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THE RESISTANCE PHENOMENON IN MICROBES AND INFECTIOUS DISEASE VECTORS Implications for Human Health and Strategies for Containment Workshop Summary Stacey L. Knobler, Stanley M. Lemon, Marjan Najafi, and Tom Burroughs, Editors Forum on Emerging Infections Board on Global Health INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu
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THE NATIONAL ACADEMIES PRESS 500 Fifth Street N.W.Washington, DC 20001 NOTICE: The project that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. Support for this project was provided by the U.S. Department of Health and Human Services’ National Institutes of Health, Centers for Disease Control and Prevention, and Food and Drug Administration; U.S. Agency for International Development; U.S. Department of Defense; U.S. Department of State; U.S. Department of Veterans Affairs; U.S. Department of Agriculture; American Society for Microbiology; Burroughs Wellcome Fund; Eli Lilly & Company; Pfizer; GlaxoSmithKline; and Wyeth-Ayerst Laboratories. This report is based on the proceedings of a workshop that was sponsored by the Forum on Emerging Infections. It is prepared in the form of a workshop summary by and in the name of the editors, with the assistance of staff and consultants, as an individually authored document. Sections of the workshop summary not specifically attributed to an individual reflect the views of the editors and not those of the Forum on Emerging Infections. The content of those sections is based on the presentations and the discussions that took place during the workshop. International Standard Book Number: 0-309-08854-2 Library of Congress Number 2003005451 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, N.W., Box 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2003 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Cover: The background for the cover of this workshop summary is a photograph of a batik designed and printed specifically for the Malaysian Society of Parasitology and Tropical Medicine. The print contains drawings of various parasites and insects; it is used with the kind permission of the Society.
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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Shaping the Future for Health
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THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org
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FORUM ON EMERGING INFECTIONS ADEL MAHMOUD (Chair), President, Merck Vaccines, Whitehouse Station, New Jersey STANLEY LEMON (Vice-Chair), Dean, School of Medicine, The University of Texas Medical Branch, Galveston, Texas DAVID ACHESON, Chief Medical Officer, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Rockville, Maryland STEVEN BRICKNER, Research Advisor, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut GAIL CASSELL, Vice President, Scientific Affairs, Eli Lilly & Company, Indianapolis, Indiana GORDON DEFRIESE, Professor of Social Medicine, University of North Carolina, Chapel Hill, North Carolina CEDRIC DUMONT, Medical Director, Department of State and the Foreign Service, Washington, DC JESSE GOODMAN, Deputy Director, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland RENU GUPTA, Vice President and Head, U.S. Clinical Research and Development, and Head, Global Cardiovascular, Metabolic, Endocrine, and G.I. Disorders, Novartis Corporation, East Hanover, New Jersey MARGARET HAMBURG, Vice President for Biological Programs, Nuclear Threat Initiative, Washington, DC CAROLE HEILMAN, Director, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland DAVID HEYMANN, Executive Director, Communicable Diseases, World Health Organization, Geneva, Switzerland JAMES HUGHES, Assistant Surgeon General and Director, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia SAMUEL KATZ, Wilburt C. Davison Professor and Chairman Emeritus, Duke University Medical Center, Durham, North Carolina PATRICK KELLEY, Colonel, Director, Department of Defense Global Emerging Infections System, Walter Reed Army Institute of Research, Silver Spring, Maryland MARCELLE LAYTON, Assistant Commissioner, Bureau of Communicable Diseases, New York City Department of Health, New York, New York JOSHUA LEDERBERG, Raymond and Beverly Sackler Foundation Scholar, The Rockefeller University, New York, New York
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CARLOS LOPEZ, Research Fellow, Research Acquisitions, Eli Lilly Research Laboratories, Indianapolis, Indiana LYNN MARKS, Global Head of Infectious Diseases, GlaxoSmithKline, Collegeville, Pennsylvania STEPHEN MORSE, Director, Center for Public Health Preparedness, Columbia University, New York, New York MICHAEL OSTERHOLM, Director, Center for Infectious Disease Research and Policy and Professor, School of Public Health, University of Minnesota, Minneapolis, Minnesota GARY ROSELLE, Program Director for Infectious Diseases, VA Central Office, Veterans Health Administration, Department of Veterans Affairs, Washington, DC DAVID SHLAES, Executive Vice President for Research and Development, Idenix, Cambridge, Massachusetts JANET SHOEMAKER, Director, Office of Public Affairs, American Society for Microbiology, Washington, DC P. FREDRICK SPARLING, J. Herbert Bate Professor Emeritus of Medicine, Microbiology, and Immunology, University of North Carolina, Chapel Hill, North Carolina MICHAEL ZEILINGER, Infectious Disease Team Leader, Office of Health and Nutrition, U.S. Agency for International Development, Washington, DC Liaisons ENRIQUETA BOND, President, Burroughs Wellcome Fund, Research Triangle Park, North Carolina NANCY CARTER-FOSTER, Director, Program for Emerging Infections and HIV/AIDS, U.S. Department of State, Washington, DC EDWARD McSWEEGAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Staff STACEY KNOBLER, Director, Forum on Emerging Infections MARJAN NAJAFI, Research Associate LAURIE SPINELLI, Project Assistant (until June 2002)
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BOARD ON GLOBAL HEALTH DEAN JAMISON (Chair), Senior Fellow, Fogarty International Center, National Institutes of Health, Bethesda, Maryland YVES BERGEVIN, Chief, Health Section, UNICEF, New York, New York PATRICIA DANZON, Professor, Health Care Systems Department, University of Pennsylvania, Philadelphia, Pennsylvania RICHARD FEACHEM, Executive Director, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland NOREEN GOLDMAN, Professor, Woodrow Wilson School of Public and International Affairs, Princeton University, Princeton, New Jersey MARGARET HAMBURG, Vice President for Biological Programs, Nuclear Threat Initiative, Washington, DC GERALD KEUSCH, Director, Fogarty International Center, National Institutes of Health, Bethesda, Maryland ARTHUR KLEINMAN, Maude and Lillian Presley Professor of Medical Anthropology/Professor of Psychiatry and Social Medicine, Harvard Medical School, Boston, Massachusetts ADEL MAHMOUD, President, Merck Vaccines, Whitehouse Station, New Jersey JOHN WYN OWEN, Secretary, Nuffield Trust, London, United Kingdom ALLAN ROSENFIELD, Dean, Mailman School of Public Health, Columbia University, New York, New York SUSAN SCRIMSHAW, Dean, School of Public Health, University of Illinois at Chicago, Chicago, Illinois DONALD BERWICK (IOM Council Liaison), Clinical Professor of Pediatrics and Health Care Policy, Harvard Medical School, Boston, Massachusetts DAVID CHALLONER (IOM Foreign Secretary), Vice President for Health Affairs, University of Florida, Gainesville, Florida Staff JUDITH BALE, Director PATRICIA CUFF, Research Associate STACEY KNOBLER, Study Director MARJAN NAJAFI, Research Associate KATHERINE OBERHOLTZER, Project Assistant JASON PELLMAR, Project Assistant MARK SMOLINSKI, Study Director LAURIE SPINELLI, Project Assistant (until June 2002)
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Reviewers All presenters at the workshop have reviewed and approved their respective sections of this report for accuracy. In addition, this workshop summary has been reviewed in draft form by independent reviewers chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the Institute of Medicine (IOM) in making the published workshop summary as sound as possible and to ensure that the workshop summary meets institutional standards. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. The Forum and IOM thank the following individuals for their participation in the review process: Steven Brickner, Pfizer, Inc., Groton, Connecticut Keith Klugman, Emory University School of Public Health, Atlanta, Georgia David Ofori-Adjei, University of Ghana, Accra, Ghana Clyde Thornsberry, Focus Technologies, Inc., Franklin, Tennessee Mary Wilson, Harvard School of Public Health, Boston, Massachusetts Kathleen Young, Alliance for Prudent Use of Antibiotics, Boston, Massachusetts
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The review of this report was overseen by Melvin Worth, M.D., Scholar-in-Residence, the National Academies, who was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the editors and individual authors.
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Preface The Forum on Emerging Infections was created in 1996 in response to a request from the Centers for Disease Control and Prevention and the National Institutes of Health. The goal of the Forum is to provide structured opportunities for representatives from academia, industry, professional and interest groups, and government1 to examine and discuss scientific and policy issues that are of shared interest and that are specifically related to research and prevention, detection, and management of emerging infectious diseases. In accomplishing this task, the Forum provides the opportunity to foster the exchange of information and ideas, identify areas in need of greater attention, clarify policy issues by enhancing knowledge and identifying points of agreement, and inform decision makers about science and policy issues. The Forum seeks to illuminate issues rather than resolve them directly; hence, it does not provide advice or recommendations on any specific policy initiative pending before any agency or organization. Its strengths are the diversity of its membership and the contributions of individual members expressed throughout the activities of the Forum. 1 Representatives of federal agencies serve in an ex officio capacity. An ex officio member of a group is one who is a member automatically by virtue of holding a particular office or membership in another body.
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ABOUT THE WORKSHOP Resistance in microbes—bacterial, viral, or protozoan—to therapeutics is neither surprising nor new. It is, however, an increasing challenge as drug resistance accumulates and accelerates, even as the drugs for combating infections are reduced in power and number. Today some strains of bacterial and viral infections are treatable with only a single drug; some no longer have effective treatments. The disease burden from multi-drug-resistant strains of tuberculosis, malaria, hepatitis, and HIV is growing in both developed and developing countries. Infections caused by resistant microbes may fail to respond to treatment, resulting in prolonged illness and greater risk of death. Treatment failures also lead to longer periods of infection, which increase the numbers of infected people moving into the community and thus expose the general population to the risk of contracting a resistant strain of infection. When infections become resistant to first-line antimicrobials,2 treatment has to be switched to second- or third-line drugs, which are nearly always much more expensive and sometimes more toxic as well. In many countries, the high cost of such replacement drugs is prohibitive, with the result that some diseases can no longer be treated in areas where resistance to first-line drugs is widespread. Most alarming of all are diseases where resistance is developing for virtually all currently available drugs. Even if the pharmaceutical industry were to step up efforts to develop new replacement drugs immediately, current trends suggest some diseases will have no effective therapies within the next ten years. More recently, the challenges of resistance are compounded by growing concerns about the possible use of biological weapons leading to large-scale disease outbreak or exposure. The ability to respond effectively to such exposures could be significantly compromised by the introduction of drug-resistant pathogens. The use of prophylactic drugs or therapies on large populations may also contribute to the development of drug resistance and thus increase both the immediate and longer-term challenges of treating infectious diseases. A number of trends in human behavior increasingly contribute to the emergence of resistance to antimicrobial agents. Host behaviors such as noncompliance with recommended treatment and self-medication are among the most complicit problems associated with the development of resistance. However, the duration of therapy for most acute infections has 2 In this report, antibiotics are defined as substances (not limited to those produced from microorganisms) that can kill or inhibit the growth of bacteria, while antimicrobials are substances that destroy or inhibit the growth of pathogenic groups of microorganisms, including bacteria, viruses, protozoa, and fungi.
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been determined empirically by treatment outcome, and more research is required on the effect of a reduction of treatment duration on the risk of the emergence of resistance. Other factors contributing to the rise in antimicrobial resistance include over-prescribing by physicians, failure to control the spread of infection in hospitals and long-term care facilities, and the overuse of antimicrobials in animals used for food products. These trends are currently outpacing scientific discovery to counter resistant pathogens. However, one promising aspect of such factors in the emergence of resistance is their amenability to change, which may be accomplished through public education, appropriate training, political action, and domestic and international regulation. Beyond the development of resistance in microbes, the ever-increasing resistance of disease vectors to biological and chemical pesticides looms as another complicating factor in efforts to control and eliminate the emergence of infectious diseases. Resistance to insecticides has appeared in the major insect vectors from every genus (e.g., mosquitoes, sand flies, ticks, fleas, and lice). Resistance has developed to every chemical class of insecticide, including microbial drugs and insect growth regulators. Insecticide resistance is predicted to have an increasing and profound effect on the reemergence of most vector-borne diseases. And where resistance has not contributed to disease emergence, it is expected to threaten disease control. Malaria control programs that already face complex challenges presented by multi-drug-resistant strains of the parasite are additionally undermined by vector mosquito populations that show increasing resistance to the pyrethroid-treated bed nets used to reduce malaria transmission. Resistance is a natural response of microbes and other organisms to selective pressure from antimicrobial and other biological and chemical countermeasures. Adaptive mechanisms in the organisms permit survival and the development of genetic resistance. While the emergence of resistance cannot be eliminated, the rate and extent of its occurrence can be contained. In order to contain the threats posed to human health by resistance, it is important to determine the magnitude and trends of resistance and to define the relative importance of different contributing factors, such as therapeutic, behavioral, economic and social, and health systems factors, as well as veterinary and agricultural misuse. Based on this understanding it may be possible to develop effective methods to contain resistance in different settings. Through invited presentations and participant discussion, the February 6–7, 2002, Forum workshop explored the causes and consequences of the resistance phenomenon. The Forum discussion also examined the scientific evidence supporting current and potential strategies for containment of resistance in microbes, vectors, and animal and human hosts. Additionally, the methods and measures of a response for industry, federal regulation,
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domestic and international public health, federal and academic research, and the private health care sector were debated. ORGANIZATION OF WORKSHOP SUMMARY This workshop summary report is prepared for the Forum membership in the name of the editors, with the assistance of staff and consultants, as a collection of individually authored papers. Sections of the workshop summary not specifically attributed to an individual reflect the views of the editors and not those of the Forum on Emerging Infections’ sponsors or the Institute of Medicine (IOM). The contents of the unattributed sections are based on the presentations and discussions that took place during the workshop. The workshop summary is organized within chapters as a topic-by-topic description of the presentations and discussions. Its purpose is to present lessons from relevant experience, delineate a range of pivotal issues and their respective problems, and put forth some potential responses as described by the workshop participants. The Summary and Assessment chapter discusses the core messages that emerged from the speakers’ presentations and the ensuing discussions. Chapter 1 is an introduction and overview of the resistance phenomenon. Chapters 2 to 7 begin with overviews provided by the editors, followed by the edited presentations made by the invited speakers. Appendix A is an authored paper describing the consequences of antimicrobial use in agriculture. Appendix B presents the workshop agenda. Appendix C is a list of information resources on resistance. Appendixes D, E, and F contain the executive summaries of three government reports on the topic of antimicrobial resistance. Appendix G presents Forum member and speaker biographies. Although this workshop summary provides an account of the individual presentations, it also reflects an important aspect of the Forum philosophy. The workshop functions as a dialogue among representatives from different sectors and presents their beliefs on which areas may merit further attention. However, the reader should be aware that the material presented here expresses the views and opinions of those participating in the workshop and not the deliberations of a formally constituted IOM study committee. These proceedings summarize only what participants stated in the workshop and are not intended to be an exhaustive exploration of the subject matter. ACKNOWLEDGMENTS The Forum on Emerging Infections and the IOM wish to express their warmest appreciation to the individuals and organizations who gave valu
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able time to provide information and advice to the Forum through participation in the workshop. The Forum is indebted to the IOM staff who contributed during the course of the workshop and the production of this workshop summary. On behalf of the Forum, we gratefully acknowledge the efforts led by Stacey Knobler, director of the Forum, and Marjan Najafi, research associate, coeditors of this report, who dedicated much effort and time to developing this workshop’s agenda, and for their thoughtful and insightful approach and skill in translating the workshop proceedings and discussion into this workshop summary. We would also like to thank the following IOM staff and consultants for their valuable contributions to this activity: Tom Burroughs, Laurie Spinelli, Judith Bale, Mark Smolinski, Katherine Oberholtzer, Patricia Cuff, Jennifer Otten, Clyde Behney, Bronwyn Schrecker, Sally Stanfield, Sally Groom, Michele de la Menardiere, and Beth Gyorgy. Finally, the Forum also thanks sponsors that supported this activity. Financial support for this project was provided by the U.S. Department of Health and Human Services’ National Institutes of Health, Centers for Disease Control and Prevention, and Food and Drug Administration; U.S. Department of Defense; U.S. Department of State; U.S. Department of Veterans Affairs; U.S. Department of Agriculture; American Society for Microbiology; Burroughs Wellcome Fund; Eli Lilly & Company; Pfizer; GlaxoSmithKline; and Wyeth-Ayerst Laboratories. The views presented in this workshop summary are those of the editors and workshop participants and are not necessarily those of the funding organizations. Adel Mahmoud, Chair Stanley Lemon, Vice-Chair Forum on Emerging Infections
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Contents SUMMARY AND ASSESSMENT Stanley M. Lemon 1 1 Introduction 19 Microbial Resistance: Adopting an Evolutionary Approach, 19 Arms Races and Antimicrobial Resistance: Using Evolutionary Science to Slow Evolution, Stephen R. Palumbi 21 Antibiotic Resistance 1992–2002: A Decade’s Journey, Stuart B. Levy 32 2 Microbe Resistance 44 Overview, 44 New Strategies Against Multi-Drug-Resistant Bacterial Pathogens, Alexander Tomasz 46 Malaria and the Problem of Chloroquine Resistance, Thomas E. Wellems 52 Drug Resistance in Treatment of Schistosomiasis, Charles H. King 59 Bacterial Infection in Irradiated Mice: Therapy and Prophylaxis (Anthrax, a Special Consideration), Thomas B. Elliott 64
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3 Vector Resistance 79 Overview, 79 Insecticide Resistance in Insect Vectors of Human Disease, Janet Hemingway 81 Managing the Emergence of Pesticide Resistance in Vectors, William G. Brogdon 88 What Is the Role of Insecticide Resistance in the Re-Emergence of Major Arthropod-Borne Diseases?, Donald R. Roberts and Paul B. Hshieh 94 4 The Economics of Resistance 107 Overview, 107 What Does Economics Have to Offer in the War Against Antimicrobial Resistance?, Richard D. Smith 108 Economic Instruments for the Control of Antimicrobial Resistance, William Jack 118 Economic Responses to the Problem of Drug Resistance, Ramanan Laxminarayan 121 5 Factors Contributing to the Emergence of Resistance 130 Overview, 130 Antibiotic Use and Resistance in Developing Countries, Iruka N. Okeke 132 Healthcare-Acquired Infections: Hospitals as a Breeding Ground for Antimicrobial Resistance, Lindsay E. Nicolle 139 The Use of Antimicrobials in Food-Producing Animals, Thomas R. Shryock 147 6 Emerging Tools and Technology for Countering Resistance 159 Overview, 159 Evolution of Multiple Mechanisms of Resistance to ß-Lactam Antibiotics, Dasantila Golemi-Kotra, Sergei Vakulenko, and Shahriar Mobashery 160 Using Phage Lytic Enzymes to Control Antibiotic-Resistant Pathogenic Bacteria on Mucous Membranes, Vincent A. Fischetti 167 Roles for Pharmacokinetics and Pharmacodynamics in Drug Development for Resistant Pathogens, Jerome J. Schentag and Alan Forrest 174
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7 Strategies to Contain the Development and Consequences of Resistance 196 Overview, 196 Development of the Public Health Action Plan to Combat Antimicrobial Resistance and CDC Activities Related to Its Implementation, David M. Bell 198 Antibiotic Resistance: Encouraging the Development of New Therapies, Preserving the Usefulness of Current Therapies, Mark J. Goldberger 206 The Centers for Disease Control and Prevention’s Campaign to Prevent Antimicrobial Resistance in Health Care Settings, Julie L. Gerberding 210 Antimicrobial Resistance Containment Strategies of the Rational Pharmaceutical Management Plus Program, Terry Green and Anthony Savelli 215 Antimicrobial Resistance and Future Directions, Mary E. Torrence 223 APPENDIXES A Public Health Consequences of Use of Antimicrobial Agents in Agriculture 231 B Agenda: Issues of Resistance: Microbes, Vectors, and the Host 244 C Information Resources 249 D Executive Summary: WHO Report 256 E Executive Summary: GFHR Report 274 F Executive Summary: Interagency Task Force Report 279 G Forum Member, Speaker, and Staff Biographies 287
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