents (24). The development of infected pressure ulcers, nursing home-acquired aspiration pneumonia, and catheter-associated urinary tract infections (UTI) are all “high inoculum” infections. Furthermore, these infections all occur in the setting of altered natural barriers. Malnutrition, poor skin integrity, diminished gag reflex, and poor bladder emptying all contribute to the impaired host defense. In addition, the loss of helper T-cell function with age, decreased response to mitogens, and altered interleukin-2 production contribute to the susceptibility to infection (see Chapter 4). The higher the inoculum of infection and the more compromised the host defenses are, the more likely that the same pathogen that rarely causes infection in the young will cause significant infection in the elderly (24). In fact, the mortality rates of pneumonia and sepsis are three times greater in the elderly when compared with the young; pyelonephrititis carries a 10 times greater mortality (1,24). Most disturbing is that these syndromes appear many times with the absence of fever—a poor prognostic sign. A decline in functional status may be the only clue to infection. Guidelines have been published to assist the clinician with the assessment of infection and the initiation of therapy (25). In the setting of LTCFs where antibiotic resistance is endemic, treatment of these infections becomes even more problematic. For example, the fear of ampicillin or TMP-SMX-resistant Escherichia coli or Klebsiella pneumoniae may force a clinician to consider use of a third-generation cephalosporin, -lactam -lactamase inhibitor combinations, or quinolone therapy for the treatment of a UTI. The problem becomes more acute when empirical treatment of nursing home-acquired aspiration pneumonia is considered. Despite the knowledge that Streptococcus pneumoniae is the most common pathogen and that Legionella is uncommon in certain geographic areas, should the clinician always choose a quinolone to “cover penicillin-resistant pneumococci” and “atypicals?” Should empirical treatment for MRSA and anaerobes be added also? If one considers every possibility, it is easy to see how broad-spectrum therapy results. Omission of the appropriate antibiotic (i.e., choosing the incorrect empirical therapy) can result in a fatal outcome. However, it is recognized that methicillin-resistant Staphylococcus aureus (MRSA) are no more virulent than methicillin susceptible Staphylococcus aureus (MSSA). The concern for resistance influences clinicians to escalate therapy. This practice increases cost and length of therapy, and possibly even toxicity. Antibiotics can cause a number of unwanted side effects that are more severe in the elderly (e.g., delirium and prolongation of the QTc interval on electrocardiogram with certain quinolones, nephrotoxicity and ototoxicity with aminoglycosides). Hence, in many ways, antibiotic resistance is as important as the potential virulence of the infecting pathogen.

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C. Basic Microbiological Principles Certain microbiological and pharmacological principles are essential to the understanding of antibiotic resistance (26,27). These will be introduced here to ensure a complete understanding of the discussion to follow. 1. Minimum Inhibitory Concentration and Minimum Bactericidal Concentration Minimum inhibitory concentration (MIC) is the lowest concentration of antibiotic that inhibits growth of an organism after 18 to 24 hour of incubation. This is a quantitative endpoint. Factors such as pH, oxygen, cations, composition of media (liquid or solid), inoculum size, drug stability, and others, can influence the MIC. Two methods are used to determine bacterial susceptibility to antibacterial agents: disk diffusion and agar or broth dilution. Disk diffusion is performed by applying commercially available filter paper disks impregnated with specific quantities of the drug on the surface of agar plates in which a specific amount of the bacteria has been streaked. After 18 to 24 hours, the size of the clear zone of inhibition around the disc is determined. The size of the zone is related to the activity of the drug against the test strain and the size of the inoculum tested. Standards for sensitivity vary for each test organism and they are based on the concentration of the drug that can be achieved safely in the plasma. Dilution tests (agar or broth) use serially diluted concentrations. The lowest concentration of the antibiotic that prevents (i.e., inhibits) visible growth is the MIC. The value that kills 99.9% of the bacterial numbers is the minimum bactericidal concentration (MBC). In many reference laboratories, these assessments have been automated. Often a test strain may appear susceptible at a low inoculum but become resistant at a large inoculum. This is most commonly observed when E. coli or Klebsiellae spp possessing extended spectrum -lactamases are tested (see below). As an example, susceptibility to ceftazidime is observed at a concentration of 104 organisms, but resistance is seen at a higher inoculum of 106 organisms. 2. Pharmacological Principles After an antibiotic (like any other drug) has been administered by the oral, intravenous, or intramuscular route, it is absorbed and has a peak serum concentration (C max), volume of distribution (VD), and serum half-life (T1/2). The combination of these considerations and the immune status of the host are important in eradication of the organism. A critical factor is the site of infection and how well the antibiotic penetrates that site. For example, when treating infections in the chamber of the eye, low concentrations are usually achieved. In treating UTIs, high concentrations of antibiotic are obtained in the urine. The postantibiotic effect is suppression of bacterial growth despite the presence of subinhibitory drug concentrations (after removal of the antibiotic). Many

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antibiotics are advertised as having this property, but its effectiveness is unclear. Certain antibiotics’ killing properties are dependent on concentrations of the drug that are achieved above the MIC levels. The efficacy of -lactam antibiotics depends on the length of time the drug is above the MIC. Dose-dependent toxicities usually limit the amount of quinolones or aminoglycosides that are administered. D. Resistance to ␤-Lactams The safety and therapeutic efficacy of -lactams have made them the most frequently prescribed antibiotics in LTCFs. Resistance to -lactams occurs by three mechanisms: alteration in the target protein (penicillin-binding protein), production of inactivating enzymes (-lactamases), and impaired entry into bacterial cells (loss of the channels that permit the ingress of antibiotics into bacteria or active efflux). The most important mechanism is production of -lactamases. Clinically important -lactam-resistant pathogens are: ceftazidime-resistant gramnegative bacilli, gram-negative bacilli producing inhibitor-resistant -lactamases, MRSA, and penicillin-resistant pneumococci (Table 1). 1. Ceftazidime-Resistant Gram-Negative Bacilli -Lactamases are bacterial enzymes that inactivate -lactams. Certain -lactamases prefer penicillin (penicillinases), whereas other -lactamases hydrolyze cephalosporins more readily (cephalosporinases) (28,29). These inactivating enzymes may be encoded by genes on plasmids, transposons, or in the bacterial chromosome. The most concerning -lactamases are those that inactivate potent broad-spectrum penicillins (e.g., piperacillin) and third-generation cephaTable 1 Resistant Pathogens Found in Long-Term Care Facilities Multiresistant gram-negative bacilli Extended spectrum -lactamase-producing gram-negative bacilli (Escherichia coli and Klebsiella pneumoniae) Inhibitor-resistant -lactamase producing E. coli, Klebsiella spp, or Proteus spp Plasmid-mediated third-generation cephalosporin-resistant Klebsiella pneumoniae and E. coli Third-generation cephalosporin-resistant Enterobacter and Citrobacter spp Quinolone-resistant Pseudomonas aeruginosa Trimethoprim-sulfamethoxazole-resistant E. Coli Resistant gram-positive bacteria Methicillin-resistant Staphylococcus aureus Vancomycin-resistant enterococci Penicillin-resistant Streptococcus pneumoniae (resistant also to macrolides, clindamycin, sulfamethoxazole, and tetracyclines)

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losporins. In this group are the inducible chromosomal cephalosporinases (AmpC -lactamases) and the extended-spectrum -lactamases (ESBLs). The latter are so named because they “extended the hydrolytic spectum” of penicillinases and cephalosporinases to include ceftazidime, cefotaxime, ceftriaxone, and aztreonam. Most ESBLs are of the TEM and SHV variety (see www.lahey.org). An increasing number are also being discovered that are of the non-TEM and non-SHV variety (CTX-M, OXA, BES-1, and GES-1, and others). Extended-spectrum -lactamases are readily inhibited by -lactamase inhibitors (clavulanic acid, tazobactam, or sulbactam). Chromosomal cephalosporinases are able to hydrolyze third-generation cephalosporins but are not readily inhibited by -lactamase inhibitors. Extended-spectrum -lactamases are the primary threats to the efficacy of cephalosporins in LTCFs (16,18,28,30). The widespread use of third-generation cephalosporins and the emergence of ESBLs in LTCFs have been well documented. In one study, 31 of 35 selected residents from eight nursing homes in Chicago harbored an ESBL on admission to the hospital (16). These organisms (E. coli and Klebsiella spp) were multiresistant (resistant to ceftazidime, aminoglycosides, TMP-SMX, and ciprofloxacin) and harbored a common plasmid encoding TEM-10 -lactamase. AmpC -lactamases are found in Enterobacter, Citrobacter, Serratia, and Pseudomonas aeruginosa. Exposure of these bacteria to agents such as cefoxitin, clavulanic acid, or imipenem induces production of AmpC -lactamases. More recently, transferable plasmids have been reported that possess AmpC -lactamases. The transferability of some of these plasmids suggests a significant potential for spread under the appropriate selective conditions (28,31). 2. Inhibitor-Resistant -Lactamases Resistance to amoxacillin-clavulanic acid, ampicillin-sulbactam, and piperacillintazobactam) in E. coli or Klebsiella pneumoniae should raise concern (32). In the LTCF, clinicians have used -lactam -lactamase inhibitor combinations to treat infection caused by enteric bacilli and anaerobes (infected pressure ulcers and aspiration pneumonia). -Lactamases resistant to inactivation by -lactamase inhibitors have evolved (33–35). Most inhibitor-resistant -lactamases are variants of the TEM-1 enzyme. To date, there has only been one description of a clinical isolate possessing SHV resistant to inhibitors (SHV-10) (35). Piperacillintazobactam, in particular, may still be effective for the treatment of E. coli possessing certain inhibitor resistant TEM -lactamases (36). It is possible that the frequency of inhibitor-resistant -lactamases is underestimated in LTCFs. Inhibitor-resistant clinical strains of K. pneumoniae have been discovered in a nursing home in France (37). Many laboratories in the United States do not identify these strains. Clinicians are unaware of the significance of

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resistance to amoxacillin-clavulanic acid, especially when they can use a firstgeneration cephalosporin. 3. MRSA Methicillin-resistant Staphylococcus aureus (MRSA) is a true “persistent pathogen” in LTCFs (38–44) (see Chapter 22). The molecular basis of resistance to methicillin is the expression of low-affinity penicillin-binding protein (PBP) PBP2a, encoded by the mecA gene (45). The mecA gene resides in the staphylococcal chromosome within a complex 30 to 50 kilobase genetic region that frequently encodes resistance to other antibiotics. Hence, MRSA is resistant to multiple antibiotics. Vancomycin, quinupristin-dalfopristin (Synercid™), and linezolid (Zyvox™) are the only effective agents against MRSA. Fortunately, reduced vancomycin susceptibility among S. aureus remains extremely rare. 4. Penicillin-Resistant Pneumococci Streptococcus pneumoniae remains one of the most frequent causes of pneumonia. Significant outbreaks of penicillin-resistant pneumococci (PRP) have occurred in LTCFs (46,47). Remodeling of pneumococcal PBPs is responsible for the reduction in the affinity for penicillins, carbapenems, and certain cephalosporins (48). Pneumococci susceptible to penicillin have MICs less than 0.1 g/ml. Those with MICs higher than 0.1 but less than 2 g/ml are considered intermediate in their resistance. Those with penicillin MICs greater than 2 g/ml are high-level resistant. Retrospective studies suggest that penicillin is effective therapy for pulmonary infections caused by pneumococci with intermediate resistance to penicillin (49). High-level resistance compromises the utility of -lactams antibiotics in the intravenous therapy of meningitis. The reduced activity of the penicillins against high-level PRP has focused attention on the use of the newer (antipneumococcal) fluoroquinolones for the treatment of respiratory infections, as these agents retain excellent activity against S. pneumoniae regardless of the level of penicillin resistance. How effective fluoroquinolone antibiotics will be in the treatment of penicillin-resistant pneumococci in LTCFs remains to be seen. Antibiotic potency cannot compensate for a debilitated host. E. Resistance to Macrolides Erythromycin (the first macrolide) was initially isolated from Streptomyces erytherus, which are soil organisms found in the Philippines. It is so named because it contains a many-member lactone ring to which are attached one or more deoxy sugars (26,27). There are currently three macrolides in common use: erythromycin, clarithromycin, and azithromycin. Clarithromycin differs from ery-

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thromycin only by methylation of the hydroxy group at the 6 position and azithromycin differs by the addition of a methyl-substituted nitrogen atom in the lactone ring. These structural modifications improve acid stability and broaden spectrum of activity. Macrolides are concentrated within neutrophils and macrophages by an energy-dependent process. Concentration in alveolar macrophages and neutrophils are up to 23 times and 10 to 13 times greater, respectively, than the levels in extracellular fluid. This is a property of all macrolide antibiotics and is a key factor in why these drugs are used in the treatment of certain types of intracellular pathogens (see below). 1. Mechanism of Action Erythromycin (and all macrolides) inhibits protein synthesis in susceptible organisms by binding reversibly to a single high-affinity site of the 50S subunit of the 70S bacterial ribosome. The antimicrobial binding site is located in the peptidyltRNA binding region of the 50S-ribosome subunit. Erythromycin inhibits translocation wherein a newly synthesized peptidyl tRNA molecule moves from the acceptor site on the ribosome to the peptidyl (or donor site). Erythromycin does not bind to mammalian ribosomes. Gram-negative organisms are resistant to erythromycin because erythromycin cannot enter the gram-negative cell. Organisms rendered cell-wall-deficient are susceptible to erythromycin (50–52). 2. Mechanism of Resistance (Table 2) Resistance to macrolides has been described in many common pathogens (50–54). A major mechanism for resistance to macrolide antibiotics (e.g., in S. pneumoniae) is MLS B (macrolide, lincosamide, and streptogramin B) resistance, manifested when the 23S rRNA is methylated by the product of an erm gene. This modification results in the decreased binding of all known macrolide, lincosamide, and streptogramin B antibiotics to the ribosome. Several mechanisms of bacterial resistance to erythromycin have also evolved over the years. These include impermeability of the bacterial cell wall, altered intracellular targets, and drug inactivation. A number of interesting inactivating enzymes exist. These include methylases that modify the ribosomal target leading to decrease in drug binding (ermB gene) and esterases that hydrolyze the antibiotics. Chromosomal mutations that alter the 50S ribosome also confer resistance. Macrolides can also be pumped out of cells (mefE gene) in an energy-dependent manner. Regulation and expression of erm methylases are complex and apparently species dependent. Erythromycin-resistant strains can be assigned to the constitutive resistance (cMLS) phenotype or the inducible resistance (iMLS) phenotype. Clarithromycin and azithromycin offer the following advantages when compared with erythromycin: reduced gastrointestinal toxicity, increased tissue

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Table 2 Mechanisms of Resistance Mechanism Altered target

Site

Example

Penicillin-binding protein

Methicillin-resistant Staphylococcus aures, Streptococcus pneumoniae Vancomycin-resistant enterococci Erythromycin-resistant S. pneumoniae Clindamycin-resistant S. pneumoniae Escherichia coli Quinolone-resistant S. aureus Trimethoprim-sulfamethoxazoleresistant S. pneumoniae

Ligase Ribosome

Inactivating enzyme

Penetration

DNA gyrase Topoisomerase IV Dihydrofolate reductase and dihydropteric acid synthesis -lactamase

Aminoglycoside modifying enzyme Tetracycline efflux pump Porin mutation

E. coli Klebsiella pneumoniae Enterobacter Citrobacter Pseudomonas aeruginosa Proteus S. pneumoniae P. aeruginosa

absorption, and easier dosing. To date, they have not proved more effective. However, the ease of dosing and the diminished side effect profile make these newer macrolides very popular. The enhanced tissue penetration also has made these drugs the mainstays of treating nontuberculosis mycobacterial infections (Mycobacterium avium complex [MAC]) in acquired immunodeficiency syndrome (AIDS) patients. At present, physicians are using the newer macrolides (clarithromycin and azithromycin) almost exclusively. Clarithromycin is degraded to 14-OH-clarithromycin that has enhanced activity against Haemophilus influenzae, Legionella, and Helicobacter pylori. 3. Ketolides Ketolides belong to a new class of semisynthetic 14-membered-ring macrolides, which differ from erythromycin by having a 3-keto group instead of the neutral sugar L-cladinose. These are being developed in the search for more active agents against penicillin-resistant pneumococci and erythromycin-resistant H. influenzae. Some intriguing data suggest these also act as immunomodulators. Teli-

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thromycin, a ketolide, is active against streptococcal and pneumococcal strains exhibiting erythromycin-inducible resistance and resistance by active efflux (53). In addition, ketolides are highly active against other bacteria causing respiratory tract infections (Moraxella and H. influenzae), anaerobic, and intracellular pathogens (Legionella). The principal advantage of ketolides is their activity against pneumococci and macrolide-resistant streptococci while preserving the remainder of the macrolide spectrum of activity, particularly for intracellular pathogens. The recommended dose is 800 mg once a day. The safety of this dose has been validated for patients treated for 7 to 10 days for community-acquired pneumonia. Telithromycin is uniformly and highly active against pneumococci (regardless of their susceptibility or resistance to erythromycin, penicillin, or both), erythromycin-susceptible S. pyogenes and erythromycin-resistant S. pyogenes strains of the M phenotype (in which resistance is mediated by an efflux system) or iMLS-B or -C phenotype (in which resistance is mediated by a methylase encoded by the ermTR gene). Ketolides are less active against erythromycin-resistant S. pyogenes strains with the cMLS phenotype or the iMLS-A subtype (where resistance is mediated by a methylase encoded by the ermAM gene), these strains ranging in phenotype from the upper limits of susceptibility to low-level resistant. F. Resistance to TMP-SMX 1. Mechanism of Action Trimethoprim-sulfamethoxazole is a fixed-dose combination chemotherapeutic agent first introduced in Europe in 1968. It subsequently became available in the United States in 1973. It possesses a fixed ratio of one part TMP to five parts SMX. The relative amount of each drug varies with the preparation. Standarddose oral tablets have 80 mg TMP and 400 mg SMX. Double-strength tablets contain twice this amount. The two components of the drug provide sequential inhibition of enzyme systems involved in bacterial synthesis of tetrahydrofolic acid, and thereby disrupt nucleic acid synthesis. These agents selectively attack bacterial nucleic acid synthesis because bacteria (in contrast to humans) cannot use exogenous folate to metabolize proteins. Sulfonamides inhibit synthesis of dihydrofolic acid (paraaminobenzoic acid into folic acid) and bind to bacterial dihydrofolate reductase in preference to human dihydrofolate reductase, which prevents the formation of the active metabolite tetrahydrofolic acid. Trimethoprim inhibits the reduction of dihydrofolate into tetrahydrofolate. The latter is the form necessary for one-carbon transfer reactions, for example, the synthesis of thymidylate from deoxyuridylate. The combination of TMP and SMX provides inhibitory and even synergistic activity against bacteria. Trimethoprim is usually 20 to 100 times more potent than SMX.

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2. Mechanism of Resistance Resistance to TMP-SMX has become a major problem in the United States and the rest of the world (55,56). The biggest impact on resistance to these agents has been seen when treating pneumococci (otitis media, bronchitis, and pneumonia) and E. coli (UTIs). Trimethoprim-sulfamethoxazole-resistant organisms may arise by point mutations in the genes encoding these enzymes. Resistance in gramnegative bacteria is often common in LTCFs and is associated with the acquisition of a plasmid that codes for an altered dihydrofolate reductase enzyme (57). G. Resistance to Tetracyclines Tetracycline antibiotics were one of the first broad-spectrum antibiotics effective against a wide range of microorganisms. Chlortetracycline was first introduced in 1948 because of screening of natural products from the soil. Tetracyclines are now less generally used, owing in part to the evolution of other antimicrobial drugs as well as antimicrobial resistance. There are three categories of tetracyclines: the short-acting compounds chlortetracycline, oxytetracycline, and tetracycline; an intermediate group consisting of demeclocycline and methacycline; and long-acting compounds such as doxycycline and minocycline. The basic structure of tetracycline consists of a hydroxynapthacene nucleus containing, as the name implies, four fused benzene rings. Chlortetracycline was first isolated from Streptomyces aureofaciens in 1947, and oxytetracycline was isolated from Streptomyces rimosus in 1950. Doxycycline and minocycline are semisynthetic derivatives discovered in 1966 and 1972, respectively. 1. Mechanism of Action Tetracyclines are bacteriostatic drugs and act on the bacterial ribosome. Penetration of the bacterial cell wall by tetracycline occurs as the result of both passive diffusion and an active transport system. Once the drug is within the bacterial cell, inhibition of protein synthesis occurs by binding to the 30S-ribosome subunit to block the binding of aminoacyl-tRNA to the acceptor site on the mRNA ribosome complex. This prevents the addition of new amino acids to the growing peptide chain. 2. Mechanism of Resistance The mechanism of resistance has been shown to be acquisition of a resistance determinant known as tetM, a transposon-borne determinant found initially in the gene of Streptococcus and more recently Mycoplasma that has migrated into other gram-negative organisms. The major ways bacteria become resistant to tetracyclines is by decreased accumulation (blocked entry or efflux pumps), decreased access to the ribosome by protection proteins, and by enzymatic inactivation.

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3. Glycylcyclines New tetracyclines are on the horizon! Glycylcyclines are tetracycline antibiotic derivatives. Tigilcycline, formerly known as GAR-936, is novel, semisynthetic tetracycline with broad-spectrum activity. Currently, tigilcycline is in three phase II clinical trials for complicated UTIs, intra-abdominal infections, and skin structure infections. Efficacy and tolerability are becoming established. Their spectrum of activity is similar to tetracycline and includes gram positives, gram negatives, and anaerobes. In general, glycyclines are more active than minocycline and appear to be more active against MRSA, penicillin-resistant pneumococci, and vancomycin-resistant enterococci (VRE). H. Resistance to Quinolones The history of the newer 4-quinolone antibacterial agents began with the introduction of nalidixic acid in 1962. The importance of the quinolone agents is derived from broad antibacterial spectrum, unique mechanism of action, absorption in the gastrointestinal tract (bioavailability) after oral administration, excellent tissue distribution, bactericidal activity, and low incidence of adverse reactions. The quinolone agents are all structurally similar compounds. They are divided into four general groups. These are naphthyridines, cinnolines, pyridopyrimidines, and quinolones. These are all dual ring structures. 1. Mechanism of Action The molecular bases for the potent antibacterial effects of the newer quinolone agents have not been determined definitively (58–62). Previous studies indicated that the mechanism of action of nalidixic acid and the newer quinolones is inhibition of DNA topoisomerases (gyrases) of which four subunits (two A and two B monomers) have been identified. The topoisomerases supercoil strands of bacterial DNA into the bacterial cell. Each chromosomal domain is transiently nicked during supercoiling, which results in single-stranded DNA. When supercoiling is completed, the single-stranded DNA state is abolished by an enzyme that seals the nicked DNA. The enzyme, termed gyrase or topoisomerase II (nicking-closing enzyme), nicks double-stranded chromosomal DNA, introduces supercoils, and seals the nicked DNA (58). The A and B subunits are thought to introduce the nicks, the B subunits supercoil, and the A subunits seal the nick they produce initially. Quinolones trap or stabilize the enzyme DNA complex after strand breakage or resealing of DNA. This trapped complex functions as a cellular poison, possibly by generating a DNA break that the cell is unable to repair. Quinolones also inhibit topoisomerase IV that is structurally similar to DNA gyrase. It has been observed that inhibitors of RNA and protein synthesis reduce

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the bactericidal activity of some quinolones, but they do not effect their ability to inhibit bacterial synthesis of DNA. Thus, inhibition of bacterial DNA synthesis is not sufficient to account for bacterial killing and, possibly, newly synthesized gene products may be necessary. The nature of the gene products is yet to be defined. The gene products in the RecA-SOS DNA repair and recombination system, the expression which is known to be induced by damage to bacterial DNA caused by quinolones, appears to function, at least in part, to repair quinolone-induced DNA damage. Rec mutants with deficient function are hypersusceptible to quinolones. Many more genes or gene products are also suspected to be important. 2. Mechanism of Resistance There are two mechanisms of resistance: altered gyrase or altered drug permeation through the bacterial membrane (60,61). Alterations in the bacterial subunit A of gyrase (point mutations) have been identified in numerous gram-positive and gram-negative strains. Single amino acid changes in the subunit B have also been identified. The resistance caused by movement of quinolones in and out of bacterial cells involves energy-dependent processes that depend on proton motive force, carrier-mediated drug efflux pumps, porin mutations, and others. The selection in vitro of both gram-positive and gram-negative bacterial variants with reduced susceptibility to the quinolones has occurred after serial exposure of bacteria to subinhibitory drug concentrations. The resulting strains exhibit crossresistance to all quinolones. I. Resistance to Aminoglycosides The aminoglycosides are bactericidal drugs that have been in clinical use since the 1940s. Currently the most important and widely used members of this antibiotic family are gentamicin, tobramycin, and amikacin. The principal use of the aminoglycosides is against aerobic and facultative gram-negative bacilli. They frequently are used in combination with -lactam agents against life-threatening gram-negative infections, gram-negative infections in the immunocompromised host, and in Pseudomonas spp infections. They do not possess clinically useful activity against gram-positive organisms when used alone; however, these antibiotics act synergistically with a number of cell wall-active antibiotics (the penicillins, cephalosporins, and glycopeptides) against a number of gram-positive bacteria such as S. aureus, coagulase-negative staphylococci, group B streptococci, enterococci, and Listeria monocytogenes. The aminoglycosides must be administered parenterally. They are usually given intravenously, but absorption after intramuscular injection is excellent. Absorption through the gastrointestinal tract is minimal, although toxicity may occur if oral dosing is continued over a long period. The drugs have low protein binding

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(approximately 10%), but are charged at physiologic pH and are water soluble. As such, they distribute primarily to the intravascular and interstitial spaces and cross biological membranes poorly, with a volume of distribution of 0.2 to 0.3 L/kg. This distribution has clinically relevant ramifications. For example, the drugs penetrate poorly in bronchial secretions, and some have advocated the use of aerosolized aminoglycosides in the setting of severe pneumonia. The drug is excreted by the kidneys and concentrations in the urine exceed peak serum concentrations by 25- to 100-fold. 1. Mechanism of Action All aminoglycosides possess a six-member ring with an amino-group substituent (called aminocyclitol). The drugs bind to the bacterial surface, and their entry into the microorganisms results in some disruption of the lipopolysaccharide in the cell wall. However, the principal mechanism of antibiotic activity is the binding to the interface of the 30S and 50S ribosomal subunits. This binding leads to instability of the polysome and subsequent interruption in translation of messenger RNA. 2. Mechanism of Resistance Resistance to aminoglycosides is a well-established, worldwide phenomenon. Almost all resistant clinical isolates elaborate one of three enzymes, namely, aminoglycoside acetyltransferase, adenlytransferase, or phosphorylase (63). Each enzyme results in a modification of the aminoglycoside resulting in poor ribosomal binding. Some resistant clinical isolates have been identified that have decreased aminoglycoside uptake (63). Virtually all aminoglycosides share the same pattern of toxicity, namely, renal toxicity and ototoxicity. Renal toxicity usually is manifested as an elevation in serum creatinine, but acute oliguric renal failure can occur. Nephrotoxicity among children and young, healthy adults is uncommon. However, older patients, particularly those with underlying renal disease, and those given other nephrotoxic drugs concomitantly, are particularly predisposed to aminoglycoside nephrotoxicity. With regard to ototoxicity, both cochlear and vestibular toxicity occur and may be irreversible. Rarely, aminoglycosides administration can result in neuromuscular blockade from inhibition of presynaptic release of acetylcholine; the incidence of this complication is increased in intensely ill patients receiving neuromuscular blocking agents, such as pancuronium. J. Resistance to Glycopeptides The glycopeptide family is composed of two antibiotics, namely, vancomycin and teicoplanin. In the United States, currently only vancomycin is available.

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Vancomycin is bactericidal against a very broad variety of gram-positive organisms: gram-positive cocci and bacilli, and both aerobes and anaerobes. The drug is particularly useful in the treatment of MRSA and in gram-positive infections in which the organism has acquired resistance to the -lactam agents. Like the -lactam antibiotics, vancomycin exerts its effect by interrupting peptidoglycan synthesis, but at a step proximate to that involved with the penicillins and cephalosporins. The drug binds to a peptidoglycan precursor during an early reaction, leading to poor integrity of the cell wall and ultimately to bacterial swelling and breakdown. Until recently, acquired resistance to vancomycin was rare. Resistance to vancomycin by enterococci in LTCFs has emerged (64–67). This resistant phenotype is carried on a transposon containing multiple genes; together, these genes enable the organism to produce a peptidoglycan of altered biochemical structure, which is sufficient to maintain the bacteria, but which binds poorly to vancomycin.

III. CONCLUSIONS AND PROSPECTS FOR NOVEL DRUGS New antibiotics are being developed. The problem of resistant gram-positive infections (VRE, MRSA, PRP) in hospitals is accelerating the pace of new drug discovery. To that end, the newest antimicrobials being use are streptogramins, glycylcyclines (see above), and oxazolidinones (see Chapter 11) Streptogramins are members of the MLS group of antibiotics (see macrolides-lincosamides-streptogramins, above). Streptogramins act on the ribosomal level to inhibit protein synthesis. The most recent MLS released is Synercid® (combination drug, quinupristin and dalfopristin in a 30:70 tratio). Dalfopristin binds to the 50S ribosome causing a persistent conformational change. It also increases the binding affinity for quinupristin. Quinupristin prevents the extension of the peptide chain and causes incomplete chains to be released. It also inhibits peptide bond elongation. Together, there is a dual block in protein synthesis. Synercid is active against gram-positive bacteria. It is targeted against VRE, specifically vancomycin-resistant E. faecium. Resistance to Synercid has occurred by modifying the ribosomal binding site, enzymatic inactivation, and adenosine triphosphate (ATP)-driven efflux pump. Linezolid, an oxazolidinone, is also targeted against VRE. It is bacteriostatic against MRSA, penicillin-resistant pneumococci, and VRE. Site of action is the ribosome, inhibiting the formation of a functional initiation complex. This drug can be administered orally and by the intravenous route and is highly effective against VRE and other resistant gram positives. Multiple drug-drug interactions are possible, but the drug has been used safely. Unfortunately, resistance to linezolid has emerged (65).

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22 Methicillin-Resistant Staphylococcus aureus Larry J. Strausbaugh Portland VA Medical Center, and Oregon Health Sciences University School of Medicine, Portland, Oregon

I. INTRODUCTION Methicillin-resistant Staphylococcus aureus (MRSA) is defined by minimum inhibitory concentrations (MIC) of methicillin of 16 g/ml or more or oxacillin 4 g/ml or more (1). Strains of MRSA possess the mecA gene (1,2). This chromosomal gene encodes an altered enzyme, termed penicillin-binding protein 2a (or PBP 2), which has a low affinity for all beta-lactam antibiotics. This feature, presumably, allows the enzyme to perform essential functions in construction of the gram-positive cell wall, even in the presence of methicillin and other beta-lactam antibiotics. As a rule, strains of MRSA also possess resistance determinants for many other antimicrobial agents; in fact, until recently, only vancomycin provided reliable therapy for serious infections caused by this organism. This extraordinary level of resistance combined with the inherent virulence of S. aureus accounts for the level of interest and concern generated by MRSA. Strains of MRSA emerged soon after methicillin became commercially available in the early 1960s (2,3). They became increasingly prevalent in the United States in the late 1970s, appearing initially in tertiary care hospitals and disseminating subsequently to smaller facilities and other settings (2,4). By the year 2000, MRSA strains accounted for 53% of all S. aureus clinical isolates obtained from patients with nosocomial infections that were acquired in U.S. intensive care units (5). As MRSA became more prevalent in acute care settings, the continual interchange of patients between hospitals and long-term care facilities (LTCFs) ensured their spread into the latter. The first report of MRSA in a U.S. 383

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nursing home appeared in 1970 (6); however, strains of MRSA remained uncommon in this setting for the next 15 years. Accordingly, this chapter largely focuses on the U.S. experience reported since 1985.

II. EPIDEMIOLOGY AND CLINICAL RELEVANCE A. State and Regional Surveys Surveys conducted in Minnesota (7), western New York (8), and Oregon (9) more than a decade ago indicated that MRSA had spread to many LTCFs in those areas (Table 1). Of the 48 LTCFs—12% of respondents—reporting MRSA cases in the Minnesota survey, four indicated that it was a problem, and 33 (69%) indicated that they had sought help or consultation to manage the issue. In the New York survey, 81% of responding LTCFs acknowledged caring for an MRSA case in the previous year, and 16 (27%) of 59 facilities reporting MRSA cases acknowledged an infection control problem with this bacterium. Results of the Oregon survey offered temporal and quantitative observations on the emergence of MRSA in LTCFs (9). None of the 109 reporting facilities had cases in 1985. One had cases in 1986, three in 1987, 11 in 1988, and 34 in 1989. During the same period, the total number of LTCF residents with MRSA in the reporting facilities increased annually from 21 in 1986 to 156 in 1989. Thus, from 1985 through 1989 both the number of facilities with MRSA cases and the total MRSA caseload in LTCFs increased steadily. Larger facilities were more likely to report MRSA cases: in 1989, 79% of LTCFs with MRSA cases had more than 50 beds. B. Frequency of MRSA Colonization Prevalence surveys that target both infected and colonized residents offer the most comprehensive assessment of MRSA infiltration into LTCFs because the ratio of

Table 1 Results of Three State or Regional Surveys for MRSA in LTCFs Site (reference) Minnesota (7) Eight counties in western New York (8) Oregon (9)

Year of survey

No. LTCFs surveyed

Percent responding

Percent reporting MRSA cases

1989 1990

445 81

88 93

12 81

1990

192

57

31

Abbreviations: MRSA, Methicillin-resistant Staphylococcus aureus; LTCFs, Long-term care facilities.

MRSA

385

colonized residents to infected residents generally exceeds 20 to 1 (4). Counting only infected residents underestimates the magnitude of a facility’s MRSA burden. Colonization denotes asymptomatic persons who harbor MRSA at some body site, for example, the anterior nares (10). Detection requires bacterial cultures of the colonized site. In contrast, infected individuals have symptoms and signs of disease with positive cultures from the affected site. Rates of MRSA colonization in LTCFs have ranged from 5% to 34% in prevalence studies (11–21) reported from facilities in nine states (Table 2). These studies have detected nasal carriage most frequently, but rectal, perineal, wound,

Table 2 Prevalence of MRSA in LTCFs*

Ref.

LTCF location

Study period

No. beds (LTCF type)

% Residents colonized with MRSA

11

St. Louis, MO

3/85

182 (Comm NH)

12

12

Los Angeles, CA

5/87 & 8/87

170 (Comm NH)

7.3 & 6.0

13

Pittsburgh, PA

1/86–12/88

432 (VA NHCU)

13.1

14

Vancouver, WA

3/89

120 (VA NHCU)

34

15

Chicago, IL

8/88–11/89

150 (Comm NH)

4.9 to 15.6

16

Ann Arbor, MI

6/89–5/90

120 (VA NHCU)

23 1.0 (mean monthly rate)

17

Baltimore, MD

1/89–1/90

233 (Comm NH)

22

Comment Nasal cultures of 74 residents; 7% of nursing home staff colonized Nasal and wound cultures from all residents on two separate occasions; 3.4% and 2.3% of staff colonized 981 total nasal cultures (obtained at monthly & bimonthly intervals); 32 residents persistently colonized Nasal and wound cultures from all residents; 7% of staff colonized Eight facility-wide nasal culture surveys over 15 months; overall 8.7% of 994 nasal cultures positive for MRSA Monthly cultures of nose, perineum, rectum, and wounds; 25% of residents colonized on admission; only 10% of newly admitted patients acquired MRSA Cultures of nares, pressure sores, ostomy sites, urine, and sputum; 25% of new admissions in 4 months after prevalence survey found to be MRSA colonized (continued)

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Table 2 (Continued)

Ref.

LTCF location

Study period

No. beds (LTCF type)

% Residents colonized with MRSA 22.7 1.0 (year one) 11.5 1.8 (year two) (mean monthly rate) 27.3 (VA NHCU) 8.1 (3 Comm NHs)

18

Ann Arbor, MI

6/89–5/91

120 (VA NHCU)

19

Durham, NC

12/91–1/92

120–125 beds (one VA and three Comm NHs)

20

Orange County, CA

1990–1992 (20 months)

149 (Comm NH)

7.5 (cumulative during study period)

21

Orange County, CA

1993–1994 (12 months)

149 (Comm NH)

9.7 (overall mean)

Comment Monthly cultures of nose, perineum, rectum, and wounds; mupirocin intervention introduced in year two

Nasal cultures performed on all consenting residents; differences between VA NHCU and three community nursing homes persisted over time Cultures of nares and rectum obtained quarterly over 20 months; 4.1% of nares and 2.5% of rectal cultures positive for MRSA; 3.8% of new admissions colonized Cultures of nares and rectum obtained on admission and quarterly; overall 35% of residents colonized at least once with Staphylococcus aureus—72% with MSSA and 25% with MRSA; 13% of carriers detected only with rectal cultures

Abbreviations: VA, Veterans Affairs; NHCU, Nursing Home Care Unit; Comm, Community; NH, Nursing home; MSSA, Methicillin-susceptible S. aureus; MRSA, Methicillin-resistant S. aureus; LTCF, Long-term care facility.

urine, and sputum cultures occasionally yielded MRSA. Although Veterans Affairs (VA) facilities often have higher colonization rates than community nursing homes, considerable overlap is noted. In the only direct comparison, MRSA colonization rates in a VA facility were three times higher than those in three community nursing homes (19). Whether this difference reflects unique features of the VA facilities, for instance, higher percentages of male residents or close affiliations with academic medical centers, or other factors remains unclear. Three prevalence studies reported MRSA colonization rates in LTCF healthcare workers ranging from 2.3% to 7% (Table 2). As in other healthcare settings, colonized workers serve as both reservoir and vector for MRSA (1–4,10).

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A number of other reports attest to the frequent presence of MRSA in nursing homes and other kinds of LTCFs. Three observational studies in two Chicago community hospitals during the period 1984 to 1986 indicated overall that 76 (49%) of 155 patients with S. aureus isolates admitted from 25 nursing homes had MRSA (22). In contrast, only 13% of S. aureus isolates obtained from persons admitted from the community were MRSA. In a study of the emergence of ciprofloxacin-resistant MRSA in New York healthcare facilities, 14 patients harboring this strain resided in nursing homes (23). Similarly, 12 of 43 hospitalized patients from whom this strain was isolated had been admitted from nursing homes. In vitro susceptibility studies on 301 isolates of S. aureus obtained from more than 100 nursing homes in Oklahoma disclosed that 70% were resistant to methicillin (24). A microbiological survey of residents in 25 Nebraska LTCFs recovered 91 strains of S. aureus, of which 43% were MRSA (25). A pediatric LTCF in Kentucky reported detection of 18 MRSA-colonized children during one 6-month period (26). One brief report mentions MRSA outbreaks in Canadian LTCFs (27). A retrospective study from Edinburgh indicated that 9.8% of 204 new admissions to an acute geriatric assessment and rehabilitation ward were MRSA positive (28). Finally, one older report describes MRSA colonization and infection in a rehabilitation facility. During the period October 1977 to May 1980, 84 colonizations or infections occurred in 81 residents of a 600-bed rehabilitation hospital in Los Angeles (29). C. Introduction of MRSA into LTCFs New residents who are already colonized or infected with MRSA bring this organism into LTCFs at the time of their admission and serve as the initial reservoir (10,14). Asymptomatic residents transferred directly from acute care facilities where MRSA strains are prevalent probably account for most of this spread. Screening cultures in various types of facilities have indicated that 2% to 25% of new residents harbor this organism in their nose or at some other body site (15–17,20). D. Natural History of MRSA in LTCFs Once it has entered an LTCF, MRSA tends to spread and persist. Spread may be dramatic. For example, 15 months after the introduction of MRSA into a VA Nursing Home Care Unit (NHCU) in Vancouver, WA, a prevalence survey indicated that 34% of residents and 7% of staff were colonized with the outbreak strain (14). A nasal prevalence study conducted almost 3 years later indicated that 10% of the facility’s residents remained colonized (30). Serial prevalence studies in other LTCFs also testify to MRSA’s persistence in this environment (13,15,16, 18,20–22). Individual residents may remain colonized for months to years.

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An outbreak of symptomatic disease has signaled the arrival of MRSA in some facilities. For example, the transfer of five patients with MRSA pneumonia during a 1-week period in 1985 brought the problem to attention in one St. Louis area nursing home (11). These cases followed in the wake of a community-wide outbreak of influenza A. A prevalence survey later indicated that 12% of the facility’s residents were colonized with MRSA. E. Transmission of MRSA As in other healthcare settings, colonized or infected residents and colonized staff constitute the reservoir for MRSA (2,4,10,31–34). Person-to-person spread accounts for most transmission, and direct contact of residents with the hands of transiently colonized healthcare workers probably represents the principal mode of acquisition (31–34). Although uncommon, hand carriage of MRSA by healthcare workers has been documented in LTCFs (35,36). Resident-to-resident transmission may also occur. In a 1-year prevalence study, nine residents—approximately 25% of residents acquiring MRSA in the facility that year—became colonized with the same phage type as their roommate (16). In that situation, direct contact with the roommate or indirect contact with contaminated objects in the environment or colonized healthcare workers represents the likely means of spread. Of note, only 3% of the 258 residents at risk became colonized with MRSA during that year. Environmental contamination with MRSA has been documented in LTCFs (16,34,37), but its role in transmission remains undefined. It is not known how frequently resident contacts with MRSA lead to prolonged colonization, but carriage rates in LTCFs suggest that it occurs commonly. F. Infection Caused by MRSA Eight studies of more than 1-year’s duration (11,13,18,19,20,21,29,38) have described 125 MRSA infections in LTCF residents (Table 3). Skin and soft tissue infections, urinary tract infections, and respiratory tract infections accounted for at least 46, 25, and 20 of these infections, respectively. Because these three types of infections predominate in LTCFs (39), MRSA’s involvement is not unexpected. Like methicillin-susceptible S. aureus (MSSA) in LTCFs, MRSA causes skin and soft tissue infections with greater frequency than any other types of infections (21,38). In the eight studies (Table 3), bacteremia complicated at least nine infections, and at least four patients succumbed to their infections. The care of at least 27 of these patients required transfers to hospital. Generally, MRSA infections arise in residents who have been colonized for various lengths of time. The risk of colonized residents developing infection varies considerably and depends to some extent on comorbid conditions such as

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Table 3 MRSA Infections in LTCFs

Ref.

Facility (mos of study)

Types of Total no. MRSA infections MRSA infections SSTI UTI RTI Other

29

Rehab. Hosp (32)

28

15

11

0

2

11

Com NH (13)

17

3

2

12

0

13

VA NHCU (24) VA INCU (30)

15

VA NHCU (60)

28

38

Not stated

15

5

5

3

Comments on rates and complications Prospective surveillance on all wards; 56 colonized residents also detected; one bacteremia Retrospective and prospective surveillance; 5 pneumonias associated with influenza outbreak; no bacteremias; one death 25% of persistent carriers of MRSA carriers had episode of staphylococcal infections, compared with 4% of persistent MSSA carriers and 4.5% of noncarriers; rate of development of infection among MRSA carriers: 15% for every 100 days of carriage; high percentage of infections in dialysis patients Incidence of MRSA infection ranged from 0.07 to 0.32 cases per 1000 resident care days; incidence of MSSA infection ranged from 0.15 to 0.29 cases per 1000 resident care days; 3 bacteremias; 12 MRSA infections required transfer to hospital; 3 MRSA infections were fatal (continued)

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Table 3 (Continued)

Ref.

Facility (mos of study)

Types of Total no. MRSA infections MRSA infections SSTI UTI RTI Other

18

VA NHCU (24)

15

8

NS

NS

7

19

VA NHCU and 3 Com NHs (12)

8

1

2

1

4

20

Com NH (20)

12

5

6

1

0

21

Com NH (12)

14

4

5

2

3

Comments on rates and complications MRSA carriage rates averaged 11% to 22% during study period; MRSA accounted for less than 5% of LTCF infections; mupirocin intervention in year 2; 2 bacteremias; 10 hospitalizations; no deaths 3 bacteremias; risk of infection 6.4 times higher in those previously colonized with MRSA; rates of infection not different between VA and 3 community nursing homes 7% of 15 colonized newly admitted residents and 5% of in house colonized residents developed infection No hospitalizations; bacteremias not mentioned; 15 MSSA infections during study period; patients colonized with MRSA not more likely to develop infection than MSSA colonized residents

Abbreviations: MRSA, Methicillin-resistant Staphylococcus aureus; LTCF, Long-term care facility; SSTI, Skin and soft tissue infection; UTI, Urinary tract infection; RTI, Respiratory tract infection; Com NH, Community nursing home; VA, Veterans Affairs; NHCU, Nursing home care unit; INCU, Intermediate care unit; MSSA, Methicillin-sensitive Staphylococcus aureus.

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pressure ulcers and influenza. Three studies in VA facilities have addressed this risk in different ways. In one report, the highest estimates of infection in MRSAcolonized residents found that 25% of 32 persistently colonized residents developed staphylococcal infections (13). In contrast, only 4% of residents persistently colonized with MSSA and 4.5% of residents not colonized with S. aureus became infected. Thus, in this study, persistent colonization with MRSA carried a significantly greater risk of subsequent infection. The high frequency of infection in residents in the intermediate nursing care unit who had higher rates of chronic obstructive pulmonary disease and chronic renal failure requiring dialysis may have accounted for the higher rates of infection (40). Other VA studies have reported much lower percentages of infection in MRSA-colonized individuals. For example, in a 1-year study, only 3% of 341 patients at risk developed MRSA infection even though MRSA carriage rates exceeded 20% (16). In a 5-year study, the overall rate for S. aureus infections remained fairly stable after the introduction of MRSA into the facility during year 2, even though 34% of residents became colonized with MRSA (38). Annual rates for all S. aureus infections ranged from 0.29 to 0.47 infections per 1000 resident care days over the entire period. The percentage of infections caused by MRSA increased over time, but the overall percentage of infections caused by S. aureus remained in the narrow 13% to 17% range. Moreover, infection rates for the entire facility remained steady. In another recent study, the risk of infection in MRSA-colonized residents in one VA facility and three community nursing homes was 6.4 times (95% confidence interval (CI), 2.3 to 18.0) greater in residents colonized at baseline (19). No statistically significant increased risk in the VA facility was detected. However, the risk of infection in MRSA-colonized residents in the three community nursing homes was 15 times (95% CI, 13.3 to 73.3) that seen in noncolonized residents. The rates of MRSA infection in the VA facility and three community nursing homes did not differ significantly in the 1-year of study, even though colonization rates were higher in the former. Of note, the 0.16 and 0.12 per 1000 resident care-day MRSA infection rates observed in the VA and three community nursing homes, respectively, were similar in magnitude to those previously reported (38). Finally, a study of both MSSA and MRSA infections in a community skilled nursing facility over the course of a year noted that MRSA infections arose in previously colonized individuals at the same rate that MSSA infections arose in previously colonized individuals (21). In this study, MRSA and MSSA infection rates approximated one another—0.27 and 0.29 infections per 1000 resident care days, respectively. In sum, MRSA infections usually arise in colonized residents, but only a small percentage of colonized residents become infected. Infections caused by MRSA in LTCFs are similar to those caused by MSSA in this environment. Unlike other common bacterial pathogens in LTCFs, they cause skin and soft tissue infections with greater frequency than urinary or respiratory tract infections.

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G. Risk Factors for Colonization and Infection by MRSA in LTCFs Risk factors for MRSA colonization and infection in LTCFs mirror those associated with other antimicrobial-resistant bacteria (10). In general terms, these include poor functional status, conditions that cause skin breakdown, presence of invasive devices, prior antimicrobial therapy, and a history of antecedent colonization. Studies using multivariate analysis have identified the following specific risk factors for MRSA colonization in LTCFs: male gender (17); urinary incontinence (17); fecal incontinence (19); presence of wounds (18), pressure ulcers (17–19); nasogastric intubation (12); antibiotic therapy (12); and hospitalization within previous 6 months (19). Studies using only univariate analysis have identified similar putative risk factors for MRSA colonization in LTCFs: bedridden or chair/bed confined status (15), poor functional status (16), pressure ulcers (15), feeding tubes (15), urinary catheters (15), prior LTCF-associated infections (20), and therapy with nonquinolone antimicrobial agent in prior 3 months (20). Only two VA studies have examined risk factors for MRSA infection in LTCFs. Using stepwise logistic regression analysis, one study found persistent MRSA colonization and dialysis to be significantly associated with infection with odds ratios (ORs) of 5.9 (95% CI, 2.2–15) and 4.7 (95% CI, 1.8–12), respectively. Another study used similar methods and identified diabetes mellitus (OR 5.1; 95% CI, 2.1–18.6) and peripheral vascular disease (OR 4.3; 95% CI, 1.3–14.3) as risk factors for MRSA infection (18).

III. CLINICAL MANIFESTATIONS A. Syndromes and Pathogenesis Methicillin-resistant Staphylococcus aureus and MSSA appear to have equivalent virulence for humans (1–4). Accordingly, the kinds of infections caused by MRSA and their clinical features are virtually identical to those caused by MSSA. In the 5-year experience of one VA facility (38), there was no significant correlation between the site of infection and the methicillin susceptibility of the infecting strain of S. aureus. In that study, which compared all MRSA and MSSA infections, skin and soft tissue infections (including conjunctivitis and otitis externa) accounted for 38% of all staphylococcal infections. Pneumonia accounted for 30% of staphylococcal infections, and urinary tract infections for 25%. Staphylococcus aureus on cutaneous surfaces combined with breeches in the integrity of skin and mucous membranes likely give rise to skin and soft tissue infections, which may include: cellulitis, surgical site and other wound infections,

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bursitis, perianal and skin abscesses, infected pressure sores, infected leg ulcers, and paronychia (38). Nasal colonization in association with aspiration probably contributes to the development of pneumonia. Staphylococcus aureus on perineal skin or genital membranes and the presence of indwelling urinary catheters likely predisposes LTCF residents to staphylococcal urinary tract infections. Both MRSA and MSSA can invade the bloodstream and give rise to distant site infections such as arthritis, endocarditis, osteomyelitis, visceral abscesses, and others. Bacteremias and distant site infections account for a small percentage of staphylococcal infections in LTCF residents (18,38). In some cases, bone and joint involvement may result from local invasion, for example contiguous spread from infected pressure ulcers. B. Clinical Features The manifestations of various infectious syndromes caused by MRSA in LTCF residents are similar to those caused by other pyogenic bacteria. For example, residents with cutaneous abscesses usually exhibit fever and varying degrees of redness, swelling, warmth, and tenderness surrounding the abscess. Residents with pneumonia generally manifest fever in association with respiratory symptoms such as cough and shortness of breath. Likewise, residents with MRSA urinary tract infections characteristically exhibit fever and local symptoms such as dysuria, frequency, urgency, and suprapubic pain. Residents with MRSA conjunctivitis exhibit inflamed conjunctivae and purulent discharge (41). Notwithstanding these generalities, elderly nursing home residents often have atypical presentations for MRSA infections as they do for those caused by other etiological agents. Local and systemic inflammatory response may be diminished, resulting in decreased temperature elevations and blunting of local manifestations (39,42). Neurological deficits and cognitive impairment, which are common in elderly nursing home residents, may also obscure symptoms and signs of MRSA and other types of infection. Accordingly, LTCF practitioners maintain a high index of suspicion for infection and subtle signs, such as minor changes in mental or functional status, as possible indicators of MRSA and other types of infections.

IV. DIAGNOSTIC APPROACH A. Recognition and Delineation of Clinical Syndrome Methicillin-resistant Staphylococcus aureus-infected LTCF residents come to clinical attention in the usual ways. Reports from nursing staff about temperature elevation or other alteration in vital signs often prompt evaluation, as do those that

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describe specific symptoms or signs of infection. Diminished cognitive function and inability to perform usual activities of daily living (ADLs) also bring patients to clinical attention (42). Often the resident’s history and a limited physical examination disclose the presence of MRSA infection. For example, residents with a new cough, tachypnea, and rales over one lung field probably have pneumonia. Pneumonia caused by MRSA enters the differential diagnosis from the outset in known carriers and in facilities with high rates of colonization or infection. Similarly, the resident with a colonized pressure ulcer who develops fever and redness, swelling, and tenderness extending out from the margins of the ulcer likely has an MRSA secondary infection of that site. The use of laboratory tests, radiography, and other ancillary procedures in the diagnosis of MRSA infections conforms to current guidelines (42). Leukocytosis, infiltrates on chest radiographs, pyuria, and bacteriuria (especially in uncatheterized residents), and meaningful Gram stain results from respiratory secretions or cutaneous exudates, all help to define syndromic diagnoses. B. Etiological Diagnosis On Gram-stained smears, both MSSA and MRSA appear as gram-positive cocci, often in clumps, or grape-like clusters. Gram-stain findings do not distinguish the two. Strains of both bacteria grow easily on most nonselective media, such as, blood agar, yielding white to yellowish colonies within a day or less (1). Rapid tests for coagulase production readily distinguish S. aureus from other species of Staphylococcus (43). Distinguishing MRSA from MSSA usually requires antimicrobial susceptibility tests, which typically necessitate a second day for completion. Therefore, isolation of MRSA strains generally requires 36 to 48 hours. Some clinical laboratories offer faster service by identifying MRSA strains with gene probes that detect mecA (43). The etiologic diagnosis awaits finalization of culture results and their interpretation in the context of the resident’s illness and course. Isolation of MRSA from the blood cultures of symptomatic residents virtually always indicates MRSA infection, whereas isolation from respiratory secretions, cutaneous exudates, and urine require interpretation to distinguish colonization from infection. In residents with strong clinical evidence for a specific infectious syndrome, isolation of MRSA in pure culture often solidifies the etiologic diagnosis, especially when Gram-stain results indicate that the bacterium is present in large numbers. Isolation of MRSA with other potential pathogens in the same culture and isolation of MRSA from a site not clearly involved by an infectious process, for example, from urine in a catheterized resident with no genitourinary symptoms, provoke the greatest diagnostic uncertainty. Nevertheless, from a therapeutic standpoint, few practitioners can dismiss such isolates obtained from symptomatic residents because MRSA may be an etiological participant.

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V. THERAPEUTIC INTERVENTIONS A. Vancomycin The glycopeptide antibiotic, vancomycin, is the drug of choice for serious MRSA infections. Most strains of MRSA and MSSA are inhibited by concentrations less than 4 g/ml. A few reports have described strains of MRSA with decreased susceptibility to vancomycin (MICs 4 but 16 g/ml), but they remain rare (44). In patients with normal renal function, vancomycin is administered intravenously in a dose of 1.0 g every 12 hours (45). Patients with renal insufficiency require dosage modifications. Many clinicians measure peak and trough serum concentrations at least once during therapy, aiming to keep peak concentrations less than 50 g/ml and trough concentrations in the 5 to 10 g/ml range. Treatment courses for most MRSA infections generally range from 10 to 14 days; however, endocarditis and osteomyelitis necessitate treatment courses of 4 to 6 weeks’ duration. In the past, the need for intravenous vancomycin therapy and monitoring necessitated transfer of MRSA-infected residents to hospital. Now, many nursing homes can manage these requirements. Adverse reactions include fever, chills, and phlebitis at the infusion site, which slow infusion rates may prevent. Slow infusion rates also prevent the “red-man” syndrome. Rash, other allergic manifestations, leukopenia, thrombocytopenia, and eosinophilia are occasionally observed but resolve when vancomycin is discontinued. Ototoxicity, the most worrisome side effect, occurs infrequently when serum concentrations are kept below 30 g/ml (45). In the past, vancomycin was thought to be highly nephrotoxic. This is not the case with current preparations, but vancomycin can potentiate the nephrotoxicity of aminoglycoside antibiotics when used concurrently with them. B. Linezolid Since 2000, linezolid, an oxazolidinone derivative, has offered an alternative to vancomycin for MRSA infections. Concentrations of 4 g/ml inhibit most clinical isolates of MRSA (46). Oral or intravenous doses of 400 mg or 600 mg administered every 12 hours produce serum concentrations that range from 4 to 25 g/ml throughout the dosing interval (47). Orally administered preparations offer an apparent advantage for treating infections in LTCFs, but experience is limited. To date, few adverse reactions have complicated linezolid therapy. Diarrhea, nausea, and headache have occurred in less than 3% of recipients (46). Leukopenia, abnormal liver function tests, and rash have occurred less frequently (see Chapter 11). Limited clinical observations have indicated that linezolid offers effective therapy for staphylococcal and enterococcal infections (46,48). In a randomized, double-blind, controlled trial conducted in patients with nosocomial pneumonia, results with linezolid compared favorably to those with vancomycin (49). Specifically, linezolid therapy eradicated MRSA in 15 (65%) of 23 infections and van-

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comycin eradicated MRSA in 7 (78%) of 9 infections. Notwithstanding these results, linezolid’s limited track record dictates that vancomycin remain the drug of choice. However, linezolid has considerable promise. Its use will increase as optimal circumstances and indications for treatment of MRSA infections in LTCFs become delineated. C. Other Systemic Antimicrobial Agents In vitro susceptibility tests sometimes suggest that cephalosporin antibiotics possess inhibitory activity against MRSA, but clinical failures have attended their use (50). They should not be used. Ciprofloxacin once appeared to have therapeutic promise for MRSA; however, resistance has become widespread (37). The combination of quinupristin and dalfopristin, which is marketed as Synercid®, may offer another therapeutic alternative for MRSA infections, but experience is limited (45). Strains of MRSA possess resistance to virtually all other antimicrobial agents except rifampin, trimethoprim-sulfamethoxazole, minocycline, and clindamycin. These agents have occasionally been used in efforts to eradicate colonization, and in the treatment of less serious MRSA infections or in follow-up to vancomycin therapy when oral therapy was desired (31,32,37,51). Such uses have been successful, but resistance can emerge rapidly, and this problem has greatly limited their use for MRSA. D. Topical Agents For the most part, topical agents have no role in the treatment of MRSA infections. Occasionally, however, patients with superficial MRSA skin infections who lack systemic symptoms or signs may benefit from topical therapy with mupirocin ointment (52). Mupirocin also has been used to eradicate colonization of residents in LTCFs and other settings (31,32,52–55). Over the years, therapeutic efforts to eradicate MRSA nasal colonization in asymptomatic carriers—decolonization therapy—have involved other topical agents, such as bacitracin ointment, neomycin, vancomycin, and gentamicin, but none have proved consistently efficacious (31,52). Similarly, efforts to eliminate MRSA from the skin have included skin cleaning agents containing chlorhexidine, hexachlorophene, triclosan, and povidone iodine (31,55). Their efficacy in decolonization regimens remains unproven. E. Role of Drainage, Debridement, and Other Surgical Procedures Cure of MRSA and MSSA infections associated with abscesses, devitalized tissue, and closed spaces, such as, joints or pleural cavity, usually requires drainage

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or debridement (1). Abscesses, depending on their location and size, require either drainage from percutaneously placed catheters or needles or drainage from an open surgical procedure. Repeated needle aspirations generally suffice for infected joints, except for the hip, which requires open surgical drainage. Pleural empyemas require chest tube thoracostomies and, rarely, decortication procedures. Surgical debridement is necessary to cure chronic osteomyelitis or osteomyelitis associated with peripheral vascular disease. Also, MRSA-infected arthroplasties and other infections involving prosthetic material generally necessitate removal of foreign material and surgical debridement. Management of endocarditis may require valve replacement surgery. It is apparent that management of these infections will generally require transfer to an acute care facility.

VI. INFECTION CONTROL MEASURES A. General Considerations In LTCFs, opinions about appropriate measures for controlling MRSA run the gamut from those favoring do-nothing, laissez-faire approaches on one extreme to those favoring do-everything, hospital-like approaches on the other. Unfortunately, there are virtually no controlled trials of different strategies to focus the discussion or to inform the development of policy (see Chapters 8, 9, and 10). Nevertheless, the last decade has witnessed the emergence of consensus on key principles for management of MRSA in LTCFs (Table 4). Some areas of controversy persist, but there is general agreement on the following points (10,31,33,34,56–63): 1. Virtually all LTCFs can provide good care for MRSA-colonized and infected residents without jeopardizing the well being of other residents. In a review of the literature, the author noted, “In five nursing homes where MRSA was endemic, 95 infections with 5 deaths occurred during 12 years of surveillance with 12,000 admissions” (34). Others have made similar observations regarding the safety of caring for MRSA-positive residents (64). Efforts to restrict admission of colonized or infected residents usually fail because detection of carriage can be difficult. In one LTCF study, nasal cultures failed to identify 13% of MRSA carriers (21). Restricting or delaying transfers also imposes an unnecessary burden on other sectors of the healthcare system (65). There is no evidence to suggest that screening potential admissions for MRSA and decolonizing those who are positive reduces LTCF colonization or infection rates, and this approach is not recommended (10). 2. LTCFs are not hospitals. Few facilities have more than a few private rooms for isolation. Few have laboratory resources necessary for screening. Rehabilitation and socialization needs of residents and communal activities, such as eating in dining rooms, limit use of isolation and stringent barrier precautions that are often used in hospitals. Moreover, some control measures may affect resi-

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Table 4 Infection Control Measures for Management of MRSA Colonization and Infection in LTCFs Endemic situation—few infections Surveillance From microbiology reports on established residents From hospital records of new residents or returing transfers Establish baseline rates of colonization and infection Education and communication Create awareness and alleviate fear of MRSA Emphasize importance of Standard Precautions Use of antimicrobial agents Avoid unnecessary usage Monitor for appropriateness

Precautions Standard Precautions for most residents Contact Precautions for residents whose drainage or respiratory secretions cannot be contained

Outbreak or high endemic infection rate Consultation With experienced epidemiologist from local/regional hospital or state/local health department Consultant to advice on use of measures below Enhanced surveillance Consider screening cultures of residents or staff Consider typing MRSA isolates Patient placement Consider using private rooms for MRSA cases Consider cohorting MRSA-positive residents and staff Otherwise place MRSA cases in rooms with residents who lack risk factors for colonization Other measures Consider greater use of Contact Precautions Consider (rarely) decolonization therapy

Abbreviations: MRSA, Methicillin-resistant Staphylococcus aureus; LTCF, Long-term care facility.

dents’ quality of life adversely (66). Rapid discharge of colonized residents is seldom possible. Accordingly, control strategies in LTCFs necessarily differ from those used in hospitals (10,34). 3. Prudent use of antimicrobial agents by providers plays a key role in facility management of MRSA and other antimicrobial resistant pathogens (67,68). 4. Once in LTCFs, MRSA will likely persist. Aggressive approaches after MRSA’s first appearance occasionally drive it out (69); however this result is the exception to the rule (37). 5. Long-term care facilities need to perform enough surveillance to determine their status with regard to MRSA and other antimicrobial-resistant pathogens.

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6. Judicious uses of the limited infection control resources in LTCFs necessitate distinguishing between endemic and epidemic MRSA situations as well as between MRSA colonization and infection. 7. Long-term care facility settings with predominantly endemic cases of MRSA colonization primarily require appropriate use of Standard Precautions. 8. Long-term care facility settings with MRSA outbreaks, especially those with substantial morbidity due to MRSA infections, require more stringent infection control measures in addition to Standard Precautions. B. Surveillance Knowledge of MRSA presence and prevalence requires some level of surveillance in LTCFs (see Chapter 9). For most facilities, regular scrutiny of microbiology reports and review of discharge summaries or other records for new admissions and returning transfers will suffice in nonoutbreak settings. Ordinarily, this activity falls within the purview of the infection control program, which coordinates or performs data collection and maintains records with a frequency relevant to the magnitude of the problem (70). Long-term care facilities can use this information to establish their baseline, which permits identification of outbreaks and informs decisions about control measures. Classifying MRSA cases as colonized or infected enhances all descriptions of a facility’s experience (10). Some workers in this field have advocated routine cultures of all new admissions to identify MRSA carriers (60,63), whereas others question the utility of this practice in nonoutbreak settings. Few LTCFs have the resources to perform this task. Because identification of all MRSA carriers requires multiple cultures from different sites, including the rectum, a universal screening policy is generally regarded as onerous. Finally, screening only makes sense if it dictates changes in management for MRSA-positive residents, and in most nonoutbreak settings it does not alter room assignments, precautions, or medications. In their position paper, the Society for Healthcare Epidemiology (SHEA) LongTerm Care Committee specifically recommends against this practice in nonoutbreak settings (10). C. Education and Communication In all LTCFs with MRSA or other antimicrobial-resistant pathogens, education of staff and, to some extent, residents alleviates fear about these organisms and facilitates appropriate management of colonized or infected residents (10,56–63). Periodic updates to LTCF staff using recent surveillance data help to create and maintain awareness of the issue. They may stimulate or rekindle the desire to use precautions appropriately.

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D. Antibiotic Use Physicians and other providers use a large amount of antimicrobial agents in LTCFs, and a number of surveys have indicated that much of this use is inappropriate (67,68) (see Chapter 11). Because antibiotic use predisposes to MRSA colonization (12), reducing inappropriate use may offer benefit on the individual level. It may also offer benefit on the facility level, if reducing the number of colonized residents leads to use of more narrow-spectrum agents, lessening selective pressure that favors the emergence or persistence of more resistant pathogens like MRSA. In recent years several groups have offered comprehensive guidelines for use of antimicrobial agents in LTCF residents, hoping to reduce inappropriate use and, possibly, selection pressure (67,71). E. Precautions Standard Precautions, which combine elements of Universal Precautions and Body Substance Isolation, entered the world of medicine with publication of the 1996 Guideline for Isolation Precautions in Hospitals by the Hospital Infection Control Practices Advisory Committee (72) (see Chapter 8). Standard Precautions embodies the concept that all patients and all patient specimens should be handled as if they were infectious, capable of transmitting disease. They would seem ideal for prevention of MRSA transmission, which almost exclusively involves personto-person spread by direct contact and often involves contact between healthcare workers and asymptomatic carriers (31–33). They emphasize hand washing after direct contact with patients and potentially infectious material, especially between contacts with different patients. Standard Precautions also dictates use of gloves, masks, eye protection, and gowns when necessary to prevent contact between infectious material and the healthcare worker. When used appropriately and consistently, these measures should interrupt transmission from one resident to another by the transiently contaminated hands of healthcare workers. The additional value of using antimicrobial soaps remains unclear (31). Hand-cleansing agents offer an alternative to soap and water (73). The position paper from the SHEA Long-Term-Care Committee (10) recommends that “Routine precautions in LTCFs include adequate sinks, education, and incentives to ensure good hand-washing practices throughout the facility at all times . . . and adequate supplies and education to ensure that appropriate barrier precautions are used in the management of all wounds and invasive devices.” Attention to these considerations facilitates the use of Standard Precautions in LTCFs. In nonoutbreak settings, most residents colonized or infected with MRSA do not require use of additional precautions in their care. Moreover, as long as they do not have large wounds or other lesions that cannot be contained by dressings or tracheostomies with excessive secretions, most authorities would not limit their movement within the LTCF or their participation in LTCF activities (10). Never-

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theless, residents known to be colonized or infected with MRSA should not be placed in rooms with debilitated, nonambulatory residents, that is, those at greatest risk for subsequent colonization and infection. Residents with large wounds or draining lesions that cannot be contained and those with tracheostomies and difficulty handling secretions generally require a higher level of scrutiny and, often, an additional layer of precautions (10). If such residents can be linked epidemiologically to MRSA infection in other residents, then placing them in a private room or cohorting them with similar residents is prudent, as is restriction of their movement and participation in group events. In addition, Contact Precautions, which require gowns and gloves for all persons entering the room, as well as handwashing after glove removal, should be strongly considered (72). F. Outbreak Management Issues 1. Definition Fundamentally, an outbreak represents an increase in caseload that exceeds the baseline rate. The more accurate baselines reflect several years of experience and delineate an expected range of random variation. The SHEA position paper advocates defining outbreaks in terms of infections, not colonization (10). As examples, it suggests that more than three infections in a week or twice the number of infections in a month than had been observed in each of the three preceding months qualify as an outbreak. Lastly, this paper suggests that situations with high endemic rates of infection, which it defines as more than one infection per 1000 resident care days, be treated like outbreaks (see Chapter 10). 2. Consultation Once an MRSA outbreak or high endemic rate of infection is recognized, the SHEA position paper recommends consultation with an experienced epidemiologist. Hospital epidemiologists at local or regional hospitals, senior infection control practitioners, state or local health officials, and others may qualify for this role, especially if they are knowledgeable about infection control issues in LTCFs. Consulting epidemiologists can offer independent confirmation of the problem, provide an analysis of possible causes, and offer potential solutions. Ideally, they customize their approaches to the specific circumstances and needs of a given facility. As a rule, their judgments will dictate consideration of enhanced surveillance, additional isolation precautions, and decolonization efforts. 3. Enhanced Surveillance Outbreaks and high endemic rates of infection usually precipitate some discussion about culturing new admissions, established residents, or staff to identify asymptomatic carriers who might be playing a pivotal role in transmission. Costs and un-

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certainty about management of identified carriers generally discourage such screening, except in the presence of severe and protracted outbreaks. Typing of MRSA strains can solidify epidemiological links between cases and generate hypotheses about transmission. Investigations of hospital outbreaks frequently involves molecular typing methods (2); investigations of a few LTCF outbreaks also have used them (14,16,20). Cost, availability, and time issues preclude their use in most LTCF settings. Of note, antibiograms perform poorly in comparison to molecular typing methods (2,74). 4. Isolation and Cohorting In the setting of outbreaks and high endemic rates of infection, segregation of MRSA-colonized and -infected residents may diminish transmission (10,56– 58,61,62) Depending on the facility layout, segregation could involve use of single rooms for MRSA-colonized or -infected individuals, especially for those linked epidemiologically to other cases and those likely shedding large numbers of bacteria (from large, uncovered wounds, for example). Although disruptive, cohorting MRSA-colonized and -infected residents and, possibly, colonized staff may protect susceptible residents from additional exposure. When private rooms and cohorting fail to provide adequate segregation, placing MRSA cases in rooms occupied by healthier individuals without risk factors for colonization or infection may limit transmission. Control of outbreaks and reduction of high endemic rates may also require limiting admissions, restricting movement of MRSA-positive residents, and selective use of Contact Precautions (72). Because these actions disrupt the functioning of most LTCFs and cause considerable hardship for residents, their use requires sufficient provocation and justification. Individual facilities should modify or adjust the use of such measures to their specific circumstances. 5. Decolonization Because a large percentage of MRSA infections arise in colonized individuals (13,75,76), various investigators have attempted to eradicate the carrier state with antimicrobial therapy. If successful, this therapy would reduce an individual’s risk of infection and diminish a facility’s reservoir of MRSA. Unfortunately, when used to quell outbreaks or reduce high endemic rates of colonization in LTCFs or hospitals, the combined use of several different control measures has obscured evaluation of decolonization therapy, per se (2,10,11,18,26,31,37,54,69). Consequently, the concept of decolonization lacks supporting evidence of efficacy. There are several other problematic considerations. First, decolonization is not always successful; it frequently fails in debilitated patients with significant underlying disease, especially in those with open wounds or invasive devices (2,37,51,53–55). Paradoxically, decolonization often fails in those who have the

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greatest risk of infection. Second, use of various agents in decolonization regimens invariably induces resistance to the agents used. For example, in one study using rifampin-containing regimens, rifampin-resistant isolates were recovered from 80% of the 20 residents who remained persistently colonized or became recolonized with MRSA during the 30-day follow-up period (37). Likewise, during a 7-month mupirocin intervention trial in one facility, mupirocin-resistant MRSA was isolated from 10.8% of residents (54). Finally, decolonization entails considerable expense, and it exposes residents to the various toxicities of the agents used. For these reasons, routine use of decolonization therapy is not recommended in healthcare settings (32,33). Longterm care facilities should consider this strategy only in the setting of an outbreak associated with substantial morbidity, and even then, with careful monitoring by an experienced epidemiologist. In the rare circumstance when an LTCF uses a decolonization strategy, mupirocin would probably be the agent of choice. Topical application of 2% mupirocin ointment to nares for 5 days and to colonized cutaneous sites for 2 weeks will eradicate colonization in 90% of residents (1,18,52–55). However, colonization commonly recurs in 20% to 30% of residents during the weeks and months that follow treatment. Orally administered antimicrobial regimens for decolonization usually contain rifampin with or without one or two other agents (1,2,37,51). After a week of such therapy, follow-up cultures are negative in 60% to 90% of recipients. More than half will become recolonized in the weeks and months that follow. Therefore, decolonization therapy is effective in the short run, a period of 1 to 2 weeks. For a sizeable percentage of residents, however, the effect is not sustained, and resistance to the agent used appears in isolates obtained subsequently.

VII.

PREVENTION

No single measure can prevent MRSA colonization or infection. However, attention to several basic principles will likely minimize acquisition by uncolonized residents. Prudent use of antimicrobial therapy, avoidance of invasive devices, such as nasogastric tubes, and efforts to prevent pressure ulcers will probably lower an individual’s risk for colonization. Consistent use of Standard Precautions and Contact Precautions, when indicated, will interrupt the cycle of transmission. All of these efforts require a knowledgeable and compliant staff, underscoring the need for education, communication, and feedback in the infection control program. Surveillance activity helps to maintain awareness and serves to identify trends that may require additional attention. Although controversial, on occasion an elective surgical procedure on an LTCF resident may prompt consideration of preoperative decolonization and prophylactic antimicrobial therapy with vancomycin (77,78). For example, known

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MRSA carriers scheduled for total hip arthroplasty may have reduced risks of postoperative surgical site infections if they receive decolonization therapy preoperatively. This same possibility applies to MSSA-colonized residents, and the results of a trial that used preoperative therapy with mupirocin to eradicate staphylococcal carriage are eagerly awaited. No formal recommendation currently supports its use (78). Using vancomycin instead of a first-generation cephalosporin antibiotic for perioperative prophylaxis may also reduce postoperative MRSA infection rates, but this approach is generally reserved for hospitals with high rates of MRSA surgical site infections (77,78). Its routine use is not recommended (78). Both the preoperative decolonization and vancomycin prophylaxis strategies await additional evidence of benefit before they can receive a firm endorsement for use as a preventive measure in LTCF residents undergoing elective surgical procedures.

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23 Vancomycin (Glycopeptide)Resistant Enterococci Lona Mody University of Michigan, and Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan

Shelly A. McNeil Dalhousie University, Halifax, Nova Scotia, Canada

Suzanne F. Bradley University of Michigan, and Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan

I. EPIDEMIOLOGY AND CLINICAL RELEVANCE A. The Enterococcus: An Overview The Enterococcus is a normal component of the endogenous gastrointestinal and perineal flora. Overall, the ability of enterococci to cause disease (virulence) is limited relative to other common pathogens such as Staphylococcus aureus, group A beta-hemolytic streptococci, or aerobic gram-negative bacilli. As a result, enterococcal infections occur primarily when normal host defenses are impaired (1–5). When the host is compromised, the Enterococcus becomes a significant opportunistic pathogen causing many of the major clinical infectious syndromes affecting man. Enterococcus faecalis, and less often E. faecium, are frequent causes of urinary tract infection (UTI), intra-abdominal and pelvic infection, soft tissue infection, bacteremia, and endocarditis. Enterococci commonly coexist with other pathogens in the setting of gastrointestinal and soft-tissue infections. Other enterococcal species, E. gallinarum, E. casseliflavus, and others, rarely cause infection (1–4), (Table 1). The emergence of resistance to glycopeptide antibiotics 411

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Table 1 Prevalence of Enterococcal Species Among Clinical Isolates Glycopeptide-resistant strains (%) All clinical isolates (64)

Percent

United States (78)

Europe (79)

Enterococcus faecalis Enterococcus faecium Enterococcus casseliflavus Enterococcus gallinarum Enterococcus durans Enterococcus avium Enterococcus raffinosus Other enterococcal species

80–90 5–15 5

2.4 46.9 17.6

0.1 3.8 19.1

Source: References 64, 78, 79.

(vancomycin and teicoplanin) in enterococci is important primarily because effective treatment for serious infection is so difficult (6–8). B. Significance of Glycopeptide Resistance in Enterococci In the United States, enterococci resistant to glycopeptide antibiotics are found predominantly among seriously ill patients in the acute care setting, primarily in intensive care units, in association with prolonged hospital stays, prolonged use of broad-spectrum antibiotics, and frequent use of invasive devices (9,10). Approximately 10% of enterococcal bloodstream isolates from hospitals have been found to be resistant to vancomycin (11). Mortality caused by vancomycin-resistant enterococci (VRE), particularly bacteremia, has been high. However, it has not been possible to establish vancomycin resistance as an independent risk factor for mortality in hospitalized patients (12,13). Increased mortality from VRE has been thought to be the result of the lack of effective antibiotic treatments for infection and to the severity of illness in populations at risk rather than an increase in the virulence of VRE (14). Enterococcus faecalis has been the most common enterococcal species causing 80% to 90% of infections; however, E. faecium is the predominant species manifesting vancomycin resistance (2,4) (Table 1). In the United States, VRE are found infrequently in non-intensive care unit and outpatient settings (15,16). Healthy healthcare workers have rarely been found to be colonized with vancomycin-resistant E. faecium or E. faecalis (9). In parts of Europe, VRE commonly colonizes healthy humans and pets in the community, but most are rarely pathogenic enterococcal species (17,18). It is thought that VRE have emerged because of the selective pressure of antibiotic use. Enterococci resistant to antibiotics, such as glycopeptides, exist in na-

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ture, albeit in small numbers. These clones are selected in the gastrointestinal tract when a patient is exposed to antibiotics and normal flora is suppressed, allowing resistant enterococci to emerge. In Europe, community-based strains emerged initially in livestock because of the use of glycopeptide antibiotics, such as avoparicin, in animal feeds (6). Ingestion of meat contaminated with these enterococci may have contributed to widespread colonization in humans. In the United States, specific antibiotics, such as the glycopeptides themselves, third-generation cephalosporins, and antibiotics with anaerobic activity, have been particularly associated with the emergence of VRE (19). Enterococci also thrive readily on inanimate surfaces. In hospital, patients may acquire antibiotic-resistant enterococci from other VRE-colonized patients or from contaminated hands of healthcare workers or environmental sources (9,10). C. Resistant Enterococci in Nursing Homes: Not a New Problem Residents of long-term care facilities (LTCFs) are frequently found to harbor antibiotic-resistant bacteria upon admission to hospital and may represent a reservoir for these organisms (20). For instance, outbreaks in hospitals have been frequently traced to residents of LTCFs who were found to be colonized upon admission to acute care (21–23). Frequent colonization with antibiotic-resistant enterococci in LTCF residents is not a new problem. Studies of high-level gentamicin-resistant enterococci (HGRE) done a decade earlier in long-term care were predictive of many of the risk factors for VRE later identified in that setting. High-level gentamicin-resistant enterococci colonization was common in residents of LTCFs, with rates of 35% to 47% observed in a single nursing home (24,25). More residents were already colonized with HGRE at the time of admission (~22%) than those who acquired it (14%) during their stay in the nursing home (25). Many of the LTCF strains were closely related to strains found in the attached acute care facility, suggesting that acquisition might have occurred in hospital (24). In one LTCF, residents colonized with HGRE were more likely to have poor functional status, wounds, prior antibiotic therapy, colonization with methicillinresistant Staphylococcus aureus (MRSA), and require urethral catheterization than uncolonized residents (24–26). Rectum, wounds, and perineum were the most common sites of colonization (10,11). Over a 3-year period, HGRE accounted for 6% to 11% of infections occurring in 4% of residents, most of whom had previously been colonized (10,11). Most of those infections were urinary tract or soft tissue infections that were not severe. D. The Epidemiology of VRE in LTCFs: What is Known The prevalence of VRE carriage in residents of LTCFs is only now being established. Most of the information on VRE in the LTCF is based on studies of asymp-

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tomatic rectal carriage rather than infection. In the acute care setting, the prevalence of VRE infection has varied widely with geographic area. Rates of colonization with VRE in LTCFs are likely to parallel those seen in local hospitals. In three studies of nursing home residents admitted to hospital, rates of colonization varied from 10% to 47% (21–23). Surveillance of patients in an acute care hospital without a VRE infection problem revealed 18 carriers of vancomycin-resistant E. faecium and three carriers of E. gallinarum on acute care wards and only one carrier of E. faecalis on the chronic care ward (27). Point prevalence surveys for VRE colonization in residents of a Michigan LTCF were performed over 2 years at 6-month intervals. The prevalence of VRE colonization in rectum ranged from 9% to 22% with infrequent colonization of wounds (28). Residents of LTCFs colonized with VRE have significant debility. Many have significant comorbid illnesses or wounds (33%), urinary devices (47%), or feeding tubes (22%), and were frequently co-colonized with MRSA (47%) or Clostridium difficile (19%) (29). At least half the colonized patients had received recent treatment with vancomycin, a cephalosporin, or both (29). Many of the residents colonized with VRE had been recently hospitalized and may have introduced VRE into the LTCF (28–33). In one study, 67% of residents were already positive for VRE upon admission to the LTCF (29). Residents of LTCFs with VRE were four times more likely to have been recently discharged from hospitals where the organism was endemic than uncolonized residents (30). Strains obtained from those LTCF residents were closely related genetically to VRE strains that predominated in the transferring hospitals (30). All VRE identified in an LTCF may not represent the same organism or be proof that spread is occurring. Multiple, rather than single, strains often circulate in an LTCF at the same time (28,34). In addition, individual LTCF residents have been shown to carry multiple strains of VRE at the same time, which then emerge when antibiotic therapy is initiated (34). The prevalence of VRE may remain high in LTCFs because carriage can persist for months (28,29) and can be prolonged by the use of antimicrobial therapy (29). Roommates had not been shown to share the same strain of VRE in one study, but spread could occur from the environment or the hands of personnel who were frequently colonized with multiple strains of VRE (28,32). Data on VRE infection, rather than colonization in LTCF residents, are scant. A 1992 surveillance study of clinical isolates submitted to an Oklahoma laboratory from 100 nursing homes revealed that 3% of 243 E. faecalis and 12% of 32 E. faecium were resistant to vancomycin (35). Whether these clinical isolates represented true infection or asymptomatic carriage could not be determined by the design of the study. In prospective surveillance studies, severe infection with VRE has been uncommon, relative to rates of colonization. Over 2 years or more of surveillance, seven UTIs, one bacteremia, and no deaths attributable to VRE infection were noted in two nursing homes where VRE colonization was common (28,29).

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II. CLINICAL MANIFESTATIONS Enterococci have the potential to cause infection in older adults residing in LTCFs; however, the prevalence of VRE infection is unknown. The clinical manifestations of vancomycin-susceptible enterococci and VRE are identical (Table 2). Urinary tract infection (UTI) is the most common infection in LTCF residents (36). Gram-negative bacilli clearly predominate as the major causes of UTI in residents of LTCFs, but infections with enterococci are more common in older adults requiring hospitalization than in healthy community dwellers (37). Enterococci have been reported to cause 2% to 13% of UTIs in the long-term care setting (38–43). Urethral catheterization may be an important risk factor for enterococcal UTIs in LTCF residents as almost 20% of this population had enterococci colonizing or infecting their urine (44). Skin and soft tissue infections associated with enterococci are rarely mentioned in the long-term care setting (39,41). Despite the facts that enterococci have been isolated from 7% to 46% of diabetic polymicrobial foot infections and that diabetes mellitus and its complications are common in older adults, enterococcal infections have been rarely reported in series of soft tissue infection among residents of LTCFs (39,41,45). Enterococci have also been recovered from the polymicrobial flora of pressure ulcers (36). Whether enterococci are significant pathogens in polymicrobial soft tissue infections and require specific antimicrobial therapy is controversial (45–48). Aging is associated with increased prevalence of hepatobiliary disease, diverticulosis, and other gastrointestinal pathology with a risk of infectious complications (49,50). Polymicrobial infection, including enterococci from biliary sources and after intra-abdominal surgery, is not uncommon (49–51). Enterococcal infections specifically associated with intra-abdominal/gastrointestinal sources have not been noted in surveys of infection in LTCFs; however, clinicians should be aware that older adults may develop intra-abdominal sources of enterococcal infection during their stay.

Table 2 Clinical Syndromes Associated with Enterococci Syndrome Asymptomatic colonization Urinary tract infection Skin/soft tissue infection Intra-abdominal infection Bloodstream infection Endocarditis Meningitis/pneumonia (true infections extremely rare)

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Overall, bacteremia accounts for 2.7% to 16.3% of nursing home-acquired infections in different series (39,41,52,53). Reports of the prevalence of bacteremia in LTCFs may be misleading, as many facilities may not have the resources to obtain routine blood cultures. Most bloodstream infections originated from a urinary source (55% to 56%) or less often from a soft tissue infection (7%–14%); gastrointestinal sources were rarely described (52,54,55). Gram-positive cocci have accounted for 33% to 35% of bloodstream isolates, with S. aureus predominating in most series (36,52,54,55). Enterococci were noted in 3.3% to 9.1% of bloodstream infections (31–34). Isolation of enterococci occurred most commonly in the setting of polymicrobial bacteremia with another organism. Enterococcal bacteremia from a urinary source was often associated with the use of a urinary device (52,56,57). Because bacteremia appears to be an uncommon event in LTCFs, it might be assumed that metastatic seeding of a distant site with enterococci, such as a heart valve, would be unlikely. However, the instrumentation of a colonized urinary tract or gastrointestinal tract, typically in an older man, with subsequent transient bacteremia and seeding of a native heart valve is the classic scenario for the development of enterococcal endocarditis. Infection with enterococci has been reported in 7% to 20% of older adults with endocarditis (58–62). Whether enterococcal endocarditis occurs more often in older adults as a consequence of increased frequency of genitourinary and gastrointestinal pathology, instrumentation, or predisposing valvular disease remains a subject of debate (58–62).

III. DIAGNOSTIC APPROACH Enterococci can be easily isolated from cultures of urine, stool, wounds, blood, abscess material, and rectal swabs using standard culture media. It is important for the laboratory to speciate all enterococci and screen for the presence of vancomycin resistance. Detection of vancomycin resistance in colonizing or infecting strains of enterococci requires the use of appropriate microbiological methods. Standard broth microdilution methods, disk diffusion, or E-test methods can be used. However, some automated methods are unreliable in detecting VRE (63,64). Different VRE species also vary in their antimicrobial susceptibility patterns (Tables 1,3,4). Patterns of resistance to vancomycin and teicoplanin and the level of resistance to those antibiotics have been used as phenotypic markers for the five mechanisms of resistance currently described in enterococci (Table 3). These five VRE phenotypes are termed VanA, VanB, VanC, VanD, and VanE. These phenotypes provide additional information regarding the likelihood that vancomycin resistance might spread or respond to certain antibiotics (64–66). Vancomycin resistance in enterococci is defined by a minimum inhibitory concentration (MIC) of 2 g/ml or more. Resistance to vancomycin at low levels (MIC, 2–32 g/ml) and susceptibility to teicoplanin is typical of E. casseliflavus,

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Table 3 Phenotypes of Vancomycin-Resistant Enterococci Based on Antimicrobial Susceptibilities to Vancomycin and Teicoplanin Phenotype

Resistance element

VanA

Acquired/transferable

VanB

Acquired/transferable

VanC

Intrinsic/not transferable Acquired/not transferable Acquired/not transferable

VanD VanE

Common species

Vancomycinresistance

Teicoplaninsusceptible

Enterococcus faecium, E. faecalis E. faecium, E. faecalis E. gallinarum, E. casseliflavus E. faecium

High level

No

High level

Yes

Low level

Yes

High level

No

E. faecalis

Low level

Yes

E. gallinarum, and E. flavescens. These species are referred to phenotypically as VanC strains, and rarely cause clinically significant disease. VanC-mediated resistance is an intrinsic and chromosomally mediated characteristic of these organisms that is not transferable to other bacteria (64–66). Vancomycin resistance also can be acquired from other organisms by some enterococci. VanA and VanB strains are found most commonly and are important epidemiologically because they can spread or transfer vancomycin resistance elements to other bacteria. Acquisition of resistance elements can lead to high-level resistance to vancomycin (MIC, 64 g/ml) and teicoplanin (MIC, 16 g/ml) in strains that have required the VanA gene. Acquired resistance to vancomycin with susceptibility to teicoplanin is referred to as a VanB strain. VanA and VanB strains are most often found among strains of E. faecium and E. faecalis. VanA strains are found widely throughout the United States, with VanB strains present on a regional basis (64–66). The diagnosis of infection with VRE is based on the isolation of the organism in association with symptoms and signs consistent with an appropriate clinical syndrome (2,5) (Table 2). The clinical presentation of these syndromes is addressed elsewhere. Isolation of VRE in the absence of clinically apparent symptoms or signs represents asymptomatic colonization of urine, skin, or stool, or contamination of wounds or blood cultures. In the appropriate clinical setting, vancomycin-resistant E. faecium and E. faecalis are more likely to represent true pathogens (7). Isolation of E. casseliflavus, E. gallinarum, E. flavescens, and other species likely represents colonization, unless obtained from a sterile site, on multiple occasions, and in high inoculum (5,7,64).

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Table 4 Treatment of Vancomycin-Resistant Enterococcal Infection* Antibiotic

Route

Ampicillin

IV, PO

Quinupristin/Dalfopristin

IV

Linezolid

PO, IV

Nitrofurantoin Doxycycline

PO PO, IV

Quinolones

PO, IV

Chloramphenicol

IV

Teicoplanin

IV

Indication Efficacious in susceptible Enterococcus faecalis strains Bactericidal for E. faecalis in combination with gentamicin or streptomycin unless high-level aminoglycoside resistance is present E. faecium strains generally resistant to normal regimens of ampicillin High-dose IV ampicillin/beta-lactamase inhibitor regimens experimental E. faecium, only use in serious infections E. faecalis not susceptible Bacteriostatic agent for enterococci Toxicities common: myalgias, phlebitis Resistance described, but rare E. faecium or E. faecalis, only use in serious infections Oral formulation 100% bioavailable. Bacteriostatic Efficacious for urinary tract infection only May be effective in treatment of urinary tract infections. Efficacy in serious infections unpredictable May be effective in treatment of urinary tract infections Efficacy in serious infections unpredictable Many E. faecium susceptible Efficacy in serious infection not established Significant hematologic toxicities Serious infections VanB strains only Not available in the United States

* Enterococcal strains must demonstrate sensitivity to an agent using approved antimicrobial susceptibility methods. Abbreviations: IV, intravenous; PO, oral (per os).

IV. THERAPEUTIC INTERVENTIONS Compared with other gram-positive cocci, the Enterococcus is relatively resistant to the bactericidal effects of cell wall-active antibiotics. Even among vancomycinsusceptible enterococci, intrinsic resistance to many antibiotic classes is common. Penicillins and vancomycin remain the most reliable treatments for infections

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caused by susceptible enterococci, but their activities are bacteriostatic rather than bactericidal. Only the addition of an aminoglycoside to vancomycin or penicillins provides reliable and effective bactericidal activity for the treatment of serious enterococcal infections (6–8,64–68). Unfortunately, resistance to vancomycin in enterococci is usually associated with resistance to multiple antibiotics, including penicillins and aminoglycosides. Most vancomycin-resistant E. faecium and many E. faecalis are resistant to normally achievable levels of penicillin and ampicillin and high-levels of gentamicin or streptomycin (6–8,64–68) (Table 4). In the event of resistance to penicillin in VRE, antimicrobial susceptibilities to other antibiotic classes should be assessed. If susceptible, nitrofurantoin may be effective in treating a UTI caused by VRE. However, despite in vitro susceptibility to tetracyclines, chloramphenicol, and quinolones, clinical success in the treatment of serious VRE infections has been infrequent (6–8,64–68). Newer agents may be effective in treating milder infections, but their antimicrobial activity remains bacteriostatic. A new streptogramin, quinpristin/dalfopristin (Synercid®) is active against E. faecium but not E. faecalis, whereas the oxazolidinone, linezolid (Zyvox®), is active against both species. Teicoplanin is active only against VanB and VanC strains but is not approved for use in the United States. Newer antibiotic classes active against VRE, such as the lipoglycopeptides (ramoplanin), the acidic lipopeptides (daptomycin), and glycylcyclines are under investigation. Many of the agents have significant toxicities and may not be bactericidal for the Enterococcus. Surgical incision and drainage with removal of foreign devices, whenever possible, remains a mainstay of treatment for infections caused by VRE (6–8,64–68).

V. INFECTION CONTROL MEASURES In the acute care setting, VRE infections lead to increased morbidity and increased costs of treatment. The extensive use of infection control resources in the hospital setting can, therefore, be easily justified. It is not clear that VRE is a cause of serious infection or that transmission of VRE is common in the LTCF setting. In addition, a significant proportion of residents of LTCFs may be colonized with more than one drug-resistant bacterium for prolonged periods. Hospital-based infection control procedures, such as long-term confinement in a private room, if implemented in an LTCF, would have a significant impact on the psychological, social, and physical needs of the residents. The controversies surrounding the control of VRE and other antibiotic-resistant bacteria in LTCFs have been addressed by the Society for Healthcare Epidemiology of America (SHEA) Committee on Long-Term Care (69,70) (Table 5). Their infection control recommendations are modifications of Contact Precau-

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Table 5 Strategies and Procedures for the Control of VRE in LTCFs Strategies/Procedures Employee education Surveillance of cultures obtained for clinical reasons/symptomatic infection Establishes the rate of VRE infections in an individual LTCF Establishes what is the normal infection rate for an LTCF Defines when an infection rate is abnormal and potential epidemic transmission Defines when to start procedures to control an outbreak Maintain listing of VRE carriers that are already known Useful information if an outbreak of infection suspected in LTCFs or hospitals Transferring facilities should routinely provide this information to receiving facilities, if known Use of routine surveillance cultures specifically to detect asymptomatic VRE colonization May be falsely reassuring if negative Increased cultures, need for isolation not cost effective unless documented that infections are prevented Isolation procedures Private room/cohorting with other colonized residents recommended, but efficacy in LTCFs not established VRE-colonized residents with good hygiene, no diarrhea or draining wounds may room/share bathrooms with uncolonized residents who are not severely compromised, do not have urinary catheters, drainage devices, or wounds, and are not on broadspectrum antibiotics VRE-colonized resident with good hygiene, no diarrhea and draining wounds contained by a dressing need not be confined to their rooms Isolation can be discontinued after two successive negative cultures of stool or wounds Hand washing Mandatory before and after caring for all residents Antimicrobial soaps and hand disinfectants suggested, but efficacy not established in LTCFs Gloves/gowns Use if contact with body fluids for all residents Use in the room before contact with a VRE-colonized or infected resident or his inanimate environment Gowns recommended if contamination of healthcare worker clothes likely Environmental disinfection Daily cleaning of room surfaces and equipment recommended, but efficacy and optimum germicide not established in LTCFs Dedicated equipment for VRE-colonized or infected residents, if available Antibiotic use Monitor antibiotic use Reduce unnecessary use of antibiotics

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Table 5 (Continued) Strategies/Procedures Follow guidelines for appropriate use of vancomycin Serious gram-positive infections resistant to beta-lactam antibiotics Serious allergies to beta-lactam antibiotics Clostridium difficile infections unresponsive to metronidazole Prophylaxis for residents at high risk of endocarditis Prophylaxis for surgical procedures with prosthetic devices and risk of methicillinresistant staphylococcal infection Limit vancomycin prophylaxis to only two doses Decolonization regimens for VRE Frequent relapses No evidence of efficacy, particularly in residents of LTCFs Emergence of resistance likely Abbreviations: VRE, Vancomycin-resistant enterococci; LTCF, Long-term care facility. Source: Ref. 69.

tions for drug-resistant bacteria recommended for acute care facilities (71,72) (see Chapter 8). These precautions acknowledge the limited infection control resources in nursing homes and those that are achievable in facilities that provide long-term care. A. Screening for VRE The essential element of an infection control program to minimize the spread of VRE includes the routine use of barrier precautions in all residents of LTCFs. Routine screening cannot completely exclude that VRE is present in stool at low levels. Detection of VRE colonization may occur only under certain circumstances, such as during therapy with specific antibiotic classes (19). The SHEA guidelines recommend discontinuation of VRE precautions in an LTCF if two rectal or wound cultures are negative on successive days. However, if VRE are present in referring hospitals or in the LTCF itself, it may be prudent to assume that all residents are potential VRE carriers. Moreover, given the limits of detection of VRE, it may not be reasonable to accept residents with negative stool cultures for VRE into a nursing home while refusing others with positive cultures if VRE is clearly known to be present in referring institutions. Routine use of screening procedures to detect carriers for the purposes of elimination of VRE from an LTCF in an endemic geographic locale is unlikely to be cost effective and is not recommended. Routine surveillance cultures to detect VRE colonization in residents of LTCFs is only recommended if rates of VRE infection are increasing despite routine infection control precautions and transmission is suspected (69).

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B. Controlling VRE Transmission In light of scant data regarding transmission of VRE in LTCFs, the SHEA guidelines recommend that VRE-colonized or -infected patients should optimally be placed in a private room or share a room with a roommate colonized with the same organism (69). Given that residents may be colonized with various combinations of VRE, MRSA, resistant gram-negative bacilli, and C. difficile, these isolation recommendations can pose significant logistical problems for infection control professionals in LTCFs. The SHEA guidelines alternatively recommend that VRE-colonized residents can be placed with or share bathrooms with noncolonized individuals if the colonized resident is continent of stool and does not have diarrhea or open wounds. In addition, the noncolonized roommate should not be severely compromised; receiving broad-spectrum antibiotics; or have a urinary catheter, drainage device, or open wounds (69). Careful hand washing by colonized and noncolonized residents is emphasized. Restriction to rooms is not recommended in residents who are continent, use good hygiene, and have draining wounds contained by bandages. Private rooms or cohorting techniques have been used in LTCFs, but most of these facilities allowed VRE-colonized residents to participate freely in social activities (32,33,73). Direct contact between colonized and noncolonized residents was restricted in only one facility (73). Lack of further transmission of VRE could not be directly attributed to the use of these cohorting techniques. Precautions to disrupt the transmission of antibiotic-resistant pathogens recognize body fluids and the environment as major reservoirs of VRE and the hands of personnel as potential vectors. Therefore, routine hand washing by personnel before and after providing care to a resident is essential. Some studies have shown that standard soaps may not remove VRE from hands as effectively as hand disinfectants with antimicrobial activity (10). Antimicrobial soaps and alcohol disinfectants have been used in LTCFs with VRE, but whether these interventions are effective in preventing transmission has not been established (28,32,33,73). It is recommended that clean, nonsterile gloves be worn when contact with body fluids from any patient is likely, as part of standard infection control precautions (71). In an LTCF, it has been recommended that gloves also be worn within the room of a VRE-colonized or infected resident before initiating any direct contact with the patient or inanimate environment (69). The effectiveness of infection control by donning gowns before entry into the rooms of VRE-colonized or -infected patients in acute care hospitals remains controversial (10). In an LTCF, it has been recommended that gowns be worn only if the clothes of healthcare workers are likely to become soiled with body fluids (69). In uncontrolled studies, no transmission of VRE was documented in six LTCFs where the use of gowns and gloves was required (29,32,33,73). In one facility, gloves were also required for any casual contact with colonized residents outside of

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their room (73). However, universal gloving for care of uncolonized as well as colonized resident in an LTCF may be just as effective as identifying and restricting colonized patients to their rooms and requiring the use of gowns and gloves in preventing transmission of VRE, MRSA, and multidrug-resistant gram-negative bacilli (74). Because VRE is most likely transmitted by environmental sources, the SHEA guidelines recommend the use of dedicated equipment for colonized or infected patients (69). The optimum methods and frequency of disinfection have yet to be defined in hospitals or LTCFs, but daily cleaning of environmental surfaces within the resident’s room with an appropriate germicide was recommended (10,69). In uncontrolled studies of four LTCFs, environmental cleaning of the resident’s room ranged from thrice weekly to twice daily with a quaternary ammonium compound or germicide (32,73). Small equipment/wheelchairs were left in the rooms (32,33) and/or wheelchairs were decontaminated with 1:10 dilution of bleach twice daily (33,73). More randomized, controlled trials are necessary to define the minimum, least costly, and most effective means of infection control in LTCFs. Despite the diversity of infection control measures used above, the superiority of one approach in preventing colonization has not been established (29,32,33,73). No infections or deaths could be attributed directly to VRE in these studies (29,32,33,73).

VI. PREVENTION In the hospital setting, oral antimicrobial agents such as bacitracin, doxycycline, and novobiocin alone or in combination, have been used to eradicate VRE from urine, stool, or wounds with frequent recurrences and emergence of further resistance (7,8,64). As a result, experts have generally not recommended VRE decolonization except in patient populations at extreme risk of infection (8). In the LTCF setting, decolonization of VRE-colonized residents with oral bacitracin regimens has been tried with variable success (33,73). However, it should be recognized that many VRE-colonized residents clear their colonization spontaneously after decolonization failed or without antibiotics (25,28,32,73). It is likely that increased antibiotic use will perpetuate the problem of VRE. Prevention of the emergence of VRE in susceptible populations requires reducing the unnecessary use of antibiotics in animal feed, in hospital, and in the LTCF setting. The Hospital Infection Control Practices Advisory Committee (HICPAC) recommends that vancomycin use be limited to treatment of serious gram-positive infections resistant to beta-lactam antibiotics, treatment of patients with serious beta-lactam allergy, and treatment of C. difficile unresponsive to metronidazole (75). Brief courses of vancomycin prophylaxis should be limited to high-risk en-

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docarditis prevention or surgical procedures involving prosthetic devices with high rates of infection caused by MRSA (6,75). In the hospital setting, restricting the use of third-generation cephalosporins and antibiotics with antianaerobic activity has been associated with declines in rates of VRE infection (64,68). Further studies need to be done to ascertain if antibiotic restriction leads to declines in the burden of VRE colonization in residents of LTCFs. Antibiotics are frequently continued in the long-term care setting even if cultures are negative, the infection is resistant to the antibiotic chosen, or the organism is likely to represent contamination (76). Significant improvements in antibiotic use in the long-term care setting can be achieved in the meantime. Modification of risk factors that predispose residents of LTCFs to colonization and infection with antibiotic-resistant bacteria, such as use of feeding tubes, urinary catheters, intravenous devices, presence of wounds, and C. difficile infection, can be made with appropriate geriatric assessments and interventions (77).

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24 Gram-Negative Bacteria Vinod K. Dhawan Charles R. Drew University of Medicine and Science, and UCLA School of Medicine, Los Angeles, California

I. EPIDEMIOLOGY AND CLINICAL RELEVANCE Gram-negative bacteria are common causes of infection among residents of longterm care facilities (LTCFs). Emergence of antimicrobial resistance in the gramnegative bacteria has been a growing problem in nursing homes, hospitals, and even the community. Antibiotic-resistant organisms may be introduced into nursing homes with the admission of new residents who are already colonized or infected. Alternatively, bacterial resistance may emerge in the endogenous flora of residents upon exposure to antimicrobial agents, through either selection of resistant strains or spontaneous mutation or gene transfer. There is ample evidence that bacterial resistance negatively impacts the outcome of infections. Data from the Centers for Disease Control and Prevention (CDC) has linked bacterial resistance with higher rates of mortality and morbidity (1). A. Mechanisms of Resistance The development of antimicrobial resistance in microorganisms is a perfect example of contemporary biological evolution. Over the years, the introduction of new antibiotics has been matched by the development of new mechanisms of resistance by the bacteria. Gram-negative bacteria use a variety of strategies to avoid the inhibitory effect of antibiotics and have evolved highly efficient means for dissemination of resistance traits (Table 1) (see Chapter 21). Among the mechanisms that create resistance to antibiotics in gram-negative bacilli, the production of lactamase is the single most important factor. -Lactamases are enzymes that hydrolyze the amide bond in the -lactam ring of the antibiotic, leading to its inac429

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Table 1 Mechanisms of Antibiotic Resistance Among Gram-Negative Bacteria Mechanism Enzymatic inhibition Decreased membrane permeability Active efflux of antibiotic Altered ribosomal target Altered target enzymes Overproduction of target enzymes Bypass of inhibited steps by organisms

Antibiotics affected -lactams, aminoglycosides, chloramphenicol -lactams, aminoglycosides, chloramphenicol, trimethoprim, sulfonamides Quinolones, tetracyclines Aminoglycosides, chloramphenicol, tetracyclines -lactams, quinolones, trimethoprim, sulfonamides Trimethoprim, sulfonamides Trimethoprim, sulfonamides

tivation. The ability of a -lactamase to cause resistance varies with its activity, quantity, and its cellular location within the gram-negative bacteria. A variety of -lactamases, encoded chromosomally or by plasmids (TEM, SHV, or Oxa -lactamases) have been described in gram-negative bacteria. The -lactamases have been classified based on their sequences into evolutionary distinct classes A, B, C,

Table 2 The Bush-Jacoby-Medeiros Classification of -Lactamases Preferred substrate

Group 1 2a 2b 2be 2br 2c 2d 2e 2f 3 4

Cephalosporins Penicillins Penicillins, cephalosporins Penicillins, narrow and extended-spectrum cephalosporins, monobactams Penicillins Penicillins, carbenicillin Penicillins, cloxacillin Cephalosporins Penicillins, cephalosporins, carbapenems Most -lactams, including carbapenems Penicillins

Source: Ref. 2.

Inhibition by clavulanate No Yes Yes Yes Diminished Yes Yes Yes Yes No No

Molecular class C A A A A A D A A A B Not determined

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431

and D. In addition, a functional classification of -lactamases (group 1, 2, 3, and 4) based on their substrate and inhibitor profiles has been proposed (Table 2). 1. Extended-Spectrum -Lactamases The originally discovered -lactamases (TEM-1, TEM-2, SHV-1) had a rather restricted spectrum of activity against antibiotics. More recently, resistance of some gram-negative bacilli to broad-spectrum cephalosporins has been noted to be mediated by the extended-spectrum -lactamases (ESBLs) designated as Group 2be. Extended-spectrum -lactamases are a group of enzymes that confer resistance to oxyimino cephalosporins (e.g., cefotaxime, ceftazidime, and ceftriaxone) and monobactams. The ESBLs are not capable of hydrolyzing cephamycins and carbapenems (3). Most ESBLs found in gram-negative bacilli are plasmid-borne variants of the original TEM-1 and SHV-1 enzymes in which one or more amino acid substitutions have expanded the substrate specificity. The ESBLs were first discovered in Europe in 1983 and their prevalence has since increased throughout the world. The ESBLs are most commonly expressed in Klebsiella pneumoniae, K. oxytoca, and Escherichia coli, although they have been detected in other organisms including Salmonella spp, Pseudomonas aeruginosa, Proteus mirabilis, and other Enterobacteriaceae (4–8). Currently, more than 100 of these variants have been described. An updated list of ESBLs is maintained at the website http://www.lahey.org/studies/webt.htm. Different substitutions in ESBLs produce variable effects on the susceptibility of cefotaxime, ceftazidime, and aztreonam to the -lactamases. An emerging mechanism of resistance to -lactamase inhibitors, mediated by the derivatives of TEM and SHV enzymes with a limited number of nucleotide substitutions, has occurred in Europe (9). These types of -lactamases have been designated Bush-Jacoby-Medeiros Group 2br or inhibitor-resistant TEM (IRT) (2). Plasmid-encoded -lactamases can be transmitted among different gram-negative bacteria, resulting in the horizontal spread of antimicrobial resistance. Such plasmids often carry resistance to other antibiotics, including tetracyclines, aminoglycosides, chloramphenicol, trimethoprim, and sulfonamides (8). 2. Inducible Chromosomal -Lactamase AmpC Another important mechanism of resistance in gram-negative organisms is the production of inducible chromosomal -lactamases, most notably AmpC (Bush-Jacoby-Medeiros group 1). The presence of a -lactam can cause depression of regulatory genes in these organisms, resulting in -lactamase hyperproduction and inducible resistance to third-generation cephalosporins. Such enzymes are present in 24% to 48% of Enterobacteriaceae strains (10). They have also been noted in some strains of Serratia marcescens, Pseudomonas, Citrobacter, and indole-positive Proteus (11,12). This results in cross-resistance to other -lactams, except

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carbapenems such as imipenem (10) or the fourth-generation cephalosporin, cefepime (13). Concomitant aminoglycoside therapy does not prevent the emergence of this resistance (14). The appearance of plasmid-mediated -lactamases similar to AmpC in some strains of K. pneumoniae has resulted in their resistance to cephamycins, oxyimino- lactams, and -lactam inhibitors. The potential plasmid-mediated transfer has raised concerns about horizontal spread of this resistance trait (15). 3. Metallo-Beta-Lactamases Inducible chromosomal enzymes, called metallo--lactamases, confer resistance to -lactam antibiotics in organisms such as Stenotrophomonas maltophilia. Two major functional groups of metallo--lactamases have been identified (16). One group is a set of enzymes with broad substrate specificities capable of hydrolyzing most -lactams, except monobactams. A second group is composed of the “true” carbapenemases—enzymes that exhibit poor hydrolysis of penicillins and cephalosporins. This latter group has been found primarily in Aeromonas spp. Metallo-lactamases have been recovered from Bacteroides fragilis, S. marcescens, Aeromonas spp, and P. aeruginosa in Japan, but resistance to imipenem has not become widespread (16). Carbapenem resistance in K. pneumoniae also can be modulated by plasmid-mediated metallo- lactamase production, raising concerns about widespread dissemination of this resistance mechanism (17). Plasmid-mediated resistance to carbapenems is likely to increase and limit the use of these agents as a therapeutic option. 4. Porin Channels Resistance of some gram-negative bacilli to the -lactam antibiotics may also occur through the loss of porin channels in the outer cellular membrane, which decreases antibiotic entry into periplasmic space. This often leads to increased resistance to cephalosporins, cephamycins, and -lactam inhibitors (10,18,19). In P. aeruginosa, carbapenem resistance can occur by mutational loss of a porin channel. Similarly, decreased membrane permeability secondary to porin mutations often leads to quinolone resistance in gram-negative bacilli (20). 5. Efflux Pump Mechanisms A set of multidrug efflux systems in some gram-negative bacteria enables them to survive in a hostile environment (21). The efflux mechanisms pump the antimicrobial agent out of the cell, preventing its access to the target site. Each efflux pump of gram-negative bacteria consists of three components: the inner membrane transporter, the outer membrane channel, and the periplasmic lipoprotein. The molecular mechanism of the drug extrusion across a two-membrane envelope of gram-negative bacteria may involve the formation of the membrane adhesion

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sites between the inner and the outer membranes. Quinolone resistance is often modulated by antibiotic efflux systems in addition to alteration in the DNA gyrase, topoisomerase II and, to a lesser extent, topoisomerase IV (22). 6.

Aminoglycoside Resistance

Aminoglycoside resistance is modulated by bacterial enzymes, which inactivate the aminoglycoside by variously acetylating, adenylating, or phosphorylating the antibiotic molecule (23). B. Prevalence of Antibiotic-Resistant Gram-Negative Bacteria Most of the information regarding the prevalence of antibiotic-resistant organisms in nursing homes and other LTCFs is derived from surveillance studies of infections or outbreak investigations. No studies have defined the overall magnitude of this problem in a systematic manner. The available data suggest that antibiotic-resistant organisms, including gram-negative bacilli, are frequent in the nursing home population (24). Antibiotic resistance among gram-negative bacteria has steadily increased over the years. The antibiotic susceptibility profile of common gram-negative bacilli, as published by the American Society of Clinical Pathologists, is presented in Table 3 (25). Current rates of prevalence of ampicillin or amoxicillin resistance in strains of E. coli are about 40% in the United States, 40% to 50% in the United Kingdom and France, 58% in Spain, and 63% in Israel (26). Ampicillin-resistant isolates of E. coli and cephalothin-resistant isolates of Klebsiella spp are common in nursing homes (24). Aminoglycoside resistance has been noted in a significant proportion of uropathogens isolated from nursing home residents (27). In one study 33% of such organisms were noted to be resistant to gentamicin (28). Another study detected colonization of urine or perineum with trimethoprim-resistant gram-negative bacilli in 52% of residents in a Department of Veterans Affairs (VA) nursing home (29). Resistance of gram-negative bacilli to fluoroquinolones has also been described. Prospective surveillance in seven skilled nursing facilities in southern California found about a third of the urinary Pseudomonas isolates and 12% of isolates of the family Enterobacteriaceae were resistant to norfloxacin (30). Extended-spectrum -lactamase-producing organisms, which are being identified worldwide (Table 4), are probably more prevalent than currently recognized because they are often undetected by routine susceptibility testing methods (31). These organisms are commonly encountered in nosocomial infections and have been implicated in several nursing home outbreaks (32,33). The prevalence of ESBL-producing K. pneumoniae is on the incline with rates approaching as high as 40% in some hospitals in the northeast United States (34). As reported by the CDC, in 1998, the rate of ceftazidime-resistant K. pneumoniae reached 10.7% and ceftazidime-resistant E. coli reached 3.2% in intensive care units

5 NA NA NA —

40 NA NA NA —

3–25

NA

NA

3–17 NA

Cefazolin

—

0–35 ESBL

— 20–42 inducible NA

Cefotaxime

Abbreviations: NA, Not applicable; ESBL, Extended spectrum -lactamases. Source: Ref. 25.

Escherichia coli Enterobacter cloacae Pseudomonas aeruginosa Serratia marcescens Klebsiella pneumoniae

Microorganism

Ampicillin -clavulanic Ampicillin acid

0–19

0-18

0–3 20–42 inducible 5–27

Ceftazidime

0

0–19

4–28

0–1 0–2

Imipenem

Percent resistant to tested antibiotics

Table 3 Prevalence of Antibiotic Resistance Among Common Gram-Negative Bacteria

0–15

0–39

4–59

0–6 0–17

Gentamicin

6–48

0–19

NA

2–27 4–22

0–11

0–22

7–36

0–5 0–13

Trimethoprimsulfamethoxazole Ciprofloxacin

434 Dhawan

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Table 4 Global Antimicrobial Resistance Survey of Attendees at 1998 ICAAC Meetings* Percent healthcare providers who had seen 5 patients with infection

Continent

ESBL-producing gram-negative bacilli

Difficult to treat Acinetobacter spp

83% 71% 50% 54% 91%

100% 71% 16% 46% 100%

Asia Africa Europe North America South America

* Attendees at the 1998 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Antimicrobial Resistance Symposium who had seen more than five infections caused by antibiotic-resistant gramnegative bacteria in the preceding year. Source: Ref. 82.

(ICUs) in the United States (35). Teaching hospitals have been shown to have a higher prevalence of resistant organisms (10). Among these ICU patients, ESBLproducing K. pneumoniae are isolated primarily from those with urinary tract infections (UTIs) (50%), whereas 15% are recovered from those with bloodstream infections (36,37). Rates of ceftazidime resistance of 34% and 21% for Enterobacter spp and P. aeruginosa, respectively, have been recently reported in U.S. ICUs (35). Organisms producing AmpC frequently are associated with infections in the ICU, representing 8% of ICU-related pneumonia isolates, 11% of UTI isolates, and 4% central line-associated bacteremia isolates. As a group, AmpC-producing organisms may represent more than 30% of isolates in ICU patients with pneumonia in some institutions (38). As many ICU patients are elderly, and some patients may eventually be transferred to an LTCF, those resistant pathogens can be expected to become an important infection control issue in this setting. C. Risk Factors Several studies have evaluated the risk factors for colonization and infection with antibiotic-resistant pathogens in nursing home residents. These risk factors include poor functional status, prior antibiotic use, presence of wounds (such as pressure ulcers), and presence of foreign bodies (such as urinary catheters) (24).

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Table 5 Factors Associated with Increased Antimicrobial Resistance in Gram-Negative Bacteria 1. 2. 3. 4. 5. 6. 7. 8.

Antibiotic use Prolonged hospitalization Stay in intensive care unit Severely ill patient status Immunocompromised status Use of intravenous catheters Ineffective infection control Interhospital transfer of patients colonized with antibioticresistant organisms

Risk factors for acquisition of ESBLs are generally similar to those reported for other hospital-acquired organisms (Table 5). Exposure to antibiotics in general, and to ceftazidime and aztreonam in particular, has been associated with increased prevalence (32,39). Emergence of ESBL has also been associated with use of other third-generation cephalosporins (32,40–42) and exposure to trimethoprimsulfamethoxazole (TMP-SMX) (32). Other risk factors include mechanical ventilation, emergency abdominal surgery, the presence of percutaneous devices, longer hospital stay, and increased patient morbidity (33,41,42).

II. CLINICAL INFECTIONS Gram-negative bacilli are common causes of a variety of infections in hospitals and LTCFs. Therefore, the development of resistance in these organisms is worrisome. Extended-spectrum -lactamase-producing organisms have been implicated in a broad range of clinical syndromes. Escherichia coli is the most common gram-negative pathogen associated with nosocomial infections, isolated from 12% of such infections. It is the leading cause of UTIs in nursing home populations (43) and among residents with nosocomial urinary tract infections, representing 24% of pathogens isolated (44). Klebsiella pneumoniae is also common, representing 5% of nosocomial infection site isolates, and 8% of hospital-acquired UTI and pneumonia isolates (44). Pseudomonas aeruginosa has been associated with 9% of all hospital-acquired infection site isolates and is the most common cause of nosocomial gram-negative pneumonia, representing 17% of isolates. Enterobacter spp represents 6% of all hospital-acquired isolates and 11% cases of pneumonia isolates (44). Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia) is a gram-negative bacillus that has been associated with bacteremia, respiratory tract infections, skin and soft-tissue infections, and endocarditis (45). Acinetobacter, a gram-negative coccobacillus, has emerged as an important noso-

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cominal pathogen. The most common site of isolation is the respiratory tract. Hospital outbreaks are often related to contaminated respiratory equipment (46,47). Acinetobacter also has been associated with other types of nosocomial infection, including bloodstream, soft tissue, urinary tract infections, abdominal infections, meningitis, and endocarditis. Patients with impaired host defenses or central venous lines and patients in the ICU are particularly susceptible (46,48). Burkholderia cepacia (formerly Pseudomonas cepacia) is an uncommon cause of infections. This organism has been reported in isolated patients with pneumonia, bacteremia, and invasive otitis. It is an important opportunistic agent of pneumonia in patients with cystic fibrosis (49) and can cause life-threatening infections in patients with chronic granulomatous disease (50).

III. DIAGNOSTIC APPROACH The laboratory diagnosis of ESBL-producing gram-negative bacilli requires special methods. Simple screening for ceftazidime or aztreonam resistance is not adequate and misses approximately 15% to 20% of ESBL-producing organisms (31). Some ESBL-containing bacteria might display in vitro susceptibility to these antibiotics, their minimum inhibitory concentrations (MIC) often are at the borderline of susceptibility, and the inoculum effect may lead to treatment failure in the presence of high in vivo bacterial concentrations. Resistance to cefpodoxime has been studied as a screening method. Using sensitivity breakpoints of 2g/mL or higher by MIC or less than 22 mm by disk diffusion (for a 30-ug cefpodoxime disk) has a sensitivity of 98% or more for ESBL detection (20,51). Extended-spectrum -lactamases are susceptible in vitro to -lactamase inhibitors such as clavulanic acid. The most effective way to detect ESBLs is to test for synergy between ceftazidime or cefotaxime and clavulanic acid and is recommended by the National Committee for Clinical Laboratory Standards for confirmation of ESBLs. Disks containing cefotaxime and ceftazidime alone and disks containing the combination of clavulanic acid with these antibiotics are placed on Mueller-Hinton agar. A 5 mm or greater increase in size of the zone diameter for either cefotaxime or ceftazidime tested in combination with clavulanic acid versus the zone for either antibiotic tested alone indicates the presence of an ESBL (10,52). An effective screening strategy might be a cefpodoxime screen followed by the confirmatory double-disk diffusion test for isolates screening positive. The Vitek ESBL test is a reliable single-test alternative. It is an automated broth microdilution test using cefotaxime and ceftazidime alone and in combination with clavulanic acid. The test has been shown to be both sensitive (99.5%) and specific (100%) for the detection of ESBLs (53,54). The E-test method, which involves testing third-generation cephalosporins with and without a -lactamase

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inhibitor, is another method. However, the test is relatively expensive and the reliability of the commercially available version of this test is questionable (10,55).

IV. THERAPEUTIC INTERVENTIONS The rapidly evolving antimicrobial resistance in gram-negative bacilli poses a significant therapeutic challenge, and multiresistance is of particular concern. The elderly patients infected with multiresistant organisms are at higher risk for death. Patients with ESBL-producing K. pneumoniae or E. coli bacteremia are significantly more likely to survive if they receive appropriate therapy within 3 days of the onset of infection (39). Appropriate therapy of infections caused by antibioticresistant gram-negative bacilli is, therefore, critical to patient survival. Currently available treatment options for the common antibiotic-resistant gram-negative bacteria are summarized in Table 6. The ESBL-producing K. pneumoniae and E. coli strains are often resistant to quinolones and aminoglycosides, leaving few therapeutic alternatives. In one study, ceftazidime-resistant isolates were resistant to gentamicin and ciprofloxacin in 67% and 45% of cases, respectively, compared with rates of 3.6% and 2.0% for ceftazidime-susceptible organisms (56). For susceptible isolates, however, aminoglycosides and quinolones remain effective treatment options. Carbapenems are highly effective in the treatment of bacteriacontaining ESBLs, with susceptibility rates ranging from 93% to 100% (56–58). Gram-negative bacilli producing AmpC may initially test as “susceptible” to third-generation cephalosporins, but resistance can emerge during treatment with these antibiotics. It is important for the clinician to realize that even when these organisms display in vitro susceptibility to the third-generation cephalosporins, treatment failures often occur in vivo (10,59). In one study, 20% of bloodstream iso-

Table 6 Treatment Options for Antibiotic-Resistant Gram-Negative Bacilli Organism ESBL-producing Klebsiella, Escherichia coli Enterobacter spp Pseudomonas aeruginosa Stenotrophomonas maltophilia Acinetobacter spp Burkholderia cepacia

Potential treatment options Imipenem or meropenem, cefepime, quinolones (for susceptible strains) Imipenem or meropenem, cefepime, quinolones Imipenem or meropenem, cefepime Trimethoprim/sulfamethoxazole, ticarcillin-clavulanic acid, quinolones Imipenem Trimethoprim/sulfamethoxazole

Abbreviation: ESBL, Extended-spectrum beta-lactamase.

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lates of E. cloacae developed resistance to third-generation cephalosporins upon exposure to these agents (60). In contrast to other cephalosporins, cefepime, a new aminothiazolylacetamido, has a wider spectrum and a greater potency against the ESBL-producing organisms. Cefepime penetrates the gram-negative cell more rapidly, targets multiple essential penicillin-binding proteins, and escapes the effects of many -lactamases because of the enzymes’ low affinity for the drug (61). Cefepime is a much weaker inducer of AmpC production. The latter characteristic is most apparent in studies of Bush group 1 -lactamases. Derepression of this class of -lactamases has lesser effect on the in vitro activity of cefepime as compared with other cephalosporins. In one study, 80% of Pseudomonas isolates and more than 99% of other AmpC-producing Enterobacteriaceae tested sensitive to cefepime (57). The carbapenems represent another treatment option. Eight-four percent of Pseudomonas isolates and more than 99% of Enterobacter and Citrobacter isolates remain sensitive (57). Cephamycins are a treatment option, but plasmid-mediated AmpC -lactamase production and porin channel mutations may limit their clinical utility (10). Quinolones and aminoglycosides are often effective, although resistance is emerging (62,63). Ceftibuten, an oral oxyimino- lactam that binds less tightly to ESBLs than other cephalosporins, has demonstrated reasonable in vitro activity, but clinical experience with this antibiotic is limited (64). -Lactam/-lactam inhibitor antibiotics have good in vitro activity against some ESBL-expressing organisms (65) and have been shown to protect against ESBL acquisition (66). However, bacterial mutation may lead to increased susceptibility to these agents. AmpC is not susceptible to -lactamase inhibitors. Because of the high prevalence of antibiotic resistance, and because of the potential for emergence of resistance during therapy, Pseudomonas infections are usually treated with two active agents. The management of infections caused by S. maltophilia is problematic, because many strains manifest resistance to multiple antibiotics. Trimethoprim-sulfamethaxazole is the treatment of choice for infections due to S. maltophilia. Ticarcillin-clavulanate is the only -lactam/-lactam inhibitor combination antibiotic that is reliably effective in the treatment of S. maltophilia. It has been suggested as the treatment of choice for patients who are unable to tolerate TMPSMX (45). Resistance to both of these agents is, however, increasing (67,68). Aminoglycosides generally are not active against S. maltophilia, possibly because of aminoglycoside-mediating enzymes and alterations in cell surface (45). Resistance rates to imipenem approach 100% (46). Cefepime has greater in vitro activity against S. maltophilia than does ceftazidime, with susceptibility rates of bloodstream isolates reported to be 88.7% and 35.3%, respectively, in one U.S. study (47). Some of the newer quinolones, notably clinafloxacin, sparfloxacin, and trovafloxacin, have better in vitro activity than ciprofloxacin (68–70). In one study, 94% of isolates were susceptible to clinafloxacin (69). Minocycline has good in vitro activity (68), but its use in clinical settings is limited. Antibiotic com-

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binations, such as TMP-SMX and either ticarcillin/clavulanate or a third-generation cephalosporin or minocycline might be more appropriate in the treatment of serious S. maltophilia infections (68,71). Acinetobacter infections are most reliably treated with carbapenems, although resistance to these agents is emerging (48,57). Quinolones may be effective treatment options for some strains. One study noted that only 17% of clinical A. baumannii isolates were susceptible to this antibiotic class (48). Aminoglycoside resistance is common in A. baumannii, occurring in approximately 85% of isolates (48). -Lactam/-lactamase antibiotics have good in vitro activity against A. lwoffi (10% are resistant) but are less effective against A. baumannii, with 30% of strains being resistant. Ceftazidime and cefepime are active against A. lwoffi, but have lesser activity against A. baumannii; resistance rates approach 12% and 30%, respectively, in the two isolates (48,58). Intrinsic resistance of B. cepacia to several antibiotics complicates treatment of infections caused by this organism. Trimethoprim-sulfamethoxazole has historically been the drug of choice. Ceftazidime, meropenem, and ciprofloxacin are also active for most of the strains.

V. INFECTION CONTROL MEASURES Nursing home residents may be an important reservoir of multiple antibiotic-resistant organisms, including ESBL-producing gram-negative bacteria. There has been little evaluation of methods to limit the spread of infections in the nursing home population. Most of the recommendations are extrapolated from programs considered effective in acute care facilities. The role of ESBL-producing organisms in hospital and nursing home outbreaks, as well as the ability of their plasmid DNA to be transferred to other bacterial species, makes effective control a growing challenge. Nursing home outbreaks can occur through either clonal spread of a specific plasmid-carrying strain or transfer of a particular plasmid to a variety of bacterial strains or even different bacterial genera (33,72,73). Use of broad-spectrum antibiotics and poor infection control practices facilitate the spread of this plasmid-mediated resistance. Efficient monitoring of antimicrobial resistance can produce timely and important data and information. One of the reasons cited for the spread of the organism in the largest outbreak of ESBL-producing K. pneumoniae, which occurred at a Brooklyn, New York hospital, was missed initial detection. Implementation of effective screening methods for the detection of ESBLs is a key factor in the control of hospital outbreaks and is necessary for accurate surveillance. Resistant organisms can be passed from patient to patient by the hands of healthcare providers (74). A recent outbreak of Enterobacter aerogenes in a geriatric acute unit was attributed to the failure to institute contact isolation (75). Patients infected or colo-

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nized with antibiotic-resistant bacteria, including ESBL-producing gram-negative bacteria, should be isolated and barrier precautions instituted to prevent the spread of these organisms in the LTCFs. Transient limitation of resident movement and interaction within the facility and specific therapy for antibiotic-resistant bacterial infections are important control measures. Appropriate planning for identifying, transferring, discharging, and readmitting residents with antibiotic-resistant gramnegative bacilli to LTCFs constitute important control measures. Restriction of cephalosporin use has been associated with control of hospital outbreaks (32,76,77). Class restriction of all cephalosporins at a New York hospital was associated with significant reduction in the prevalence of ceftazidime-resistant K. pneumoniae (77). Unfortunately, there was a significant increase in imipenem-resistant P. aeruginosa during the study period, presumably related to increased use of imipenem. Discontinuation of ceftazidime use at a hospital in Massachusetts resulted in a significant decrease in the prevalence of ESBL-producing K. pneumoniae. Education of healthcare providers, application of clinical practice guidelines, and audit and feedback activities have all been shown to have a salutary effect in altering antibiotic prescribing. Nursing homes should monitor and control antibiotic use and regularly survey antibiotic resistance patterns among pathogens. Pharmacists can play a major role through clinician education and focused clinical services. With the cooperation of healthcare teams, the effectiveness of available antibiotics may be sustained and the threat of resistance minimized.

VI. PREVENTION To control the emergence of resistant pathogens, CDC and infection control guidelines must be adhered to. Prevention of resistance emergence and the spread of antibiotic-resistant gram-negative bacilli requires prudent use of antimicrobials and strict adherence to infection control measures. There is intense antimicrobial use in LTCFs, and studies have repeatedly documented that much of this use is inappropriate (43). Attempts to improve antimicrobial use in LTCFs are complicated by characteristics of the resident population, limited availability of diagnostic tests, and the virtual absence of relevant clinical trials. Optimal use of antimicrobials is essential in the face of escalating antibiotic resistance and requires cooperation from all sectors of the healthcare system (see Chapter 11). Clinicians must alter their antibiotic prescribing habits for the treatment of infectious diseases, and patients must change their perception of the need for antibiotics. Important strategies for the prevention of antimicrobial resistance with regard to antibiotic use include monitoring of antibiotic use, improving antimicrobial prescribing by educational and administrative means, optimizing perioperative prophylaxis, optimizing the choice and duration of empirical therapies, and developing guidelines for the optimal use of antibiotics for common indications.

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Cycling of currently available antibiotics to reduce resistance is an attractive concept, because it periodically removes from the institutional environment certain classes or specific agents that could induce or select for resistance (78). For cycling strategies to be successful, their implementation must have a demonstrable impact on the prevalence of resistance determinants already dispersed throughout the patient environment. Rotational usage practices are likely to be most appropriate for drugs active against gram-negative bacilli because of the wide choices available for rotation. Antibiotic use provides an obvious stimulus for the emergence of resistance, but it is by no means the only important factor. Antibiotic recycling must be evaluated in the context of concomitant attempts to improve antimicrobial use and must take into account other factors influencing resistance (79). Large scale, nation-wide cooperative studies may provide data on this important issue. There has been a growing appreciation of the role played by the use of antibiotics in agriculture, aquaculture, and veterinary settings in the emergence of antimicrobial resistance. For example, fluoroquinolone use in aquaculture has been associated with the emergence of a variety of gram-negative bacilli, including E. coli, Aeromonas salmonicida, and other organisms (80). Subtherapeutic concentrations of tetracyclines have been shown to increase the frequency of the transfer of resistance plasmids in the guts of animals (81). Global control of antimicrobial resistance must also address the non-human use of antimicrobial agents. REFERENCES 1. 2.

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25 Candida and Other Fungi Carol A. Kauffman University of Michigan, and Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan

Sara A. Hedderwick Royal Victoria Hospital, Belfast, Northern Ireland

I. EPIDEMIOLOGY AND CLINICAL RELEVANCE The prominent fungal infections encountered in residents who reside in long-term care (LTCFs) facilities are local infections of skin and mucous membranes. Invasive fungal infections are uncommon. This is likely due to the fact that although older adults in LTCFs are chronically ill and have many underlying illnesses, most are not immunosuppressed in the classic sense. Most infections in the LTCF are caused by dermatophytes, which only superficially infect the skin and hair structures, and Candida species, which normally colonize the gastrointestinal and genitourinary tracts of humans. Filamentous fungi, such as Aspergillus, are almost always acquired from the environment and cause disease in those who are immunosuppressed. The endemic mycoses, such as histoplasmosis and blastomycosis, also are acquired from the environment. Because several of the endemic mycoses are known to reactivate years after initial infection, these infections may rarely occur in residents of an LTCF. However, discussions of the disparate disease manifestations and treatment of the various endemic mycoses are beyond the scope of this chapter. The reader is instead referred to standard infectious diseases textbooks or review articles for further details regarding these infections in older adults (1,2). Systemic fungal infections are uncommon in the LTCF, but increasingly, patients are transferred to such facilities for continuation of intravenous antimicrobial agents, including antifungal agents, initiated in the hospital. Thus, knowl449

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edge of modes of administration, side effects, and drug-drug interactions of systemic antifungal agents will be important for the care of some residents. Because these infections are uncommon in the LTCF, the diagnosis and initiation of therapy for a systemic fungal infection should be undertaken only after consultation with an infectious diseases physician. A. Dermatophytes Dermatophytes normally infect the keratinized layers of the skin and the hair shafts, rarely causing invasive disease. They are responsible for tinea corporis (ringworm), tinea pedis (athlete’s foot), tinea cruris (“jock itch”), tinea capitis, and onychomycosis. The exact prevalence of dermatophyte infections in older adults is difficult to ascertain. Most authors agree that the prevalence of onychomycosis caused by dermatophytes significantly increases with age (3,4). One study noted that 30% of patients age 60 and older had onychomycosis (4). Alternatively, scalp infection is predominantly a childhood disease and rarely seen in the elderly. Although uncommon, outbreaks of tinea corporis have been described in residents of LTCFs (5–8). The genera of dermatophytes that cause disease in humans are Trichophyton, Microsporum, and Epidermophyton. Different species of dermatophytes vary in their host specificity. Many cause disease only in humans and are transmitted directly by person-to-person contact or by fomites, such as hairbrushes. Other species have specific associations with animals and can be transmitted from pets (9) (Table 1). Table 1 Epidemiology of Fungal Infections in Long-Term Care Facilities Fungal organism Dermatophytes

Candida

Cryptococcus Aspergillus Zygomycoses

Pertinent epidemiologic characteristics Usually single cases, men more than women, chronic, relapsing infections; rarely, outbreaks occur with spread among patients and healthcare workers; potential for outbreaks of certain species (e.g., Microsporum canis) from pets brought into the facility Infection almost always from patient’s own endogenous flora, although potential for transmission exists; Candida glabrata more common in urinary tract and in older persons; infection more likely in those with indwelling intravenous and urinary catheters Acquired from outside environment; may present later as chronic meningitis or dementia in long-term care resident Acquired from outside environment; rare in LTCFs Acquired from outside environment; rare in LTCFs

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B. Yeast Infections 1. Tinea Versicolor Malassezia furfur, also known as Pityrosporum orbiculare, is the cause of tinea versicolor, a superficial fungal infection of the head, neck, and chest (10). This organism is frequently part of the normal flora found on the skin of humans. Tinea versicolor occurs most often in young adults; however, it frequently recurs and is not uncommon in older adults residing in LTCFs. 2. Candida The most common systemic fungal infections in older residents are those due to Candida spp. In acute care hospitals, Candida spp. are the fourth leading cause of nosocomial bloodstream infections and are responsible for 10% of hospital-acquired bloodstream infections (11). However, serious Candida infections, such as candidemia, appear not to be a major problem in LTCFs; local Candida infections are much more common in the LTCF (12–15). Candida species are yeasts that are part of the normal flora that colonize the human gastrointestinal and genitourinary tracts. C. albicans is the most common colonizing species and is the cause of most infections. Candida glabrata (formerly Torulopsis glabrata) is an important cause of urinary tract infection and candidemia in older adults (16,17). In some hospitals, the proportion of fungemias due to C. glabrata is strikingly higher in those age 60 and older (17). Candida glabrata is also disproportionately increased in the oropharynx of octogenarians compared with those who are ages 60 to 80, and is a cause of denture stomatitis (18) (Table 1). Candida parapsilosis and C. tropicalis, although found less frequently, also cause serious infection. Candida parapsilosis is strongly associated with infection of intravascular catheters (19,20), and C. tropicalis is prominent in patients with malignancies (16,20). The widespread use of antifungal agents, among other factors, has contributed to the emergence of more resistant species of Candida, such as C. krusei and C. lusitaniae (20,21). However, these species appear to be more problematic in the acute care setting than in the LTCF. Risk factors and patterns of yeast colonization among residents of LTCFs have been assessed in very few studies (12,13). One study noted that 84% of residents of a veterans’ LTCF were colonized with yeasts on at least one occasion; overall, 42% had intermittent colonization, and 16% were persistently colonized (12). Risk factors independently associated with colonization included neurogenic bladder, lower extremity amputation, and low serum albumin concentration. Diabetes mellitus, often considered a risk factor for Candida infections, was not associated with high rates of colonization with Candida species. However, it should be noted that that study did not assess candiduria, which has been strongly associated with diabetes mellitus (22,23).

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Most Candida infections are acquired as the result of overgrowth and subsequent invasion by Candida species that are indigenous to the host’s gastrointestinal tract. For these normally commensal yeasts to become pathogenic, interruption of the normal host defenses must occur. For many residents, infection begins with disruption of the gastrointestinal mucosal barrier and culminates in tissue invasion and hematogenous dissemination. Neutrophils and monocytes provide the major defense against Candida species that breach the mucosal barriers. Thus, residents with severe and prolonged neutropenia are at risk for candidemia and disseminated candidiasis. This type of resident is infrequently cared for in a LTCF. Somewhat ironically, cell-mediated immunity is important in the control of growth of Candida on mucosal surfaces; thus, acquired immunodeficiency syndrome (AIDS) patients with low CD4 cell counts suffer from recurrent oral, esophageal, and vaginal candidiasis but have no increased risk of candidemia. Some forms of mucocutaneous candidiasis in older adults are associated with diminished cell-mediated immunity; most, however, are the result of local physiological changes associated with aging, such as xerostomia. 3. Cryptococcosis Infection with Cryptococcus neoformans is uncommon in the LTCF. The infection is almost always acquired from the outside environment and not in the hospital or nursing home. This heavily encapsulated yeast is inhaled, causing pulmonary infection, which is usually asymptomatic. Because of the organism’s neurotropism, the most common clinical manifestations of cryptococcosis are those that occur after spread to the central nervous system. Only rarely is the source and time of exposure to C. neoformans established. Development of cryptococcal meningitis in a resident in an LTCF is most likely the result of reactivation of infection acquired years earlier. Cryptococcosis is noted most often in older adults who have been treated with corticosteroids, have received an organ transplant, or who have diabetes mellitus, renal failure, liver dysfunction, or chronic obstructive pulmonary disease. However, approximately 20% to 30% of patients, most of whom are older, have no underlying risk factors (24). C. Invasive Filamentous Fungal Infections Aspergillus and the zygomycetes, Mucor and Rhizopus, the filamentous fungi most often implicated in human disease, are ubiquitous in the environment and grow especially well in decaying organic material. Only rarely do these fungi infect residents in the LTCF (Table 1). Almost always, invasive infections with these fungi occur in immunosuppressed patients, especially those who are taking

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corticosteroids and are neutropenic. However, more indolent forms of infection with Aspergillus do occur in older adults who are not immunosuppressed or have only mild immunosuppression (25,26). The zygomycetes have a propensity to cause infection in patients with diabetes mellitus complicated by ketoacidosis and in those with iron overload states that require treatment with the iron chelator, deferoxamine (27,28). Overall, however, infections with filamentous fungi are very uncommon in the LTCF.

II. CLINICAL MANIFESTATIONS A. Dermatophyte Infections 1. Tinea Corporis (Ringworm) The dermatophytes characteristically produce annular lesions that have prominent edges and contain pustules, central clearing, and scaling. Pigmented skin can become hyperpigmented. There may be single or multiple lesions that tend to occur on the trunk or legs. Pruritus may be present, but is often mild. The rash should be differentiated from contact dermatitis, eczema, and psoriasis. 2. Tinea Cruris This manifestation is seen almost exclusively in men. Infection usually starts with scaling and irritation in the groin and then extends to involve the anterior thighs. The rash may be unilateral or bilateral and is erythematous and pustular. Tinea cruris is commonly associated with tinea pedis, which may act as a reservoir after apparent cure. The rash must be differentiated from that of intertrigenous candidiasis, erythrasma caused by Corynebacterium, and psoriasis, which can occasionally present as a rash in the groin. The absence of satellite lesions beyond the edge of the rash points toward a dermatophyte infection, rather than candidiasis, and erythrasma and psoriasis are not pustular. 3. Tinea Capitis Dermatophyte infections of the scalp vary depending on the infecting species. The main clinical appearances are scaling of the scalp skin with varying levels of erythema, pustules, and alopecia. Infections with species transmitted from animals often produce marked pustules. Tinea capitis is rarely seen in elderly residents. 4. Tinea Pedis This is another dermatophyte infection that is far more common in men than women. It is very common in institutions in which common bathing facilities are used. The infection usually starts in the web spaces of the lateral toes with char-

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acteristic peeling, fissures, maceration, and pruritus. Superinfection of web space tinea pedis by bacterial pathogens may cause a sudden worsening of symptoms. The soles and lateral borders of the feet are also involved, showing erythema and scaling. Residents who have recurrent lower extremity cellulitis should be examined carefully for signs of tinea pedis, as this is a frequent point of ingress of streptococci and staphylococci into the dermis (29). 5. Onychomycosis Fungal infection of the nail is predominantly caused by dermatophytes. Almost always, persons with onychomycosis caused by dermatophytes also have chronic tinea pedis. Several clinical types of onychomycosis have been described (30,31). The most common is distal and lateral subungual onychomycosis in which the nail bed is invaded from the distal and lateral borders. The nail becomes thickened and can take on a white, yellow, or brown hue. The distal part of the nail can completely crumble. In contrast to Candida nail infections, fingernails are much less commonly affected than toenails. B. Yeast Infections 1. Tinea Versicolor This benign skin infection usually presents as flat round patches of hypo or hyperpigmented skin on the neck, chest, or upper arms. Mild pruritus may be present, and a fine scaling can be seen. The lesions should be differentiated from those associated with vitiligo, in which no scaling is present. 2. Candida Infections (Table 2) a. Oropharyngeal Candidiasis. Oropharyngeal candidiasis (thrush) is associated with a number of different local and mechanical factors (32). These factors include the use of broad-spectrum antibiotics, inhaled corticosteroids, and radiation therapy to the head and neck areas. Additionally, xerostomia, related to a variety of systemic diseases and different medications, is associated with increased colonization and infection with Candida (33,34). Age alone is not sufficient for the development of oropharyngeal candidiasis. If thrush is present in an older adult who has no obvious risk factors, the possibility of underlying immunosuppression resulting from cancer or AIDS should be explored. White plaques appear on the buccal, palatal, and oropharyngeal mucosa; these usually are not painful and can be scraped off with a tongue depressor, revealing erythematous mucosa. With or without oropharyngeal lesions, patients may have painful cracks at the corners of the mouth (perleche or angular cheilitis) (14,32).

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Table 2 Major Clinical Manifestations of Infection with Candida Manifestation Oropharyngeal (thrush) Cutaneous (intertrigo) Onychomycosis Vulvovaginitis Urinary tract infection Candidemia Invasive candidiasis

Major characteristics White plaques on buccal mucosa, palate, tongue; under upper dentures appears as diffuse erythema Erythematous, pustular, pruritic rash in warm moist areas; satellite lesions beyond primary border common Thickened, opaque nails with onycholysis Erythema, white exudate, and discharge; vulvar pruritus Lower tract infection - dysuria, increased frequency Upper tract infection - fever, flank pain, nausea, vomiting Fungus ball may form and obstruct collecting system Fever, chills, hypotension, tachycardia,“toxic” appearance Pustular skin lesions, retinal lesions, vitritis Depends on organ involved - includes osteoarticular infections, endocarditis, meningitis, hepato-splenic candidiasis

Denture stomatitis (chronic atrophic candidosis) is a variant of oral candidiasis that has been noted in as many as 65% of residents who wear dentures and occurs particularly in those with full upper dentures (35). Lower dentures are rarely linked to the development of candidiasis. Residents who have poor oral hygiene and who do not remove their dentures at night are more likely to develop this form of oropharyngeal candidiasis. Plaques are rarely observed under the dentures; more often, diffuse erythema is seen on the hard palate when upper dentures are removed. Residents may be asymptomatic, but often complain of pain and irritation associated with their dentures. b. Candida Infections of the Skin and Nails. Candida infection of the skin (intertrigo) occurs mostly under pendulous breasts or pannus and in the perineum. The erythematous, pruritic, frequently pustular lesions have a distinct border; smaller satellite lesions provide a clue to the diagnosis of candidiasis. However, scratching may distort the typical lesions and make the diagnosis more difficult. The main differential diagnosis is tinea cruris or tinea corporis resulting from dermatophytes. Most cases of onychomycosis are caused by dermatophytes; however, Candida also can infect the nails, especially those of the hand. The nails become thickened, opaque, and wrinkled, the condition may be painful, and onycholysis is frequent (36). Older adults with diabetes mellitus can have serious consequences from onychomycosis. The thickened nails are difficult to trim, predisposing these residents to trauma and subsequent bacterial infections, such as paronychia and cellulitis. Candida can also cause paronychia; this occurs most often in those whose occupation involves frequent immersion of their hands in water and is an unlikely infection among residents in a LTCF.

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c. Vulvovaginitis. Candida vulvovaginitis is not increased in older women. After menopause, Candida vulvovaginitis actually becomes less common. This decrease is likely related, at least in part, to the estrogen dependence of Candida vaginal epithelial colonization (37). Estrogen replacement therapy to prevent menopausal vasomotor symptoms, osteoporosis, and heart disease increases vaginal Candida colonization but has not been associated with an increase in vulvovaginitis in older women. Among older women with Candida vulvovaginitis, risk factors include diabetes mellitus, corticosteroid therapy, and broad-spectrum antibiotic therapy (38). Episodes of vaginitis may recur with intermittent antibiotic therapy. Candida vulvovaginitis is manifested as vulvar pruritus, vaginal discomfort, and discharge; classically, the discharge is described as curdlike, but it can also be thin and watery. External burning is experienced with urination. The labia are often erythematous and swollen; the vaginal walls show erythema, and white plaques and discharge usually are evident. d. Candida Urinary Tract Infections. Candiduria is a frequent finding in residents of LTCFs. Factors predisposing to candiduria include diabetes mellitus, the use of broad-spectrum antibiotics, the presence of an indwelling urinary catheter, and genitourinary tract abnormalities (22,23,39,40). Most residents with candiduria are asymptomatic and probably do not have infection, but merely colonization. Residents with lower urinary tract infection can have symptoms similar to those seen with bacterial cystitis: suprapubic discomfort, dysuria, and frequency. Those who have upper urinary tract infection may present with fever, flank pain, nausea, and vomiting, these symptoms are indistinguishable from acute bacterial pyelonephritis. Uncommonly, a fungus ball composed of fungal hyphae may form and obstruct the collecting system at any level. e. Systemic Candida Infections. Risk factors for infection in older adults include broad-spectrum antibiotics, indwelling urinary and central vascular catheters, hyperalimentation, renal failure, and surgical procedures involving the gastrointestinal (GI) tract (41,42). In the LTCF, a group of residents at high risk for candidemia are those who are receiving hemodialysis. Immunosuppressive drugs, increasingly used for residents with dermatologic and rheumatologic conditions, also can contribute to the risk for development of systemic candidiasis when they cause neutropenia. The attributable mortality from candidemia approaches 38% (42) and appears to be higher in the elderly population (43). Candidemia is the most obvious manifestation of serious infection with Candida species, but patients may have septic shock or organ invasion without positive blood cultures. The patient with candidemia often appears “toxic,” and the clinical presentation cannot be distinguished reliably from that caused by bacteremia. Clinical clues to the diagnosis of candidemia include the appearance of skin and retinal lesions. The skin lesions are

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papular to pustular, have a small zone of surrounding erythema, and are not painful or pruritic. The retinal lesions appear as white exudates that can extend into the vitreous and obscure the retina. The presence of yeast in the urine is associated with both hematogenous spread and ascending urinary tract infection, and thus is not a helpful sign in the diagnosis of candidemia, especially in a patient with an indwelling urethral catheter. Once bloodstream invasion has occurred, the development of microabscesses in many organs is common. The eyes, kidneys, liver, spleen, brain, and bones are the most commonly involved sites. 3. Cryptococcosis An appreciation of the clinical findings of cryptococcal meningitis is important, as this is a treatable cause of mental status changes in older adults. Cryptococcosis typically presents as subacute meningitis, but in older persons, mental status changes without fever, headache, or focal neurological findings may be the only manifestation (44,45). Isolated pulmonary cryptococcosis occurs more often in older adults than their younger counterparts (24,46). A recent retrospective review of 316 patients who did not have concomitant human immunodeficiency virus (HIV) infection noted that mortality rates for patients with either meningitis or pulmonary cryptococcosis were higher for those older than age 60 (24). C. Invasive Filamentous Fungal Infections 1. Sino-Orbital Aspergillosis Older adults who develop sino-orbital aspergillosis usually are not overtly immunosuppressed, although some have had prior corticosteroid therapy. Orbital pain and loss of vision are the most common presenting symptoms; proptosis, ophthalmoplegia, and decreased visual acuity are noted on examination. The infection often arises in adjacent sinuses and then extends behind the orbit entrapping the optic nerve; further extension into cerebral vessels and brain may occur. 2. Chronic Necrotizing Pulmonary Aspergillosis This form of aspergillosis occurs mostly in middle-aged and elderly men who have underlying chronic obstructive pulmonary disease (25). These individuals generally are not immunosuppressed, other than occasional corticosteroid therapy. Symptoms are those of a progressive pneumonia that is unresponsive to antibacterial agents and that progresses to include cavitation and pleural involvement. Cough productive of purulent sputum with occasional hemoptysis, pleuritic chest pain, and increasing dyspnea, as well as fever, night sweats, anorexia, weight loss, and fatigue are common. The differential diagnosis includes other fungal pneumonias, such as histoplasmosis and blastomycosis, atypical mycobac-

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terial infections, nocardiosis, actinomycosis and, less commonly, chronic bacterial pneumonias. 3. Zygomycosis (Mucormycosis) This life-threatening infection is seen rarely in the LTCF. In this setting, residents likely to develop zygomycosis are diabetics who have poor glycemic control and are prone to ketoacidosis and residents who have myelodysplastic syndromes, are transfusion-dependent, and require treatment with an iron chelator. The zygomycetes have a propensity to invade through blood vessels, causing infarction and necrosis (47). Residents present with rapidly progressive painful necrotic lesions of the palate, nares, sinuses, or orbit. If this diagnosis is suspected, the residents must be transferred immediately to an acute care hospital for diagnosis and treatment.

III. DIAGNOSTIC APPROACH A. Localized Mucocutaneous Infections 1. Skin Infections The diagnosis of most dermatophyte and cutaneous yeast infections is made by clinical appearance. However, if no improvement is noted within 1 to 2 weeks of initiating local therapy or if the lesions are extensive enough to warrant systemic therapy, microscopic examination of scrapings from the lesion should be performed. This will ensure that noninfectious causes of rash are not treated inappropriately and that the appropriate antifungal agent is used for treatment. Scrapings should be taken from the edge of the lesion with a scalpel blade, collected on a piece of dark paper, and transferred to a slide, on which is added a drop of potassium hydroxide (9). Microscopic examination reveals hyphae in cases of dermatophyte infection and yeast when Candida or Malessezia is the cause of the infection. If there is a suspicion of an outbreak of dermatophyte infections or of a possible animal source of the infection, then skin scrapings should be sent for culture (in a paper packet, not in a culture transport tube as used for bacterial infections), or consultation should be sought with a dermatologist, who can provide advice and collect the appropriate samples. 2. Nail Infections For individuals with onychomycosis, full-thickness nail clippings taken as close to the nail bed as possible may show fungal elements when viewed under direct microscopy after potassium hydroxide digestion. However, for up to 50% of clinically diagnosed cases of onychomycoses, fungi will not be seen (48). Culture of

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the nail is especially useful for cases of onychomycosis, because treatment courses are long and not without side effects and drug-drug interactions (49). 3. Mucous Membrane Infections Oropharyngeal and vaginal candidiasis are diagnosed primarily by clinical appearance. Scrapings of the exudates that are then stained with Gram’s stain or visualized as a wet preparation reveal budding yeasts and, often, pseudohyphae. Culture is usually not necessary unless there is a poor response to therapy or multiple recurrent episodes. In that situation, fungal culture will show whether an unusual drug-resistant species is the cause of the infection and will guide further therapy. B. Candida Urinary Tract Infections A major dilemma arises in determining whether yeasts in a urine sample represent contamination, colonization, or infection (39,40,50) (Table 3). Contamination

Table 3 Approach to the Patient with Candiduria in the Long-Term Care Facility 1. Repeat culture to be sure not a contaminant. 2. If repeat culture is () and patient is asymptomatic: –assess predisposing factors (diabetes mellitus, antibiotics, indwelling catheters, genitourinary tract abnormalities) and correct if possible –if remains asymptomatic, observe, do not treat 3. If repeat culture is () and patient has mild symptoms suggesting lower urinary tract infection: –culture urine for bacteria and treat if found; check whether symptoms resolve –assess predisposing factors as listed above and correct if possible –bacterial infection not present, predisposing factors removed, observe clinical response and repeat urine culture to see if funguria has cleared –if remains symptomatic and funguria remains, treat with fluconazole 14 days 4. If repeat culture is () and patient appears ill: –image the genitourinary tract to be sure no obstruction present (ultrasound, CT scan) –if obstruction present, urology consult for options to relieve obstruction –obtain blood cultures to be sure not fungemic –correct predisposing factors when possible –treat with fluconazole 14 days 5. Follow urine cultures at end of therapy, if clinical condition worsens at any time during treatment, and several weeks after therapy has ended to be certain funguria has cleared. Abbreviation: CT, Computed tomography.

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may be detected by repeating the collection and culture of the urine. In older women, catheterization of the urethra may be needed to obtain an uncontaminated urine specimen. The difference between colonization and infection is less clearly defined. This problem has arisen, in part, because candiduria is usually an asymptomatic condition. Currently, no test on urine can differentiate Candida colonization from infection (23). The presence of a urinary catheter in most residents with candiduria limits the usefulness of pyuria. Yeast quantitation has not proved helpful in separating infection from colonization. The presence of pseudohyphae, although once thought to indicate urinary tract infection, also has not proved useful. For residents suspected of having upper tract infection, imaging studies are necessary. Ultrasonography, computerized tomography, or retrograde pyelography can be used to ascertain the presence of hydronephrosis; fungus balls are seen as masses obstructing the collecting system or filling the bladder. C. Systemic Infections 1. Candidiasis The diagnosis of candidiasis should be entertained in any resident in the LTCF who appears septic and who has any of the risk factors noted above, especially hemodialysis and presence of central intravenous catheters, for invasive candidiasis. Blood should be cultured using the same techniques used for bacteria. A single positive culture yielding yeast is adequate for a diagnosis of candidemia. However, blood cultures yield the organism in as few as 50% of cases of invasive candidiasis (51). Residents who are suspected of having systemic Candida infection should be transferred to an acute care facility where further diagnostic procedures can be performed. 2. Cryptococcosis Residents suspected of having cryptococcal meningitis should have a lumbar puncture performed, including measurement of opening pressure. This will usually require transfer to an acute care facility. The typical cerebrospinal fluid (CSF) findings are those of a lymphocytic meningitis with elevated protein and decreased glucose (24). A latex agglutination test for cryptococcal polysaccharide capsular antigen is available in most hospitals. This assay, which should be performed on both CSF and blood, is very sensitive and specific for cryptococcal infection. Cultures of blood and CSF readily yield C. neoformans using standard techniques. 3. Filamentous Fungi Many filamentous fungi are ubiquitous in the environment. Although easily grown from sputum, proof of infection, except in very immunosuppressed pa-

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tients, almost always requires biopsy evidence of tissue invasion. When suspicion of invasive aspergillosis or zygomycosis arises, the resident should be immediately transferred to an acute care facility so that appropriate histopathological and microbiological tests can be performed.

IV. THERAPEUTIC INTERVENTIONS A. Localized Mucocutaneous Infections 1. Skin Infections Both dermatophyte and yeast infections of the skin usually respond to topical therapy with creams or lotions (52). Lotions or sprays are easier to apply to large or hairy areas. Particularly for tinea cruris and intertrigenous candidiasis, the affected area should be kept as dry as possible; otherwise, recurrence is likely after discontinuation of the antifungal agent. Scalp infections often require systemic treatment with an antifungal agent. However, tinea versicolor rarely requires therapy with a systemic agent and often responds to the application of selenium sulfide shampoo (10). For residents who have extensive skin lesions, oral azole agents or terbinafine can be used to clear the lesions more quickly. Terbinafine or itraconazole are generally used for dermatophyte infections, and itraconazole or fluconazole for Candida infections. Terbinafine has fewer drug-drug interactions than itraconazole and, for that reason, should be used first for those older adults who require systemic therapy for dermatophyte infections. 2. Nail Infections Onychomycosis does not respond to topical therapy (31,53–55) (Table 4). Either itraconazole or terbinafine, both of which accumulate in the nail plate, can be used to treat onychomycosis. Toenail infection is more difficult to cure than fingernail infection. Treatment with oral itraconazole or terbinafine, given as pulsed therapy

Table 4 Recommended Management of Onychomycosis Keep nails short and straight to avoid ingrown toenails File nails that have become hypertrophic Wash feet daily and dry well, especially between the toes, after bathing Keep feet dry with use of antifungal powder and cotton socks Avoid sharing instruments for nail clipping and filing among patients Make a diagnosis of fungal infection by looking at nail clippings for fungal elements and, if the diagnosis is questionable, by culture of nail clippings, before treatment Treat with oral itraconazole or terbinafine for 3–6 months

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1 week out of each month for 3 to 6 months, or daily itraconazole or terbinafine for 3 months gives a higher success rate than previously seen with griseofulvin or ketoconazole (53–55). Terbinafine is less active against Candida than itraconazole and is a second-line agent for Candida onychomycosis. 3. Oropharyngeal Candidiasis Oropharyngeal candidiasis is usually easily treated with clotrimazole troches or nystatin suspension. However, unless the underlying cause is removed, the infection often returns after treatment is discontinued. Oral fluconazole or itraconazole suspension should be reserved for residents with more severe disease, such as might occur after chemotherapy or radiation therapy. Treatment of denture stomatitis requires removal of the dentures at night and vigorous brushing and disinfection of the appliance, along with topical antifungal solutions or lozenges. For recalcitrant cases, systemic therapy with oral fluconazole, in addition to local measures related to the appliance, are usually effective. Treatment options have recently been extensively reviewed (32). 4. Vulvovaginitis The successful treatment of Candida vaginitis is usually accomplished by the application of topical creams or suppositories (37,38). Older women who are frail or suffering from dementia may find topical agents difficult to apply. Single-dose fluconazole is an attractive, easily tolerated alternative for these residents and is preferred by many women. Removing any precipitating factors is important to prevent recurrence. However, some women will continue to have recurrent infection; treatment with suppressive doses of fluconazole or ketoconazole is helpful in this circumstance (38). B. Candiduria The treatment of candiduria is debated (39,40,50,51,56). Given the benign nature of candiduria and our inability to differentiate colonization from infection, antifungal therapy should not be given unless the resident appears to have symptomatic urinary tract infection or obstruction of the collecting system due to Candida (Table 3). Candiduria will often disappear with removal of the predisposing factors (22,57). Thus, the first step is to remove the indwelling urinary catheter and stop antibiotics, if possible. When treatment is deemed necessary, fluconazole, 400 mg for the first dose then 200 mg daily for 2 weeks, has been shown to be effective (51,57). However, lower doses have been used in some studies (58,59). Bladder irrigation with amphotericin B can be used to eliminate candiduria, but it is unclear whether this reflects treatment of lower tract infection or merely eradication of colonization (50,58,59).

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C. Systemic Infections The management of residents suspected of an invasive fungal infection will almost always involve transfer of the resident to an acute care facility for diagnosis and initial treatment. 1. Candidiasis Residents who develop invasive candidiasis while in the LTCF will almost always be transferred to an acute care hospital. Alternatively, residents with established Candida infection of certain sites, such as osteoarticular structures and eye, often are transferred from an acute care hospital to a LTCF after their condition has stabilized, for the purpose of receiving parenteral antifungal therapy. In this situation, it is recommended that consultation with an infectious diseases consultant be obtained. Candidemia and invasive candidiasis can be treated with either amphotericin B or fluconazole (51). For severely ill residents, those with infection caused by C. glabrata or C. krusei, and those with certain end-organ disease, amphotericin B remains the drug of choice. 2. Cryptococcosis Cryptococcal meningitis requires induction treatment with intravenous amphotericin B and oral flucytosine. Combination therapy should continue for at least 2 weeks or until the CSF cultures become negative and the resident has begun to improve (60). Consolidation therapy with oral fluconazole is given for 10 weeks or longer, depending on the resident’s response, and may be carried out in the LTCF. Pulmonary cryptococcosis without evidence of disseminated infection can be treated with fluconazole in most cases; the drug should be continued until all lesions have resolved (24). 3. Invasive Filamentous Fungi Chronic necrotizing pulmonary and sino-orbital aspergillosis are usually treated initially with amphotericin B (61). Patients are almost always in hospital during the initiation of antifungal therapy, but may continue with long-term antifungal treatment in the LTCF with either amphotericin B or itraconazole. Patients with zygomycoses are treated with amphotericin B given in high doses, because Rhizopus and Mucor species are only modestly susceptible to this drug and resistant to other antifungal agents. Surgical debridement of all necrotic tissue is essential. D. Specific Antifungal Agents 1. Azoles Azole agents have become the preferred treatment for localized yeast infections when topical agents have not proved effective, and they play an important role in

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the treatment of systemic infections (62–64). Three azole antifungal agents are currently available: ketoconazole, itraconazole, and fluconazole. Itraconazole has largely supplanted ketoconazole for treatment of localized infections, and it also has an adjunctive role in the treatment of some forms of aspergillosis. Fluconazole has a narrower spectrum of activity than itraconazole, but remains the primary azole used for the treatment of cryptococcosis and all forms of candidiasis. Fluconazole has superior pharmacological attributes, in that the oral formulation is almost 100% bioavailable, the drug distributes into most compartments including the eye and the CSF, and it is excreted as active drug in the urine. Itraconazole and ketoconazole, however, have problematic absorption, are lipophilic and accumulate in the skin and nails, and are metabolized by the liver and not excreted as active drug into the urine. Ketoconazole and itraconazole require gastric acid for absorption (63,64). In addition, the capsule formulation of itraconazole is absorbed best when given with food. Therefore, histamine receptor antagonists (H2 blockers), antacids, and proton pump inhibitors should not be administered to patients requiring therapy with ketoconazole or itraconazole (Table 5). In older adults who are more likely to have achlorhydria than younger adults, absorption of both of these agents may be erratic (65,66). The oral suspension of itraconazole, given on an empty stomach, has approximately 30% better absorption than the capsule formulation. Whether this is also true for older adults has not been established. This formulation should always be used in those patients who must also take agents that inhibit gastric acid secretion. Azoles have few side effects. Rash and nausea can occur with all azoles. Fluconazole causes reversible alopecia. Hepatitis, which can occur with all azoles, is rare, but can be life-threatening. Liver function tests should be measured at baseline and after several weeks of therapy. Mild elevations of serum alanine aminotransferase or aspartate aminotransferase (twofold to threefold increase over normal) do not require stopping the drug, but do require careful follow-up. If the levels increase further, the drug should be discontinued. Itraconazole causes hypertension, edema, and hypokalemia; although uncommon, this Table 5 Drugs That Decrease Serum Azole Levels Azole Ketoconazole Itraconazole capsules Itraconazole suspension Fluconazole

Drugs that decrease azole levels Rifampin, isoniazid, phenytoin and all drugs that decrease gastric acid* Rifampin, rifabutin, phenytoin, carbamazepine and all drugs that decrease gastric acid* Rifampin, rifabutin, phenytoin, carbamazepine Rifampin

* Includes antacids, histamine receptor antagonists (H2) blockers, proton pump inhibitors.

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Table 6 Effects of Azole Antifungal Drugs on Serum Levels of Other Drugs Drug affected

Ketoconazole

Itraconazole

Fluconazole

Cyclosporine Tacrolimus Warfarin Phenytoin Carbamazepine Terfenadine Astemizole Cisapride Digoxin Oral hypoglycemics Isoniazid Rifampin Rifabutin Triazolam, alprazolam, midazolam Lovastatin, simvastatin, etc.

Increased* Increased* Increased* Increased* None known Increased† Increased† Increased† None known Increased* Decreased Decreased None known Increased

Increased* Increased* Increased* None known None known Increased† Increased† Increased† Increased* None known None known None known None known Increased

Increased* Increased* Increased* Increased* Increased* No effect None known Increased† None known Increased* None known None known Increased Increased

None known

Increased†

None known

* Significant interaction, monitor serum levels of drug and/or clinical status. † Life-threatening interaction; avoid the combination.

complication occurs most often in older adults and often requires stopping the drug (66). The azoles have the potential to produce serious and even life-threatening drug-drug interactions through their actions on the cytochrome P450 system (62–64) (Table 6). Itraconazole and ketoconazole are the most problematic. Patients receiving cholesterol-lowering agents, such as simvastatin and lovastatin, can develop life-threatening rhabdomyolysis when given itraconazole. Increased serum levels of warfarin, phenytoin, and oral hypoglycemic agents occur when azoles are given with these commonly used drugs in older adults. Itraconazole increases serum levels of digoxin in some, but not all patients. Coadministration of an azole with cisapride, astemizole, or terfenadine is contraindicated because the azoles potentiate the electrocardiogram (QT) prolongation induced by these drugs. Thus, in older adults who take many medications and may have multiple healthcare providers, careful attention to existing drug regimens before adding an azole is important to avoid serious and life-threatening drug-drug interactions. 2. Terbinafine Oral terbinafine is readily absorbed and concentrates in the stratum corneum, hair follicles, and nails. The drug is usually tolerated well, although loss of or changes in

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taste perception can occur and are distressing to patients. Hepatitis, Stevens-Johnson syndrome, and neutropenia are serious but rare side effects. Terbinafine is metabolized by P450 enzymes in the liver, but it does not affect the metabolism of other drugs, such as warfarin, as is noted with the azoles (67). However, rifampin will increase the metabolism of terbinafine, thus decreasing serum terbinafine levels. 3. Amphotericin B Amphotericin B is the drug of choice for several serious fungal infections. This drug will rarely be initiated in the LTCF. However, patients are increasingly transferred to a LTCF to be given amphotericin B after the initial phase of the infection has been treated in hospital. Nephrotoxicity manifested by a rising creatinine, hypokalemia, or hypomagnesemia, is seen in almost all older adults receiving amphotericin B (65,66,68). Patients with underlying renal disease show a more rapid rise in creatinine. Concomitant use of other nephrotoxic drugs should be avoided. During amphotericin B treatment, salt restriction should be stopped and diuretics should be used very judiciously, because enhanced nephrotoxicity, presumably related to sodium depletion and hypovolemia, is likely to occur. Sodium loading can decrease nephrotoxicity, but this can be problematic in older adults who have pre-existing heart failure. Potassium and magnesium losses can be large and can contribute to other organ dysfunction; for this reason, electrolytes should be monitored carefully and replaced as soon as the serum levels show even a slight decrease. In many patients, intravenous repletion is ultimately required to keep pace with the renal loss. Infusion-related reactions are often experienced by patients receiving amphotericin B. Chills or rigors, fever, nausea, headache, and myalgias occur in the majority of patients treated. Many of these side effects can be diminished or eliminated by administering certain drugs before the infusion (69). Three lipid formulations of amphotericin B are currently available: liposomal amphotericin B (L-AmB; AmBisome®), amphotericin B lipid complex (ABLC; Abelcet®), and amphotericin B colloidal dispersion (ABCD; Amphotec® or Amphocil®). Each differs from the others and from standard amphotericin B in respect to composition, pharmacological parameters, recommended dosages, toxicities, and cost, but all are less nephrotoxic. These agents have been reviewed recently (70,71). Because most older patients who require more than a few days of therapy with amphotericin B will develop some degree of renal failure, the use of one of the less nephrotoxic lipid formulations is attractive. V. INFECTION CONTROL MEASURES A. Dermatophyte Infections With the exception of tinea capitis, transmission of dermatophytes from person to person is uncommon. Isolation of residents with these infections is unnecessary

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and not recommended. Rarely, transmission of tinea corporis from resident to resident or resident to healthcare worker by direct contact has occurred in LTCFs (5–8). It is important to quickly evaluate suspicious lesions to prevent transmission that can occur before treatment is begun. In at least one outbreak, spread to healthcare workers was likely facilitated by a delay in treatment (5). Tinea capitis can also be spread by fomites, such as hats or hairbrushes. Transmission can occur from areas of skin and scalp that do not appear infected; thus, sharing of hairbrushes should not be allowed at any time. Dogs and cats, increasingly common in LTCFs, have been documented as a source for dermatophyte infections, especially those caused by Microsporum canis (9). Most animals brought into LTCFs for pet therapy should be checked to be sure they are healthy. In the rare circumstance that a dog or cat is involved in an outbreak, the animal must be treated, as well as the residents, to eliminate the infection. Tinea pedis may be spread in public bathing facilities, such as pools and showers (72). Dermatophytes can remain viable on wet floors until they subsequently adhere to feet (73). Private tubs and showers help obviate spread within a facility. If these are not available, simple measures, such as drying the feet well after washing, will decrease dermatophyte adherence and the potential for infection (74). Additionally, disinfecting the tub or shower after each patient use with an appropriate agent, such as a quaternary product, will decrease spread among patients. B. Yeast Infections There is no evidence of intrafacility spread of tinea versicolor, and thus no need for isolation precautions for patients with this infection. Candida infections are primarily acquired from the person’s own endogenous flora. Transmission from person to person is distinctly unusual, although it has been documented in the acute care hospital setting (75,76). Scrupulous care of intravenous catheters, especially indwelling dialysis catheters and those used for total parenteral nutrition, using standard infection control techniques, is important to help prevent catheter-associated candidemia. Isolation precautions are not required for patients with Candida infections. Cryptococcosis is acquired outside the facility and is not spread from person to person. Hands of healthcare workers are not a means of transmission of this organism. No isolation precautions are required for patients with cryptococcal infection. C. Invasive Filamentous Fungal Infections These infections are rarely acquired in the LTCF and are not transmitted from person to person or by healthcare workers. There is no need for isolation precautions for residents with aspergillosis or zygomycosis in LTCFs.

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VI. PREVENTION A. Dermatophyte Infections Prevention of dermatophyte infections involves good local hygiene for residents of LTCFs. Skin should be kept dry and maceration avoided, if at all possible. Routine visits by a podiatrist will lead to improved care of toenails and early diagnosis and appropriate therapy for tinea pedia and onychomycosis. The feet should be washed and dried between the toes every day; heavy socks and shoes that increase sweating should be avoided and socks should be changed daily (29). Appropriate disinfection of communal showers will help decrease the risk for spread of tinea pedis. The sharing of hairbrushes, hats, and scarves should be avoided to help prevent tinea capitis. The use of standard precautions by healthcare workers will help to decrease the occurrence of outbreaks of tinea corporis (6,8). Prophylactic use of antifungal agents has no role to play in preventing dermatophyte infections. B. Yeast Infections Cutaneous yeast infections, such as intertrigo, onychomycosis, and paronychia, can be prevented by the measures described for dermatophytes. Prevention of oropharyngeal candidiasis is related directly to decreasing those factors that contribute to growth of Candida in the mouth. Avoiding drugs that cause xerostomia, decreasing the use of inappropriate broad-spectrum antibiotics, and emphasizing good dental hygiene will help to decrease the risk of thrush (32,34). The care of dentures is exceedingly important in the prevention of denture stomatitis. Dentures should always be removed at night and should be cleaned daily by brushing with a denture brush and soaking in a disinfectant solution, such as chlorhexidine, or a commercially available denture cleanser (32). Prevention of Candida vulvovaginitis and urinary tract infections should focus on removal of those factors that lead to infection. In the case of vulvovaginitis, hyperglycemia, corticosteroid use, and broad-spectrum antibiotic therapy often contribute to development of vaginitis and should be modified when feasible. Candida urinary tract infections rarely occur in the absence of indwelling urethral catheters and broad-spectrum antibiotic use. One option that can be used more readily in men than women in LTCFs is the use of intermittent rather than longterm catheterization; however, it has not been proved that this will decrease the risk for Candida urinary tract infections. Because most cases of candidemia and invasive candidiasis in the LTCF will likely occur in residents undergoing long-term hemodialysis or those with central intravenous catheters in place for nutritional supplementation or other reasons, prevention rests with scrupulous care of the catheter. Prophylactic use of azole agents to prevent Candida infections should be reserved for those patients who have frequent recurrent episodes of thrush or vulvovaginitis and for whom risk factors cannot be modified.

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C. Invasive Filamentous Fungal Infections Because infections with Aspergillus or the zygomycetes are rare in the LTCF and are not related to any specific practices in that setting, special preventive measures need not be taken. REFERENCES 1. 2. 3. 4. 5. 6. 7.

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Appendix A Definitions of Common Infections in Long-Term Care Facilities

REFERENCE McGeer A, Campbell B, Emori TG, Hierholzer WJ, Jackson MM, Nicolle LE, Peppler C, Rivera A, Schollenberger DG, Simor, AE, Smith PW, Wang EE-L. Definitions of infection for surveillance in long-term care facilities. Am J Infect Control 1991; 19:1–7. I. CONDITIONS APPLICABLE TO DEFINITIONS A. Only new symptoms or acute changes in chronic symptoms that suggest possibility of an infection should be considered. B. Potential noninfectious causes of the symptoms and signs exhibited by the resident should always be considered before diagnosing an infection. C. Infection should be diagnosed based on several supporting data and not on a single finding. Microbiological and radiological findings should be used only to confirm clinical evidence of infection. II.

RESPIRATORY TRACT INFECTION A.

Influenza-like illness 1. Temperature of 100.4°F (38°C) or higher AND 2. Presence of at least three of the following clinical manifestations: a. Chills b. New headache or eye pain c. Malaise or anorexia d. Sore throat 473

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e. Myalgia f. New or increased dry cough 3. Symptoms or signs must be present during influenza season (e.g., November to April in United States and Canada) to make the diagnosis of influenza. B. Bronchitis or tracheobronchitis 1. Presence of at least three of the following clinical manifestations: a. New or increased cough b. New or increased sputum production c. Temperature of 100.4°F (38°C) or higher d. Pleuritic chest pain e. New or increased rales, rhonchi, wheezes, or bronchial breathing on physical examination of the chest. f. Indication of a change in status or breathing difficulty: - New or increased dyspnea OR - Respiratory rate higher than 25/minute OR - Worsening mental function OR - Worsening functional status C. Pneumonia 1. Presence of BOTH of the following criteria: a. Chest radiograph showing pneumonia, probable pneumonia or presence of a new infiltrate AND b. Presence of at least two of the clinical manifestations described for bronchitis and tracheobronchitis.

III. URINARY TRACT INFECTION A.

Noncatheter symptomatic urinary tract infection 1. Presence of at least three of the following clinical manifestations in the absence of an indwelling urinary catheter: - Temperature of 100.4°F (38°C) or higher or chills - New or increased dysuria, frequency, or urgency - New flank or suprapubic pain or tenderness - Change in urine character (new blood, foul smell, increased sediment grossly or by urinalysis) - Worsening of mental or functional status B. Catheter-related symptomatic urinary tract infection 1. Chronic indwelling urinary catheters lead to bacteriuria in almost 100% of cases, and bacteriuria is generally asymptomatic and requires no evaluation or treatment.

Definitions of Common Infections

2.

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In the absence of other site(s) of infection, the presence of fever and mental/functional status change meets criteria of symptomatic urinary tract infection.

IV. SKIN INFECTIONS A.

Cellulitis and soft tissue and wound infection 1. Presence of one of the following criteria: a. Purulence present at the wound, skin, or soft tissue site OR b. Presence of four or more of the following clinical manifestations: - Temperature of 100.4°F (38°C) or higher OR worsening of mental/functional status - New or increasing heat at affected site - New or increasing redness at affected site - New or increasing swelling at affected site - New or increasing tenderness at affected site - New or increasing serous drainage at affected site B. Herpes zoster 1. Presence of both a. Vesicular rash AND b. Physician diagnosis or laboratory confirmation C. Scabies 1. Presence of both a. Maculopapular or pruritic rash, or both AND b. Physician diagnosis or laboratory confirmation

V. GASTROINTESTINAL TRACT INFECTION A.

Gastroenteritis 1. Presence of one of the following must be present: a. Two or more loose or watery stools above what is normal for a resident within a 24-hour period OR b. Two or more episodes of vomiting in a 24-hour period OR c. Both a stool culture positive for an enteric pathogen (e.g., Salmonella, Shigella, Escherichia coli 0157:H7, Campylobacter) and at least one manifestation compatible with gastrointestinal tract infection (nausea, vomiting, abdominal pain or tenderness, diarrhea).

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VI. COMMENTS Criteria for common upper respiratory tract infections (“cold,” pharyngitis), conjunctivitis, ear infection, and oral infections are not described because they are generally of mild consequences and not life-threatening. Criteria for primary bacteremia or sepsis are omitted because obtaining blood cultures in a long-term care facility has not been documented to be beneficial or cost effective (See Appendix B).

Appendix B Guide to Evaluating Fever and Infection in a Long-Term Care Setting

REFERENCE Bentley DW, Bradley S, High K, Schoenbaum S, Taler G, Yoshikawa TT. Practice guideline for evaluation of fever and infection in long-term care facilities. Clin Infect Dis 2000; 31:640–653.

I. CLINICAL EVALUATION A. Nursing aide should measure temperature, blood pressure, heart rate, and respiratory rate. 1. Fever is defined as: a. One or more rectal temperatures of more than 100° F (37.8°C) OR b. Two or more oral temperatures of more than 99° F (37.2°C) OR c. Temperature increase of 2°F (1.1°C) over baseline regardless of technique of measurement B. An initial evaluation regarding possible sites of infection should be done by the onsite nurse, and the findings should be communicated to the responsible physician, advance-practice nurse, or physician assistant. C. Document the full extent of the evaluation in the medical record. If diagnostic interventions are purposefully withheld, the reasons should be clearly stated in the record. 477

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II. LABORATORY TESTS The diagnostic tests recommended should only be implemented where there are no previous advance directives that limit aggressive medical interventions. A.

Suspected infection: complete blood cell count 1. A complete blood count, including peripheral white blood cell (WBC) count and differential cell count on all residents suspected of harboring an infection. 2. Elevated WBC count is 14,000 WBCs/mm3 or greater 3. A “left shift” is more than 6% band neutrophils or metamyelocytes OR total band neutrophil count 1,500 cells/mm3 or greater. B. Urinary tract infection 1. Diagnostic tests for suspected urinary tract infection should be reserved for only those residents who fulfill criteria for symptomatic urinary tract infection (see Appendix A). Evaluation should not be performed for asymptomatic bacteriuria. 2. Appropriately collected urine specimens are the following: a. Men 1) Clean catch or midstream specimen, provided resident is functionally capable OR 2) Freshly applied clean condom external catheter b. Women 1) Midstream specimen after proper perineal cleansing if resident is functionally capable OR 2) In-and-out catheterization 3. Initial evaluation should be a urine examination for WBCs (pyuria) by leukocyte esterase dipstick and microscopic examination for WBCs. a. If no pyuria (10 WBCs per high-power field of spun urine on light microscopy or negative leukocyte esterase test) is found, urine culture is not indicated. b. Presence of pyuria should be followed by performing a urine culture with antibiotic sensitivity tests. 4. If urosepsis is suspected, resident should be considered for transfer to an acute care facility with blood cultures, urine culture, and urine Gram stain on unspun urine performed at the acute care facility. C. Sepsis or bacteremia: Blood cultures Blood cultures are not recommended for residents of long-term care facilities (LTCFs) with suspected bacteremia or sepsis. These residents warrant transfer to an acute care facility provided there is approval by resident, resident’s family, or person with medical durable power of attorney.

Guide to Evaluating Fever and Infection

D.

479

Pneumonia 1. Pulse oximetry should be performed on residents with a respiratory rate higher than 25 per minute to document hypoxemia (oxygen saturation of 90%) as a clue to the diagnosis of pneumonia. Test is also helpful in predicting mortality and impending respiratory failure. 2. Chest radiograph should be performed if hypoxemia is documented or radiograph is suspected to identify the presence of a new infiltrate compatible with pneumonia. Test can also exclude other complicating conditions involving the lungs (e.g., abscess, effusion) 3. Respiratory secretions (expectorated sputum or nasopharyngeal aspirate) should be obtained to assess for presence of purulence. A purulent specimen should be Gram stained for organisms and cytological screening for squamous epithelial cells (to determine quality of specimen). If stain of sputum or aspirate demonstrates less than 25 squamous epithelial cells per low-power field by light microscopy, then specimen can be acceptable for culture and sensitivity studies. E. Respiratory viral infection Obtain swab samples from throat and nasopharynx from several residents at onset of an outbreak of suspected respiratory viral infection. Place swabs in a single tube containing refrigerated viral transport media and transport them to an experienced laboratory for virus isolation and rapid diagnostic testing for influenza A and other common viruses. F. Skin and soft tissue infections 1. Cellulitis Cultures should be performed under select conditions. Surface swabs are not indicated. Fine-needle aspiration of skin lesion is indicated if there is evidence of an abscess, an unusual pathogen is suspected (e.g., gram-negative bacilli in diabetics), or initial antibiotic treatment has been unsuccessful. 2. Pressure ulcers If a pressure ulcer demonstrates purulence or poor healing, send the purulent drainage or tissue obtained at surgical debridement or biopsy for culture. Surface swabs from pressure ulcers are not clinically useful. 3. Scabies Scrape several typical scabies burrows and examine by light microscopy for mites, eggs, or mite feces on mineral oil preparations.

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Appendix B

G.

Infectious diarrhea 1. Stool specimen for diarrhea evaluation is not indicated if the resident has a low-grade fever, new-onset diarrhea, and no clinical deterioration, and there is no outbreak of diarrhea in the LTCF. 2. If resident develops diarrhea and has received antibiotics within the previous 30 days, suspect Clostridium difficile etiology. Submit a stool specimen for C. difficile toxin assay. If specimen is negative for toxin and diarrhea persists, submit one or two additional stool specimens. 3. If resident has high fever, abdominal cramps, or bloody diarrhea, or demonstrates WBCs in the stool and there is no history of receiving antibiotics within the previous 30 days, submit stool for culture for isolation of common invasive enteropathogens (e.g., Salmonella, Shigella, Campylobacter, Escherichia coli 0157:H7). However, many of these residents will require transfer to an acute care facility because of associated bacteremia, sepsis, or dehydration.

III. INDICATIONS FOR TRANSFER TO AN ACUTE CARE FACILITY A. Upon admission of a person to an LTCF, general parameters for considering transfer to an acute care facility for a resident should be recorded in the chart. Advance directives should also be part of this statement. B. Decisions regarding transfer of an LTCF resident to an acute care facility should ultimately be at the discretion of the attending physician consistent with an existing advanced directive or as informed by the resident, resident’s family, or designated person with medical durable power of attorney. C. In the absence of an advance directive or directions from the resident, resident’s family, or designated person with medical durable power of attorney, the attending physician’s decision regarding a transfer should be based on available institutional policies regarding transfer to an acute care facility. If such a policy is not available, then the following parameters should be reviewed when a transfer is considered: 1. Clinical condition, underlying disease(s), and prognosis of the resident 2. Efficacy and cost-effectiveness of interventions and acute care 3. Capacity of the LTCF to provide necessary care and support to the resident

Index

Acquired immunity, 38–39 age-related changes in, 39–40 innate immunity, interaction between, 40–42 Acquired immunodeficiency syndrome, ethical issues in, 88 Acute care facility vs. long-term care facility, 15–26 initial evaluation, 18–20 recognition of infection, 17–18 staffing, 15–17 subacute care infection control, 20–21 transfer, to acute care setting, 21–22, 408 Administration of facility, alliance with, in infection control program, 125 Admission criteria, to subacute units, 9 Admissions, social worker, partnerships between, 127 Advance directives, 85–86 health care proxy, 86 preferences for treatment, 85–86 Aging (see also Geriatric healthcare) acquired immunity, age-related changes in, 39–40 bacteria, resistant, 37–38 chronic illness, in elderly, 35–38

[Aging] dietary supplements, 43–45 herpes zoster infection, changes in immunity, 37 immune dysfunction, 33–50 immune response, 38–42 immunity, 34 immunosenescence, 34 influenza, chronic illness, 35–36 innate immunity, 38–39 acquired immunity, interaction between, 40–42 medications immune potentiating effects, 43–46 with immunopotentiation, 45–46 nursing home population, 7 nutritional deficiencies, 43 modification of immunity with, 43 physiological changes associated with, 162–163 pneumonia, chronic illness, 36–37 AIDS (see Acquired immunodeficiency syndrome) Airborne precautions, 104–106 education, 105–106 resident placement, 105 481

482 [Airborne precautions] resident transport, 105 respiratory protection, 105 Amantadine, 201–202 dosing, 201–202 efficacy, 201 resistance, 202 side effects, 202 Aminoglycosides, 164–165 resistance, 375–376 mechanism of action, 376 mechanism of resistance, 376 Amphotericin B, 466 Anorexia drugs causing, geriatric population, 66 in geriatric population, drugs causing, 66 Antibiotic era, 27 Antibiotic regimens in infection control program, 124–125 pneumonia, 231 pressure ulcers, infected, 273 Antibiotic resistance, 363–382 aminoglycosides, 375–376 mechanism, 376 beta-lactams, 367–369 ceftazidime-resistant gram-negative bacilli, 367–368 glycopeptides, 376–377 glycylcyclines, 374 gram-negative bacteria, prevalence of, 433–435 impact of, 365 infection control program, 124 ketolides, 371–372 macrolides, 369–372 mechanism of action, 370 mechanism of resistance, 370–371 methicillin-resistant Staphylococcus aureus, 369 microbiological principles, 366 microorganisms, 108–111 colonized, 109 culture status of resident, 109 infected, 109 resident with, room placement, 110 uncontained, 109 minimum bactericidal concentration, 366

Index [Antibiotic resistance] minimum inhibitory, bactericidal concentrations, 366 novel drugs, future developments, 377 penicillin-resistant pneumococci, 369 pharmacological principles, 366–367 quinolones, 374–375 mechanism of action, 374–375 mechanism of resistance, 375 resistant pathogens, emergence of, 364 tetracyclines, 373–374 trimethoprim-sulfamethoxazole, 372–373 mechanism of action, 372 mechanism of resistance, 373 Antifungal agents, 168, 463–466 Antimicrobial therapy, 155–171 adverse drug events, 160–161 aging, physiological changes associated with, 162–163 aminoglycosides, 164–165 antifungal agents, 168 antituberculous agents, 168 antiviral agents, 168–169 assessment of, 156 beta-lactams, 165 clindamycin, 165–166 for common infections, 160 drug factors, 161–164 empirical antimicrobial therapy, 157–159 epidemiologic investigation, 149 fluoroquinolones, 166–167 geriatric population, 30–31 inappropriate use of, 161 initiation of, criteria for, 157, 158–159 macrolides, 165 methicillin-resistant Staphylococcus aureus, 396 optimizing use of, 156–161 pharmacodynamics, 163–164 pharmacokinetics, 162–163 absorption, 162 clearance, 163 distribution, 162–163 metabolism, 163 pneumonia, 229–232 pressure ulcers, 272 resistant organisms, 146–147, 363–472

Index [Antimicrobial therapy] tissue penetration, 163 trimethoprim-sulfamethoxazole, 167 urinary tract infection, 185–187 utilization review, 159–160 Antituberculous agents, 168 Antiviral agents, 168–169 respiratory viruses, 202 APIC (see Association for Professionals in Infection Control and Epidemiology) Appetite stimulants, 64–65 Artifact, surveillance, in epidemiologic investigation, 136–137 Aspergillosis pulmonary, chronic necrotizing, 457–458 sino-orbital, 457 Association for Professionals in Infection Control and Epidemiology, 128 Atypical presentations of infection, 72–73 Azoles, 463–465 Bacteria, resistant, 37–38 Bactericidal concentrations, 366 Bacteriuria distribution of infecting organisms, 177 symptomatic, 184–185 Baseline temperature, 75 Beneficence, 80–81 Beta-lactams, 165 AmpC, inducible chromosomal, 431–432 Bush–Jacoby–Medeiros classification, 430 extended-spectrum, 431 metallo, 432 resistance, 367–369 Body mass index, nutritional assessment and, 57 Bronchitis, 235–237 clinical manifestations, 236 diagnosis, 236 epidemiology, 235–236 infection control, 237 therapy, 236–237 Bush–Jacoby–Medeiros classification, beta-lactamases, 430

483 Candida, 451–452, 454–457, 460, 463 Capacity, decisional, ethical issues, 84–88 Case-control studies, in epidemiologic investigation, 141 Case definition, line listing, in epidemiologic investigation, 138–139 Catheters chronic indwelling, urinary tract infection, 179, 188 long-term indwelling infection control, 189 urinary tract infection, 181, 184, 190–191 CDC (see Center for Disease Control and Prevention) Ceftazidime-resistant gram-negative bacilli, 367–368 Cellulitis, 290–295 clinical manifestations, 291–292 diagnosis, 292–293 epidemiology, 290–291 infection control, 293–294 prevention, 294–295 therapy, 293 Center for Disease Control and Prevention, website, 129 Chemoprophylaxis, respiratory viruses, 201–204 Children, visits to elderly parent, 4 Chronic illness, 33–50 in elderly, 35–38 immunosenescence, 34 Chronic indwelling catheter, urinary tract infection, 179, 188 Chronic necrotizing pulmonary aspergillosis, 457–458 Clearance, antimicrobial therapy, 163 Clindamycin, 165–166 Cohort studies, in epidemiologic investigation, 141 Commercial formula supplements, 58–62 trials of, 59 Communication, infection, in healthcare facility, 101–102 Community services, availability of, 6

484 Computed tomography, infected pressure ulcers, 267 Contact isolation, ethical issues, 90–91 Contact precautions, 107–108 gloves, 107–108 gown, 108 patient care equipment, 108 patient transport, 108 resident placement, 107 Coronavirus, 212–213 clinical manifestations, 212 diagnosis, 212–213 epidemiology, 212 infection control, 213 therapy, 213 Costs ethical issues regarding, 91 geriatric population healthcare, 10 long-term care, 7–12 Cryptococcosis, 452, 457, 460, 463 Debridement infected pressure ulcers, 270–271 methicillin-resistant staphylococcus aureus, 396–397 Decisional capacity, ethical issues, 84–88 Dementia advanced, 87–88 in U.S. population, 3 Department manager, supervisors, nursing, alliance with, in infection control program, 125–127 Departments of health, 128 Dermatophytes, 450–451 infection, 453–454, 466–467, 468 Diarrhea, infectious, 305–312 antibiotic therapy, 311 clinical manifestations, 307 diagnosis, 307–309 history, 307–308 laboratory tests, 309 physical examination, 308–309 epidemiology, 305–307 etiology of, 306 infection control, 310–311 prevention, 311 therapy, 310

Index Dietary supplements, 43–45 immune potentiating effects, 43–46 Diphtheria vaccine, 353–355 Directives, advance, 85–86 healthcare proxy, 86 preferences for treatment, 85–86 Distribution, antimicrobial therapy, 162–163 Doctor-patient relationship, 83–84 Drainage, methicillin-resistant Staphylococcus aureus, 396–397 Dressings, wound, pressure ulcers, infected, 271 Droplet precautions, 106–107 education, 107 mask, 106 resident placement, 106 resident transport, 106–107 Drugs causing anorexia, geriatric population, 66 immune potentiating effects, 43–46 with immunopotentiation, 45–46 nutrient interactions with, 65 Economics ethical issues involving, 91 geriatric population healthcare, 10 long-term care, 7–12 Edemic rates, infection control program, 119–121 Education droplet precautions, 107 for employees, residents, visitors, 121–122 infection control, 105–106 in nursing management, 111–113 infection control professional, 111 Efflux pump mechanisms, gram-negative bacteria, 432–433 Elderly, 27–32 anorexia, drugs causing, 66 antimicrobial therapy, 30–31 chronic illness, 35–38 clinical manifestations, 29 epidemiology, 27–29 germ theory, 27–29 pre-antibiotic era, 27

Index [Elderly] growth of population, 4 immune response in, 337–339 infection control program, 116 life expectancy, 5 nutritional deficiencies, long-term care facility (LTCF), 53 pneumonia, chronic illness, 36–37 respiratory viruses, 200 susceptibility to infection, 29–30 vaccination, 337–339 visits by children, 4 weight loss, long-term care facility, 54 Elements, infection control program, 117–127 Emergence, resistant pathogens, 364 Employees health programs, 123–124 infection control program education, 121–122 End-of-life care, ethical issues, 90 Energy supplements, 58–62 Enterococci, vancomycin-resistant, 411–428 clinical manifestations, 415–416 diagnosis, 416–418 epidemiology, 411–414 infection control, 419–423 prevention, 423–424 therapy, 418–419 treatment, 418 Environment hygiene, infection control program, 126–127 Epidemic curve, 140 Epidemic rates, infection control program, 121 Epidemiologic investigation, 133–153 antimicrobial-resistant organisms, 146–147, 363–472 antimicrobial use, 149 case ascertainment, 139 case definition, line listing, 138–139 cohort, case-control studies, 141 epidemic curve, 140 gastrointestinal infections, 145–146 geographic assessment, 140 host factors, 139–140

485 [Epidemiologic investigation] immunization, 148–149 infection control, 147–148 infection control plan, 136 interventions, implementing, 142–143 isolation precautions, 149 key aspects, 136 line listing, influenza outbreak, 138 long-term care facilities, characteristics, 133–134 person, place, time, 139–140 preliminary hypotheses, 140–141 prevention, 147–149 respiratory tract infections, 143–145 influenza, 143–144 Legionnaire’s disease, 145 Streptococcus pneumoniae, 144–145 risk factors, 134–135 selected infectious disease outbreaks, 143–147 skin infections, 146 studies, 141–142 microbiologic/studies, 142 observational studies, 141–142 surveillance artifact, 136–137 timing, 137–138 Epidemiology, respiratory virus, 198–199 attack rate, 198–199 viral characteristics, 198 Equipment, patient care, contact precautions, 108 Ethical issues, 80–82 acquired immunodeficiency syndrome, 88 advance directives, 85–86 healthcare proxy, 86 preferences for treatment, 85–86 autonomy, 80 beneficence, 80–81 cost, 91 decision to hospitalize, 86–87 decisional capacity, 84–88 dementia, advanced, 87–88 doctor-patient relationship, 83–84 end-of-life care, 90 everyday ethics, 81–82 fidelity, 81

486 [Ethical issues] goals of care, 82–83 prioritization of, 83 health promotion, 88 human immunodeficiency virus, 88 infection control, by staff, 91–92 infectious disease interventions, 79–98 interdisciplinary team, 88–89 interventions, 89 isolation, contact, 90–91 justice, 81 medical director, 92 nonmaleficience, 80–81 promises to those with advanced illness, 93 quality of life, 85 research issues, 92–93 right to refuse care, 87 Evaluation of infection control program, 128–129 Feeding tubes, pneumonia, 234–235 Fever, 73–76, 477 definition of, 75 diminished response, 73–75 evaluation of, 477–480 robust response, 76 of unknown origin, 76 Fidelity, as ethical issue, 81 Fluoroquinolones, 166–167 Friction, pressure ulcers, infected, 261–262 Fungal infection, 449–472 antifungal agents, 463–466 epidemiology, 449–453 filamentous, 460–461 invasive, 452–453, 467 invasive filamentous, 452–453, 457–458, 463, 469 clinical manifestations, 453–458 Gastric content aspiration, pneumonia, 234–235 Gastroesophageal reflux, pneumonia, 234 Gastrointestinal infection defined, 475 epidemiologic investigation, 145–146

Index Gender, nursing home population, 7 Geographic assessment, in epidemiologic investigation, 140 Geriatric healthcare economics, 10, 11 long-term care, 7–12 changes in, 12–13 Medicaid, 9–12 Medicare, 8–9, 11 private funding, 12 source of funds, 8 Geriatric population, 27–32 anorexia, drugs causing, 66 antimicrobial therapy, 30–31 chronic illness, 35–38 clinical manifestations, 29 epidemiology, 27–29 germ theory, 27–29 pre-antibiotic era, 27 growth of, 4 immune response in, 337–339 infection control program, 116 life expectancy, 5 nutritional deficiencies, long-term care facility, 53 pneumonia, chronic illness, 36–37 respiratory viruses, 200 susceptibility to infection, 29–30 vaccination, 337–339 visits by children, 4 weight loss, long-term care facility, 54 Germ theory, 27–29 Gloves, use of, 107–108 Glycopeptide-resistant Enterococci, 411–428 clinical manifestations, 415–416 diagnosis, 416–418 epidemiology, 411–414 infection control, 419–423 prevention, 423–424 therapy, 418–419 treatment, 418 Glycopeptides, resistance, 376–377 Glycylcyclines, antibiotic resistance, 374 Gown, contact precaution, 108

Index Gram-negative bacteria, 429–448 antibiotic resistance prevalence of, 433–435 risk factors, 435–436 Bush–Jacoby–Medeiros classification, beta-lactamases, 430 clinical infections, 436–437 diagnosis, 437–438 efflux pump mechanisms, 432–433 epidemiology, 429–436 extended-spectrum beta-lactamases, 431 inducible chromosomal beta-lactamases AmpC, 431–432 infection control, 440–441 metallo-beta-lactamases, 432 porin channels, 432 resistance, 429–433 prevention of, 441–442 therapy, 438–440 treatment options, 438 Hand washing, 107–108 Healthcare workers, vaccination of, 356 Hepatitis, 313–336 clinical manifestations, 322–327 acute hepatitis, 322–323 chronic hepatitis, 323–324 hepatocellular carcinoma, 324–325 diagnosis, 323 epidemiology, 313–321 infection control, prevention, 327–333 interferon-based therapy, exclusion criteria, 326 patient selection, 326–327 therapy, 325–327 acute hepatitis, 325 chronic hepatitis, 325–327 treatment, 322–327 Hepatitis A virus, 313–316, 328 clinical course, 316 frequency, 328 postexposure protection, 330 screening, 328–329 vaccination, 329 vaccine, 329

487 Hepatitis B virus, 316–318, 330–332 chronic, 327 frequency, 331 incidence, United States, 317 postexposure protection, 331–332 screening, 331 vaccination, 331, 332 Hepatitis C virus, 318–320, 333 chronic, 327 incidence, United States, 319 postexposure protection, 333 screening, 333 vaccination, 333 Hepatitis D virus, 320–321 Hepatitis E virus, 321 Hepatitis G virus, 321 Herpes zoster, 283–289 changes in immunity, 37 clinical manifestations, 284–285 diagnosis, 285 epidemiology, 283–284 infection control, 287–289 prevention, 289 therapy, 285–287 analgesics, 286–287 anti-inflammatory, 286 antiviral therapy, 286 postherapeutic neuralgia, 287 HIV (see Human immunodeficiency virus) Home healthcare, economics, 8 Hospital acute care, vs. long-term care facility, 15–26 initial evaluation, 18–20 recognition of infection, 17–18 staffing, 15–17 subacute care infection control, 20–21 transfer, to acute care setting, 21–22 decision to hospitalize, 86–87 Human immunodeficiency virus, ethical issues in, 88 Hypotheses, preliminary, in epidemiologic investigation, 140–141

488 Identification of infection, 101–102 clinical manifestations, 101 diagnostic specimens, 101 Imaging studies, infected pressure ulcers, 266–268 computed tomography, 267 magnetic resonance imaging, 267 plain radiography, 266–267 radionuclide scintigraphy, 267–268 Immune dysfunction, 33–50 aging and, 33–50 Immune response, 38–42 Immunization, epidemiologic investigation, 148–149 Immunosenescence, 34 Infection aging demographics, 1–14 effect of, 33–50 epidemiology, 27–32 antibiotic resistance, 363–382 antimicrobial therapy, 155–171 bronchitis, 223–244 Candida, 449–472 cellulitis, 283–304 clinical manifestations of, 71–78 diarrhea, infectious, 305–312 epidemiologic investigation, 133–153 geriatric healthcare, demographics, 1–14 gram-negative bacteria, 429–448 herpes zoster, 283–304 immune dysfunction, illness-related, 33–50 infection control program, 115–132 influenza, 197–222 interventions, ethical issues, 79–98 long-term care, vs. acute care hospitals, 15–26 nursing management of, 99–114 nutrition, 51–70 pneumonia, 223–244 pressure ulcers, 257–282 respiratory viruses, 197–222 scabies, 283–304 Staphylococcus aureus, methicillinresistant, 383–410

Index [Infection] tuberculosis, 245–256 urinary tract infection, 173–195 vaccinations, 337–362 vancomycin-resistant Enterococci, 411–428 Infection control, professional, 111, 117–119 education, 111 Infection control program, 115–132, 136 administration of facility, alliance with, 125 admissions, social worker, partnerships between, 127 antibiotic resistance, 124 antibiotic utilization, 124–125 Association for Professionals in Infection Control and Epidemiology, 128 barriers to, 127 department manager, supervisors, nursing, alliance with, 125–127 departments of health, 128 education, for employees, 121–122 elements of, 117–127 employee health programs, 123–124 environment hygiene, 126–127 evaluation, 128–129 geriatric population, 116 infection control professional, 117–119 information, infection, sources for, 120 long-term care facility (LTCF) outbreak investigation, steps to, 122 policies, 123 need for, 116–117 outbreak investigation, 121 oversight committee, 117 partnerships within, 125–127 policy, procedure development, 122–123 quality improvement, 126 regulatory requirements, 116–117 federal, state, local, 116–117 resident health program, 124 resources, regional, local, national, 128 Society for Healthcare Epidemiology of America, 128

Index [Infection control program] surveillance, 119–121 edemic rates, 119–121 epidemic rates, 121 Influenza, 198–207 chronic illness, 35–36 epidemiologic investigation, 143–144 impact of age, chronic illness, 35–36 line listing, 138 vaccine, 339–343 administration, 341–343 antiviral medications, dosage, 342 effectiveness, 340–341 indications, 341 revaccination, 341–343 safety, 343 Innate immunity, 38–39 acquired immunity, interaction between, 40–42 Interdisciplinary team, 88–89 Invasive filamentous fungal infections, 452–453, 457–458, 463, 467, 469 clinical manifestations, 453–458 Investigation, of outbreak, infection control program, 122 Isolation contact, 90–91 precautions, in epidemiologic investigation, 149 Justice, as ethical issue, 81 Ketolides, antibiotic resistance, 371–372 Laboratory tests, infection, 478–480 Legionnaire’s disease, epidemiologic investigation, 145 Life expectancy, geriatric population, 5 Line listing case definition, in epidemiologic investigation, 138–139 influenza outbreak, 138 Linezolid, methicillin-resistant Staphylococcus aureus, 395–396 Local resources, infection control program, 128

489 Long-term care changes in, 12–13 demographics, 1–14 economics, 7–12 source of funds, nursing home, home healthcare, 8 Long-term care facility, vs. acute care hospital, 15–26 initial evaluation, 18–20 recognition of infection, 17–18 resources, 15–17 staffing, 15–17 subacute care infection control, 20–21 transfer, to acute care setting, 21–22 Long-term indwelling catheter infection control, 189 urinary tract infection, 181, 184, 190–191 Macrolides, 165 resistance, 369–372 mechanism, 370–371 Magnetic resonance imaging, infected pressure ulcers, 267 Malnutrition consequences of, 56–58 geriatric population, 51–56 reversible causes of, 55 Mask, for infection control, 106 Medicaid, 9–12 expenditures, 11 Medical director, 92 administration, alliance between, 125 Medicare, 8–9 geriatric population, 8–9, 11 Medications causing anorexia, geriatric population, 66 immune potentiating effects, 43–46 with immunopotentiation, 45–46 nutrient interactions with, 65 Metabolism, antimicrobial therapy, 163 Metallo-beta-lactamases, 432 Methicillin-resistant Staphylococcus aureus, 383–410 antibiotic resistance, 369 clinical manifestations, 392–393 clinical features, 393 syndromes, 392–393

490 [Methicillin-resistant] debridement, 396–397 diagnosis, 393–394 drainage, 396–397 epidemiology, 384–392 infection caused by, 388–392 infection control, 397–403 antibiotic use, 400 decolonization, 402–403 education, 399–400 isolation, 402 outbreak management issues, 401–403 precautions, 400–401 surveillance, 399 prevention, 403–404 risk factors, 392 surgical procedures, 396–397 therapy, 395–397 antimicrobial agents, 396 linezolid, 395–396 topical agents, 396 vancomycin, 395 transmission of, 388 Microbiological studies, 101 in epidemiologic investigation, 142 infected pressure ulcers, 264–266 urinary tract infection, 176–178, 181–182 Microcirculation, tissue, pressure ulcer, 260 Micronutrient supplements, 60 Mineral supplements, 62–63 Moisture, pressure ulcers, infected, 262 Mucocutaneous infections, localized, 458–459, 461–462 mucous membrane infections, 459 nail infections, 458–459 skin infections, 458 Mucomycosis, 458 Multivitamin supplements, 62–63 Nails Candida infections of, 455 infections, mucocutaneous, 458–459, 461–462 National Pressure Ulcer Advisory Panel Classification, 258

Index National resources, infection control program, 128 Nonmaleficience, 80–81 Novel drugs, future development of, 377 NPUAP (see National Pressure Ulcer Advisory Panel) Nursing, supervisors, department manager, alliance with, in infection control program, 125–127 Nursing home care (see also Longterm care) community services available outside of, 6 demand for, 1–7 economics, 7–12 factors affecting need for, 2 fever, 75 infection presentations, 73 Nursing management, 99–114 airborne precautions, 104–106 education, 105–106 resident placement, 105 resident transport, 105 respiratory protection, 105 antibiotic-resistant microorganisms, 108–111 colonized, 109 infected, 109 resident’s culture status, 109 uncontained, 109 communication, 101–102 contact precautions, 107–108 gloves, 107–108 gown, 108 hand washing, 107–108 patient care equipment, 108 patient transport, 108 resident placement, 107 droplet precautions, 106–107 education, 107 mask, 106 resident placement, 106 resident transport, 106–107 education, 111–113 infection control professional, 111 staff education, 111–112

Index [Nursing management] identification of infection, 101–102 clinical manifestations, 101 diagnostic specimens, 101 microbiology, 101 nursing process, 100 prevention, 102–111 risk for acquiring infection, with resistant microorganism, 109–110 room placement, resident with antibiotic-resistant microorganisms, 110 standard precautions, 102–104 hand washing, 102–103 occupational health, bloodborne pathogens, 104 personal protective equipment, 103–104 surveillance, 99–101 Nursing process, 100 Nutrition, 51–70 anorexia, in geriatric population, drugs causing, 66 appetite stimulants, 64–65 barriers to consumption, geriatric population, 52 body mass index, nutritional assessment and, 57 commercial formula supplements, 58–62 trials of, 59 drug-nutrient interactions, 65 interventions, in LTCF, 58–63 malnutrition consequences of, 56–58 geriatric population, long-term care facility, 53 modification of immunity with, 43 reversible causes of, 55 micronutrient supplementation trials, 60 mineral supplements, 62–63 multivitamin supplements, 62–63 nutritional deficiencies, geriatric population, 53 pneumonia, 63 pressure ulcers, 63–64 protein-energy supplements, 58–62

491 [Nutrition] status assessment, 56–58 supplements, 43–45 micronutrient, 60 urinary tract infections, 64 weight loss, geriatric population, 54 Observational studies, in epidemiologic investigation, 141–142 Occupational Health and Safety Administration, website, 129 Onychomycosis, 454 management of, 461 Oral hygiene, pneumonia, 234 Oropharyngeal candidiasis, 454–455, 462 Oseltamivir, 203–204 dosing, 203 efficacy, 203 resistance, 204 side effects, 204 OSHA (see Occupational Health and Safety Administration) Out-of-pocket expenditures, geriatric population, 11 Outbreak investigation infection control program, 121 steps to, 122 Oversight committee, infection control program, 117 Parainfluenza, 210–212 clinical manifestations, 211 diagnosis, 211 epidemiology, 210–211 infection control, 211–212 therapy, 211 Partnerships, in infection control program, 125–127 Penicillin-resistant pneumococci, 369 Pharmaceuticals causing anorexia, geriatric population, 66 immune potentiating effects, 43–46 with immunopotentiation, 45–46 nutrient interactions with, 65 Pharmacodynamics, antimicrobial therapy, 163–164

492 Pharmacokinetics, antimicrobial therapy, 162–163 absorption, 162 clearance, 163 distribution, 162–163 metabolism, 163 Placement, resident airborne precautions, 105 contact precautions, 107 infection control, 106 Plain radiography, infected pressure ulcers, 266–267 Pneumococcal vaccine, 343–351 antibody response, 349–350 cost effectiveness, 350 drug interactions, 351 efficacy, 345–349 microbiology, 343–344 safety, 350–351 Pneumococci, penicillin-resistant, 369 Pneumonia antibiotic regimens, 231 chronic illness, 36–37 clinical manifestations, 226 diagnosis, 226–227 epidemiology, 223–226 etiology, 225 incidence, 223–224 mortality, 225–226 pathogenesis, 224–225 risk factors, 224 feeding tubes, 234–235 gastric content aspiration, 234–235 impact of age, chronic illness, 36–37 nutrition and, 63 prevention, 233–235 gastroesophageal reflux, 234 oral hygiene, 234 pharmacologic interventions, 234 vaccination, 233–234 therapy, 227–232 antimicrobial agent, 229–232 duration of treatment, 229 initial route of treatment, 228 oral therapy, switch to, 229 treatment location, 228

Index [Pneumonia] vaccine, 233–234 volume depletion, 232 Porin channels, gram-negative bacteria, 432 Pre-antibiotic era, 27 Precautions, standard, 102–104 hand washing, 102–103 occupational health, bloodborne pathogens, 104 personal protective equipment, 103–104 Pressure ulcers, infected, 257–282 adjunctive measures, 271 antibiotic regimens, 273 antimicrobial therapy, 272 clinical assessment, 264 clinical manifestations, 263–264 cost of, 263 debridement, 270–271 diagnosis, 264–268 epidemiology, 257–263 friction, 261–262 imaging studies, 266–268 computed tomography, 267 magnetic resonance imaging, 267 plain radiography, 266–267 radionuclide scintigraphy, 267–268 incidence, 257–259 infection control, 272–276 locations of, 261 microbiological evaluation, 264–266 moisture, 262 National Pressure Ulcer Advisory Panel Classification, 258 nutrition and, 63–64 pressure, 259–261 reduction of, 270 prevention, 276–278 risk factors, 259–262 reducing, 269 shearing stress, 262 surgery, 271–272 therapy, 268–272 tissue microcirculation, 260 wound care, 269–272 dressings, 271

Index Prioritization, goals of care, 83 Private funding, geriatric healthcare, 12 Procedure development, infection control program, 122–123 Promises, to those with advanced illness, ethics in, 93 Protein-energy supplements, 58–62 Proxy, healthcare, 86 Pulmonary aspergillosis, chronic necrotizing, 457–458 Quality improvement, in infection control program, 126 Quality of life, 85 Quinolones, resistance, 374–375 mechanism of action, 374–375 mechanism of resistance, 375 Race, nursing home population representation, 7 Radionuclide scintigraphy, infected pressure ulcers, 267–268 Refusal of care, right to, 87 Regional resources, infection control program, 128 Regulatory requirements, 116–117 infection control program, 116–117 Research, ethical issues in, 92–93 Resident health program, 124 Residents, infection control program education, 121–122 Resistance amantadine, 202 antibiotic, 124, 363–382 gram-negative bacteria, 430, 434 antimicrobial, 435 in gram-negative bacteria, 436 infection control program and, 124 mechanisms of, 371 oseltamivir, 204 rimantadine, 202 zanamivir, 204 Respiratory protection, 105 Respiratory syncytial virus, 207–210 clinical manifestations, 208 diagnosis, 209

493 [Respiratory syncytial virus] epidemiology, 207–208 infection control, 210 therapy, 209–210 Respiratory tract infection defined, 473–474 epidemiologic investigation, 143–145 influenza, 143–144 Legionnaire’s disease, 145 Streptococcus pneumoniae, 144–145 Respiratory viruses, 197–222 amantadine, 201–202 dosing, 201–202 efficacy, 201 resistance, 202 side effects, 202 antiviral drugs, 202 chemoprophylaxis, 201–204 clinical manifestations, 199 control, 204–207 infection control, 204–205 vaccination, 205–207 coronavirus, 212–213 clinical manifestations, 212 diagnosis, 212–213 epidemiology, 212 infection control, 213 therapy, 213 diagnosis, 199–200 epidemiology, 198–199 attack rate, 198–199 viral characteristics, 198 geriatric population, clinical manifestations, 200 influenza, 198–207 oseltamivir, 203–204 dosing, 203 efficacy, 203 resistance, 204 side effects, 204 parainfluenza, 210–212 clinical manifestations, 211 diagnosis, 211 epidemiology, 210–211 infection control, 211–212 therapy, 211

494 [Respiratory viruses] respiratory syncytial virus, 207–210 clinical manifestations, 208 diagnosis, 209 epidemiology, 207–208 infection control, 210 therapy, 209–210 rhinovirus, 213–214 clinical manifestations, 214 diagnosis, 214 epidemiology, 213 infection control, 214 therapy, 214 rimantadine, 201–202 dosing, 201–202 efficacy, 201 resistance, 202 side effects, 202 therapy, 200–204 zanamivir, 203–204 dosing, 203 efficacy, 203 resistance, 204 side effects, 204 Rhinovirus, 213–214 clinical manifestations, 214 diagnosis, 214 epidemiology, 213 infection control, 214 therapy, 214 Right to refuse care, 87 Rimantadine, 201–202 dosing, 201–202 efficacy, 201 resistance, 202 side effects, 202 Ringworm, 453 Room placement, resident with antibioticresistant microorganisms, 110 Scabies, 295–300 clinical manifestations, 296 diagnosis, 297 epidemiology, 295–296 infection control, 298–299 prevention, 299–300 therapy, 297–298

Index SHEA (see Society for Healthcare Epidemiology of America) Shearing stress, pressure ulcers, infected, 262 Sino-orbital aspergillosis, 457 Skin infection Candida, 455 defined, 475 epidemiologic investigation, 146 mucocutaneous, 458, 461 Skin test criteria, positive tuberculin reaction, 251 Social worker, admissions, partnerships between, 127 Society for Healthcare Epidemiology of America, 128 Source of funds, long-term care, 8 Staff education of, 111–112 infection control, 91–92, 111–112 Staphylococcus aureus, methicillinresistant, antibiotic resistance, 369 Streptococcus pneumoniae, epidemiologic investigation, 144–145 Subacute units, admission criteria, 9 Supervisors, department manager, nursing, alliance with, in infection control program, 125–127 Supplements, 43–45 energy, 58–62 immune potentiating effects, 43–46 micronutrient, 60 mineral, 62–63 multivitamin, 62–63 nutritional, commercial formula, 58–62 Surgical procedure methicillin-resistant Staphylococcus aureus, 396–397 pressure ulcers, infected, 271–272 Surveillance, infection control program, 119–121 edemic rates, 119–121 epidemic rates, 121 Surveillance artifact, in epidemiologic investigation, 136–137 Symptomatic bacteriuria, 184–185

Index Syncytial virus, respiratory, 207–210 clinical manifestations, 208 diagnosis, 209 epidemiology, 207–208 infection control, 210 therapy, 209–210 Team, interdisciplinary, 88–89 Temperature, baseline, 75 Terbinafine, 465–466 Tetanus vaccine, 351–352 Tetracyclines, resistance, 373–374 mechanism of action, 373 Tinea capitis, 453 Tinea corporis, 453 Tinea cruris, 453 Tinea pedis, 453–454 Tinea versicolor, 451, 454 Tissue microcirculation, pressure ulcer, 260 Tissue penetration, antimicrobial therapy, 163 Topical agents, methicillin-resistant Staphylococcus aureus, 396 Transfer, to acute care facility, indications for, 480 Transport of resident, 105, 106–107, 108 Trimethoprim-sulfamethoxazole, 167 resistance, 372–373 mechanism of action, 372 mechanism of resistance, 373 Tuberculosis, 245–256 assessment, 253 clinical manifestations, 247 drug regimens, 252 education, 253–254 epidemiology, 245–247 impact of age, chronic illness, 36–37 infection control, 247–254 containment, 249–253 diagnosis, 248–249 surveillance, 248–249 treatment, 250–251 pathogenesis, 246–247 prevention, 251–253 skin test criteria, positive tuberculin reaction, 251 treatment regimens, 250

495 Ulcers, pressure, 257–282 adjunctive measures, 271 antibiotic regimens, 273 antimicrobial therapy, 272 clinical assessment, 264 clinical manifestations, 263–264 cost of, 263 debridement, 270–271 diagnosis, 264–268 epidemiology, 257–263 friction, 261–262 imaging studies, 266–268 computed tomography, 267 magnetic resonance imaging, 267 plain radiography, 266–267 radionuclide scintigraphy, 267–268 incidence, 257–259 infection control, 272–276 locations of, 261 microbiological evaluation, 264–266 moisture, 262 National Pressure Ulcer Advisory Panel Classification, 258 nutrition and, 63–64 pressure, 259–261 reduction of, 270 prevention, 276–278 risk factors, 259–262 reducing, 269 shearing stress, 262 surgery, 271–272 therapy, 268–272 tissue microcirculation, 260 wound care, 269–272 dressings, 271 Urinalysis, 182–183 Urinary tract infection, 64, 173–195 bacteriuria, distribution of infecting organisms, 177 Candida, 459–460 catheter chronic indwelling, 179 long-term indwelling, 181 clinical impact, 178–179 clinical manifestations, 180–181

496 [Urinary tract infection] defined, 474–475 diagnosis, 181–184 catheter, long-term indwelling, 184 clinical diagnosis, 183–184 microbiological diagnosis, 181–182 urinalysis, 182–183 epidemiology, clinical relevance, 174–179 host response, 178 infection control, 188–189 catheter, long-term indwelling, 189 general, 188–189 microbiology, 176–178 prevalence, incidence, 174–175 prevention, 189–191 catheter, long-term indwelling, 190–191 risk factors, 176 therapy, 184–188 antimicrobial treatment, 185–187 catheter, chronic indwelling, 188 duration of treatment, 187–188 symptomatic bacteriuria, 184–185 Vaccination, 337–362 diphtheria, 353–355 geriatric population, immune response, 337–339 of healthcare workers, 356 influenza, 339–343 administration, 341–343 antiviral medications, dosage, 342 effectiveness of, 340–341 indications, 341 revaccination, 341–343 safety, 343 pneumococcal vaccine, 343–351 antibody response, 349–350 cost effectiveness, 350 drug interactions, 351 efficacy, 345–349

Index [Vaccination] microbiology, 343–344 safety, 350–351 pneumonia, 233–234 respiratory viruses, 205–207 tetanus, 351–352 varicella vaccine, 355 Vancomycin-resistant Enterococci, 411–428 clinical manifestations, 415–416 diagnosis, 416–418 epidemiology, 411–414 infection control, 419–423 prevention, 423–424 therapy, 418–419 treatment, 418 Vancomycin-resistant Staphylococcus aureus, 395 Varicella vaccine, 355 Visitors, infection control program education for, 121–122 Volume depletion, pneumonia, 232 Vulvovaginitis, 457, 462 Weight loss, geriatric population, longterm care facility, 54 World-Wide Web Virtual Library: Epidemiology, 129 Wound care dressings, 271 pressure ulcer, 269–272 Yeast infections, 451–452, 454–457, 467, 468 epidemiology of, 449–453 Zanamivir, 203–204 dosing, 203 efficacy, 203 resistance, 204 side effects, 204 Zygomycosis, 458

About the Editors

THOMAS T. YOSHIKAWA is Chairman and Professor of the Department of Internal Medicine, Charles R. Drew University of Medicine and Science and Martin Luther King, Jr.–Charles R. Drew Medical Center, Los Angeles, California. The author of numerous journal articles, book chapters, and books, including Antimicrobial Therapy in the Elderly Patient and Acute Emergencies and Critical Care of the Geriatric Patient (both titles, Marcel Dekker, Inc.), he is a Fellow of the American College of Physicians–American Society of Internal Medicine, the Infectious Diseases Society of America, and the Gerontological Society of America, as well as a member of the American Geriatrics Society and the American Society for Microbiology, among others. He is Editor-in Chief of the Journal of the American Geriatrics Society. He received the B.A. degree (1962) from the University of California, Los Angeles, and the M.D. degree (1966) from the University of Michigan, Ann Arbor. JOSEPH G. OUSLANDER is Director of the Division of Geriatric Medicine and Gerontology and the Emory Center for Health in Aging; Chief Medical Officer of the Wesley Woods Center; and Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia. The author or coauthor of numerous journal articles, book chapters, and books, he is past president of the American Geriatrics Society and serves as Deputy Editor for the Journal of the American Geriatrics Society. He is a Fellow of the American Geriatrics Society and the Gerontological Society of America. Among other awards, he was named David H. Solomon Lecturer (2001). Dr. Ouslander received the B.A. degree (1973) from The Johns Hopkins University, Baltimore, Maryland, and the M.D. degree (1977) from Case Western Reserve University, Cleveland, Ohio. 497