Antimicrobial Resistance: Issues and Options

Workshop Report

Forum on Emerging Infections

Polly F. Harrison and Joshua Lederberg, Editors

Division of Health Sciences Policy

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.
1998



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Antimicrobial Resistance: Issues and Options Workshop Report Forum on Emerging Infections Polly F. Harrison and Joshua Lederberg, Editors Division of Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C. 1998

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this report 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. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. Support for this project was provided by Centers for Disease Control and Prevention; the National Institute of Allergy and Infectious Diseases, National Institutes of Health; the Department of Veterans Affairs; the Department of State; the Food and Drug Administration; and several private pharmaceutical companies, private foundations, and associations. The views presented are those of the Institute of Medicine Forum on Emerging Infections and are not necessarily those of the funding organizations. International Standard Book No. 0-309-06084-2 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's on-line bookstore at http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at http://www2.nas.edu/iom. Copyright 1998 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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FORUM ON EMERGING INFECTIONS JOSHUA LEDERBERG1 (Chair), Sackler Foundation Scholar, The Rockefeller University, New York VINCENT I. AHONKHAI, Vice President and Director, Anti-Infectives and Biologicals, SmithKline Beecham Corporation, Collegeville, Pennsylvania STEVEN J. BRICKNER, Manager of Medicinal Chemistry, Central Research Division, Pfizer, Inc., Groton, Connecticut GAIL H. CASSELL,2 Vice President for Infectious Diseases Research, Drug Discovery Research, and Clinical Investigation, Eli Lilly & Company, Indianapolis GORDON H. DEFRIESE,2 Director and Professor of Social Medicine, Epidemiology, Health Policy, and Administration, Sheps Center for Health Services Research, University of North Carolina, Chapel Hill NANCY CARTER FOSTER,3 Director, Program for Emerging Infections and HIV/AIDS, Department of State, Washington, D.C. RENU GUPTA, Senior Medical Director, Infectious Diseases, Bristol-Myers Squibb Company, Princeton, New Jersey MARGARET A. HAMBURG,2 Assistant Secretary for Planning and Evaluation, Department of Health and Human Services, Washington, D.C. DIETER HINZEN, Professor and Head of Preclinical Research, F. HoffmannLaRoche, A.G., Basel, Switzerland JAMES M. HUGHES,3 Assistant Surgeon General, and Director, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta J. STANLEY HULL, Vice President, Global Commercial Development, Glaxo Wellcome, Research Triangle Park, North Carolina SAMUEL L. KATZ,2 Chairman of the Board, Burroughs Wellcome Fund, and Wilburt C. Davison Professor, Department of Pediatrics, Duke University Medical Center KENNETH W. KIZER,3 Under Secretary for Health, Veterans Health Administration, Department of Veterans Affairs, Washington, D.C. WILLIAM KOHLBRENNER, Director, Antiviral Research, Abbott Laboratories, Abbott Park, Illinois JOHN R. LaMONTAGNE,3 Deputy Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland CARLOS LOPEZ, Executive Director, Infectious Disease Research, Eli Lilly Research Laboratories, Indianapolis 1   Member, Institute of Medicine and National Academy of Sciences. 2   Member, Institute of Medicine. 3   Ex-officio member.

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STEPHEN S. MORSE, Assistant Professor of Epidemiology, Columbia University School of Public Health, and Defense Advanced Research Projects Agency/Defense Sciences Office, Washington, D.C. SOLOMON MOWSHOWITZ, Vice President, Research and Development, Applied Microbiology, Inc., Tarrytown, New York STUART L. NIGHTINGALE,3 Associate Commissioner for Health Affairs, Food and Drug Administration, Department of Health and Human Services, Rockville, Maryland MICHAEL T. OSTERHOLM, State Epidemiologist and Chief, Acute Disease Epidemiology Section, Minnesota Department of Health, Minneapolis DAVID M. SHLAES, Vice President, Infectious Disease Research, Wyeth-Ayerst Research, Pearl River, New York JOHN D. SIEGFRIED, Deputy Vice-President, Science and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C. P. FREDERICK SPARLING, Chair of Medicine, University of North Carolina, Chapel Hill, and President, Infectious Diseases Society of America, Washington, D.C. Liaisons to the Forum BARRY R. BLOOM,2 Investigator, Howard Hughes Medical Institute, and Albert Einstein College of Medicine, Yeshiva University, Hastings-on Hudson, New York ENRIQUETA C. BOND, President, Burroughs Wellcome Fund, Morrisville, North Carolina GARY CHRISTOPHERSON, Senior Advisor, Health Affairs, Department of Defense, Washington, D.C. MICHAEL HUGHES, Office of the Undersecretary, Veterans Health Administration, Department of Veterans Affairs, Washington, D.C. STEPHANIE JAMES, Parasitology and International Programs Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland C. MICHELLE LIMOLI, Special Assistant to the Director, Office of International Affairs, Food and Drug Administration, Rockville, Maryland STEPHEN M. OSTROFF, Acting Deputy Director, and Associate Director for Epidemiologic Science, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta GARY ROSELLE, Program Director for Infectious Disease, Veterans Administration, Cincinnati, Ohio

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FRED TENOVER, Chief, Nosocomial Pathogens Laboratory Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta Study Staff JONATHAN R. DAVIS, Senior Program Officer (from February 1998) POLLY F. HARRISON, Senior Program Officer (to January 1998) GRETCHEN G. KIDDER, Research Assistant (to February 1998) CHRISTINA THACKER, Research/Project Assistant Division Staff LINDA DEPUGH, Administrative Assistant ANDREW M. POPE, Acting Director (from January 1998) VALERIE P. SETLOW, Division Director (to December 1997) JAMAINE TINKER, Financial Associate

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Preface THE FORUM The Forum on Emerging Infections was created in response to a request from the Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases (NIAID). Its goal is to provide structured opportunities for representatives from academia, industry, professional and interest groups, and government 1 to examine and discuss scientific and policy dilemmas of shared interest that are specifically related to research on and prevention, detection, and management of emerging infections.2 In accomplishing this task, the Forum can foster 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. We underscore here that the Forum seeks to illuminate issues rather than resolve them directly; it does not provide advice or recommendations on any policy pending before any agency or organization. Its strength rests on its diversity of membership and the commitment of individual members to attend on a recurrent basis. A critical part of the Forum's work is a series of workshops. The first of these, held in February 1997, addressed the theme of publicand private-sector collaboration.3 The second workshop, on which this document reports, was held in July 1997 and explored aspects of antimicrobial resistance. The third workshop, held in March 1998, examined the implications of health care restructuring for addressing emerging infectious diseases; a report should be forthcoming in fall 1998. The fourth workshop will assess the core capacity of public- and private-sector laboratories for emerging infectious disease surveillance and response.

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THE REPORT AND ITS ORGANIZATION We ask the reader to remember, first, that any single workshop is necessarily incomplete and, second, that its proceedings can report only on what was said, so that this report cannot pretend to be an exhaustive exploration of its subject matter. Organized as a topic-by-topic synthesis of exchanges during the workshop, its purposes are to highlight lessons from relevant experience, delineate a range of pivotal issues and the problems they present, and put on the table some simplified ideas about possible responses. All information reported in the text emerged in the workshop itself. When presenters provided supporting written material or visuals, where references were made to a specific document, if critical information required updating, or where a key allusion needed more explication to be intelligible to the reader, an endnote is provided. The names of the individuals who made presentations on individual topics are identified in footnotes at the beginning of each section; these individuals have reviewed and approved the sections for accuracy. All Forum members who were present at the workshop have also reviewed the document and responded that they believe the report accurately reflects what was said. At the same time that this report provides an account of individual presentations, the dynamics of the Forum are such that the report also reflects a very important aspect of the Forum philosophy, that is, its function as a dialogue among representatives from different sectors and their thinking about what areas of action and research might merit further attention. However, the reader should understand that the material presented here expresses the views and opinions of those participating in the workshop, not the deliberations of a formally constituted Institute of Medicine (IOM) study committee. ACKNOWLEDGMENTS On behalf of the Forum and the IOM, we wish to express our warmest appreciation to the individuals and organizations who gave valuable time to provide information and advice to the Forum through participation in this workshop. Each of the following contributed greatly: David Bell, CDC; Bob Buchanan, United States Department of Agriculture, Agricultural Research Service, Eastern Region Research Center; Mitchell Cohen, CDC; David Fidler, University of Indiana; John Gay, Washington State University; Tom Gingeras, Affymetrix; Mark Goldberger, Food and Drug Administration; Renu Gupta, Bristol-Myers Squibb; Mich Hein, EPIcyte; David Heymann, World Health Organization (WHO); Karl Kristinsson, CEM/NET; Stuart Levy, Tufts University; Donald Low, Canada; Michael Marcy, Kaiser Permanente; Laurence McCarthy, MRL Pharmaceutical Services; George Miller, Schering-Plough Research Institute; Gerald Mossinghoff, George Washington School of Law; Michael Osterholm, Minnesota Department of Health; Thomas Quinn, Johns Hopkins University; Paul Sundberg,

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National Pork Producers Council; Fred Tenover, CDC; David Relman, Stanford University; Robert Rubin, The Lewin Group; Craig Venter, Institute for Genomic Research; Mark Wilhite, Environmental Protection Agency; Rosamund Williams, WHO. We also want to note the fine work of Christina Thacker for drafting the sections on judicious antibiotic use, food production issues, and legal concerns, and Gretchen Kidder for drafting the sciences and surveillance sections as well as the appendix on surveillance systems and the Glossary and Acronyms. We especially thank Jonathan Davis, who has dedicated much effort and time to refining the manuscript to its final form and guiding it through the review process. Finally, we thank Peter Slavin, who incorporated into the first draft the many pieces of written material presented during this workshop. This report has been reviewed by individuals 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 authors and the IOM in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The content of the review comments and the draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review process: J. Claude Bennett, M.D., BioCryst Pharmaceuticals, Inc.; Charles C. J. Carpenter, M.D., Brown University; David E. Housman, Massachusetts Institute of Technology; and P. Frederick Sparling, M.D., University of North Carolina, Chapel Hill. While the individuals listed above have provided many constructive comments and suggestions, responsibility for the final content of this report rests solely with the authoring committee and the IOM. NOTES 1.   Representatives of federal agencies serve in an ex-officio capacity. 2.   Emerging infectious diseases are diseases of infectious origin whose incidence in humans has increased within the past two decades or threatens to increase in the near future (Institute of Medicine. Emerging Infections: Microbial Threats to Health in the United States. Lederberg J, RE Shope, SC Oaks Jr, eds. Washington, D.C.: National Academy Press, 1992.) 3.   Institute of Medicine. Orphans and Incentives: Developing Technologies to Address Emerging Infections. Workshop Report. Harrison PF, J Lederberg, eds. Washington, D.C.: National Academy Press, 1997.

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Contents     Workshop Summary   1     Workshop Report   8     Introduction   8     The Topic   8     The Workshop   9     The Costs of Antimicrobial Resistance   9     Background   9     Recent Case Material   10     Tracking the Problem: Current Approaches to Surveillance   11     Characteristics of an Ideal Resistance Surveillance System   12     Local-Level Surveillance   13     National Systems   14     International Systems   19     Surveillance and the Laboratory   22     What Is Needed   23     How Can the Sciences Help?   26     Implications of Mapping the Genome   26     Molecular Detection of Genes Associated with Antimicrobial Resistance   28     High-Density Oligonucleotide Arrays   29     Applications of Genomics and Bioinformatics to the Development of Anti-Infectives   31

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    A Role for New Therapeutic Approaches in Combating Antimicrobial Resistance   32     Applications of Field Surveillance in the United States and Globally   33     What Is Needed   36     Sources of Resistance and Antibiotic Use   37     Sources of Resistance   37     Antibiotic Use   38     Resistance and Food Production: Issues and Needs   50     Concerns and Perspectives from Producers   50     The Ecology of Resistance on the Farm   52     U.S. Department of Agriculture   53     U.S. Environmental Protection Agency   53     Areas for Consideration and Action in Food Production   54     Legal and Regulatory Concerns   56     Matters of Law and Possible Responses   56     Intellectual Property Protection   60     Collaborative Research and Development   62     Regulatory FDA Responses to Antimicrobial Resistance   63     Summary of Areas for Consideration   64     Surveillance   65     Response: Prolonging Effectiveness   66     Response: Developing New Products   68     Agricultural Use   69     Final Comments   70     Notes   71     Appendixes     A   Inventory of Surveillance Systems   75 B   American Society for Microbiology Recommendation   94 C   Glossary and Acronyms   104 D   Workshop Agenda   112