ANTIBIOTIC RESISTANCE

Implications for Global Health and Novel Intervention Strategies

Workshop Summary

Eileen R. Choffnes, David A. Relman, and Alison Mack, Rapporteurs

Forum on Microbial Threats

Board on Global Health

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Eileen R. Choffnes, David A. Relman, and Alison Mack, Rapporteurs Forum on Microbial Threats Board on Global Health

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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 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. This project was supported by contracts between the National Academy of Sciences and the U.S. Department of Health and Human Services: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, and Food and Drug Administration; U.S. Department of Defense, Department of the Army: Global Emerging Infections Surveillance and Response System, Medical Research and Materiel Command, and Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Development; American Society for Microbiology; Sanofi Pasteur; Burroughs Wellcome Fund; Pfizer; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-15611-0 International Standard Book Number-10: 0-309-15611-4 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 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 2010 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 image: This 2005 colorized scanning electron micrograph depicts numerous clumps of methicillin-resistant Staphylococcus aureus (MRSA) bacteria. MRSA infections, e.g., bloodstream, pneumonia, bone infections, occur most frequently among persons in hos - pitals and healthcare facilities, including nursing homes and dialysis centers. SOURCE: CDC, Public Health Image Library (PHIL 10046). Suggested citation: IOM (Institute of Medicine). 2010. Antibiotic resistance: Implica- tions for global health and novel intervention strategies. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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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. Ralph J. Cicerone 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. Charles M. Vest 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 examina - tion 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. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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FORUM ON MICROBIAL THREATS1 DAVID A. RELMAN (Chair), Stanford University and Veterans Affairs Palo Alto Health Care System, Palo Alto, California JAMES M. HUGHES (Vice Chair), Global Infectious Diseases Program, Emory University, Atlanta, Georgia RUTH L. BERKELMAN, Emory University, Center for Public Health Preparedness and Research, Rollins School of Public Health, Atlanta, Georgia ENRIQUETA C. BOND, Consultant, Marshall, Virginia ROGER G. BREEZE, Centaur Science Group, Washington, DC STEVEN J. BRICKNER, SJ Brickner Consulting, LLC, Ledyard, Connecticut PAULA R. BRyANT, Medical S&T Division, Defense Threat Reduction Agency, Fort Belvoir, VA JOHN E. BURRIS, Burroughs Wellcome Fund, Research Triangle Park, North Carolina GAIL H. CASSELL,2 Eli Lilly & Company, Indianapolis, Indiana PETER DASZAK,3 EcoHealth Alliance, New York, New York JEFFERy DUCHIN,3 Public Health–Seattle and King County, Seattle, Washington JONATHAN EISEN,3 Genome Center, University of California, Davis MARK B. FEINBERG, Merck Vaccine Division, Merck & Co., West Point, Pennsylvania JACQUELINE FLETCHER,3 Oklahoma State University, Stillwater S. ELIZABETH GEORGE, Biological and Chemical Countermeasures Program, Department of Homeland Security, Washington, DC JESSE L. GOODMAN, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland EDUARDO GOTUZZO, Instituto de Medicina Tropical–Alexander von Humbolt, Universidad Peruana Cayetano Heredia, Lima, Peru JO HANDELSMAN, Yale University, New Haven, Connecticut CAROLE A. HEILMAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland DAVID L. HEyMANN, Health Protection Agency, London, United Kingdom PHILIP HOSBACH, Sanofi Pasteur, Swiftwater, Pennsylvania STEPHEN ALBERT JOHNSTON, Arizona BioDesign Institute, Arizona State University, Tempe 1 IOM forums and roundtables do not issue, review, or approve individual documents. The responsi- bility for the published workshop summary rests with the workshop rapporteurs and the institution. 2 Forum member until October 31, 2010. 3 Forum member since October 15, 2010. v

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KENT KESTER, Walter Reed Army Institute of Research, Silver Spring, Maryland GERALD T. KEUSCH, Boston University School of Medicine and Boston University School of Public Health, Massachusetts RIMA F. KHABBAZ, Centers for Disease Control and Prevention, Atlanta, Georgia LONNIE J. KING, Ohio State University, Columbus STANLEy M. LEMON, School of Medicine, University of North Carolina, Chapel Hill EDWARD McSWEEGAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland MARK MILLER,3 Fogarty International Center, Bethesda, Maryland PAUL F. MILLER, Pfizer, Groton, Connecticut STEPHEN S. MORSE, Center for Public Health Preparedness, Columbia University, New York MICHAEL T. OSTERHOLM,2 Center for Infectious Disease Research and Policy, School of Public Health, University of Minnesota, Minneapolis GEORGE POSTE, Complex Adaptive Systems Initiative, Arizona State University, Tempe JOHN C. POTTAGE, JR., GlaxoSmithKline, Collegeville, Pennsylvania GARy A. ROSELLE, Veterans Health Administration, Department of Veterans Affairs, Washington, DC ALAN RUDOLPH,3 Defense Threat Reduction Agency, Fort Belvoir, Virginia KEVIN RUSSELL, Global Emerging Infections Surveillance and Response System, Department of Defense, Silver Spring, Maryland JANET SHOEMAKER, American Society for Microbiology, Washington, DC P. FREDERICK SPARLING, University of North Carolina, Chapel Hill TERENCE TAyLOR, International Council for the Life Sciences, Washington, DC MURRAy TROSTLE, U.S. Agency for International Development, Washington, DC MARy WILSON,3 Harvard School of Public Health, Harvard University, Boston, Massachusetts Staff EILEEN CHOFFNES, Director KATE SKOCZDOPOLE, Senior Program Associate (until July 2010) KATHERINE McCLURE, Senior Program Associate (from May 2010) LEIGHANNE OLSEN, Program Officer (from June 2010) COLLIN WEINBERGER, Research Associate (from April 2010) ROBERT GASIOR, Senior Program Assistant ALISON MACK, Science Writer vi

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BOARD ON GLOBAL HEALTH1 Richard Guerrant (Chair), Thomas H. Hunter Professor of International Medicine and Director, Center for Global Health, University of Virginia School of Medicine, Charlottesville Jo Ivey Boufford (IOM Foreign Secretary), President, New York Academy of Medicine, New York Claire V. Broome, Adjunct Professor, Division of Global Health, Rollins School of Public Health, Emory University Jacquelyn C. Campbell, Anna D. Wolf Chair, and Professor, Johns Hopkins University School of Nursing, Baltimore, Maryland Thomas J. Coates, Professor, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles Valentin Fuster, Director, Wiener Cardiovascular Institute Kravis Cardiovascular Health Center, and Professor, Cardiology, Mount Sinai School of Medicine, Mount Sinai Medical Center, New York Peter J. Hotez, Professor and Chair, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC Fitzhugh Mullan, Professor, Department of Health Policy, George Washington University, Washington, DC Staff Patrick Kelley, Director Angela Mensah, Program Associate 1 IOM boards do not review or approve individual workshop summaries and are not asked to en - dorse conclusions and recommendations. The responsibility for the content of the workshop summary rests with the authors and the institution. vii

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Reviewers This report has been reviewed in draft form 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 institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evi - dence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this report: Martin Blaser, New York University School of Medicine Roger G. Breeze, Centaur Science Group David Heymann, Health Protection Agency, United Kingdom , Mary E. Wilson, Harvard School of Public Health Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Dr. Melvin Worth. Appointed by the Institute of Medicine, he 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 authoring committee and the institution. ix

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Acknowledgments The Forum on Emerging Infections was created by the Institute of Medicine (IOM) in 1996 in response to a request from the Centers for Disease Control and Prevention and the National Institutes of Health. The purpose of the Forum is to provide structured opportunities for leaders from government, academia, and industry to regularly meet and examine issues of shared concern regarding research, prevention, detection, and management of emerging, reemerging, and novel infectious diseases in humans, plants, and animals. In pursuing this task, the Forum provides a venue 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. For this reason, it does not provide advice or recommendations on any specific policy initiative pending before any agency or organization. Its value derives instead from the diversity of its membership and from the contributions that individual members make throughout the activities of the Forum. In September 2003, the Forum changed its name to the Forum on Microbial Threats. The Forum on Microbial Threats and the IOM wish to express their warmest appreciation to the individuals and organizations who gave their valuable time to provide information and advice to the Forum through their participation in the planning and execution of this workshop. A full list of presenters, and their biographical information, may be found in Appendixes B and F, respectively. The Forum is indebted to the IOM staff who contributed throughout the plan - ning and conduct of the workshop and the production of this workshop summary report. On behalf of the Forum, we gratefully acknowledge the efforts led by Dr. Eileen Choffnes, director of the Forum; Dr. LeighAnne Olsen, program officer; xi

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xii ACKNOWLEDGMENTS Kate Skoczdopole, senior program associate; Katherine McClure, senior program associate; Collin Weinberger, research associate; and Robert Gasior, senior pro - gram assistant, for dedicating much effort and time to developing this workshop’s agenda and for their thoughtful and insightful approach and skill in planning for the workshop and in translating the workshop’s proceedings and discussion into this workshop summary report. We would also like to thank the following IOM staff and consultants for their valuable contributions to this activity: Alison Mack, Jordan Wyndelts, Jill Grady, Jackie Turner, and Heather Phillips. Finally, the Forum wishes to recognize the sponsors that supported this activ- ity. Financial support for this project was provided by the U.S. Department of Health and Human Services: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, and Food and Drug Administration; U.S. Department of Defense, Department of the Army: Global Emerging Infections Surveillance and Response System, Medical Research and Materiel Command, and the Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Development; American Society for Microbiology; Sanofi Pasteur; Burroughs Wellcome Fund; Pfizer; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. The views presented in this workshop summary report are those of the workshop participants and rapporteurs and are not necessarily those of the Forum on Microbial Threats or its sponsors.

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Contents Workshop Overview 1 Organization of the Workshop Summary, 2 Antimicrobial Drug Resistance in Context, 3 Microbial Evolution and the Origins of Resistance, 8 Anthropogenic Influences on AMR, 15 Staying Ahead of AMR, 32 Workshop Overview References, 57 Appendixes A Contributed Manuscripts 75 A1 The Case for Pathogen-Specific Therapy, 75 Arturo Casadevall A2 Waves of Resistance: Staphylococcus aureus in the Antibiotic Era, 83 Henry F. Chambers and Frank R. DeLeo A3 Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis, 116 Michael A. Kohanski, Mark A. DePristo, and James J. Collins A4 Antibiotic-Induced Resistance Flow, 141 Patrice Courvalin A5 Actinobacteria: The Good, The Bad, and The Ugly, 149 Vivan Miao and Julian Davies A6 Antibiotics for Emerging Pathogens, 160 Michael A. Fischbach and Christopher T. Walsh xiii

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xiv CONTENTS A7 Averting a Potential Post-Antibiotic Era, 174 Shelley Hearne A8 Antibiotic Effectiveness: New Challenges in Natural Resource Management, 190 Markus Herrmann and Ramanan Laxminarayan A9 The Role of Health Care Facilities, 206 Ramanan Laxminarayan A10 Responding to the Global Antibiotic Resistance Crisis: The APUA Chapter Network, 222 Stuart B. Levy A11 Challenges and Opportunities in Antibiotic Discovery, 233 Kim Lewis A12 Population Mobility, Globalization, and Antimicrobial Resistance, 257 Douglas W. MacPherson and Brian D. Gushulak A13 Population Mobility, Globalization, and Antimicrobial Drug Resistance, 276 Douglas W. MacPherson, Brain D. Gushulak, William B. Baine, Shukal Bala, Paul O. Gubbins, Paul Holtom, and Marisel Segarra-Newnham A14 The Bacterial Challenge: A Time to React, Executive Summary, 287 European Centre for Disease Prevention and Control and European Medicines Agency Joint Working Group— Dominique L. Monnet A15 The Effects of Antibiotic and Pesticide Resistance on Public Health, 294 David Pimentel A16 Clinical Issues and Outcomes Associated with Rising Antimicrobial Resistance, 301 Louis B. Rice A17 World Health Organization Activities for Control of Antimicrobial Resistance Due to Use ofAntimicrobials in Animals Intended for Food, 308 Jørgen Schlundt and Awa Aidara-Kane A18 The Antibacterial Pipeline: Why Is It Drying Up, and What Must Be Done About It?, 326 Brad Spellberg A19 Challenges in Antimicrobial Susceptibility Testing of Clinical and Environmental Isolates, 365 Fred C. Tenover A20 Measuring the Cost of Antimicrobial-Resistant Infections:

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xv CONTENTS The Feasibility and Accuracy of Economic Analysis Using Electronic Medical Record Databases, 379 Rebecca R. Roberts, Linda M. Kampe, Ibrar Ahmad, Bala Hota, Edward K. Mensah, and Robert A. Weinstein A21 The Antibiotic Resistome, 401 Gerard D. Wright B Agenda 420 C Acronyms 424 D Glossary 427 E Forum Member Biographies 437 F Speaker Biographies 465

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Tables, Figures, and Boxes TABLES WO-1 Burden of Multidrug-Resistant Bacteria in the European Union, Iceland, and Norway, 2007, 21 WO-2 Major Antimicrobial Agent Classes Approved for Non-Therapeutic Use in Animals, 24 A2-1 Lineages of Common Nosocomial MRSA Strains, 87 A2-2 Comparison of Staphylococcal Chromosome Cassette mec Allotypes, 96 A2-S1 Virulence Factors of Staphylococcus aureus, 113 A3-1 Cross-Resistance Following Ampicillin Treatment and Primary Resistance Selection with Five Different Classes of Antibiotics, 124 A3-2 Cross-Resistance for S. aureus Following Ampicillin Treatment and Primary Resistance Selection with Five Different Classes of Antibiotics, 128 A3-3 Cross-Resistance for E. coli Clinical Isolate NCDC C771 Following Ampicillin Treatment and Primary Resistance Selection with Four Different Classes of Antibiotics, 129 A3-S1 PCR Primers and Sequencing Primers, 139 A5-1 Some Beneficial Actinobacteria, 153 A5-2 Some Actinobacterial Pathogens (human, animal, and plant), 157 xvii

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xviii TABLES, FIGURES, AND BOXES A12-1 Mobile Populations by Category and Estimates of Domestic and International Arrivals, 263 A13-1 Global Estimates of Annual Migrant Populations, 279 A18-1 Antibiotic-Mediated Mortality Reductions for Specific Infections, 328 A19-1 Examples of Supplementary Tests to Identify Resistance Phenotypes, 368 A20-1 Mean Cost per Day for Individual Hospital Resources and Cumulative Daily Totals, 386 A20-2 Differences Between Mean Unadjusted Original Precise Cost Based on Charge Review and Sequential Average Costs by Patient Subgroups, 387 A20-3 Attributable Cost for Antimicrobial-Resistant Infection Using Ordinary Least Squares Regression: Difference Between Precise Cost and Sequential Cost Averages, 388 A20-4 Resistant Organism Subgroups: Difference Between Precise Cost and Sequential Cost Averages for Ordinary Least Squares Linear Regression, 390 A20-5 Treatment Setting Subgroups: Difference Between Precise Cost and Sequential Average Costs When Using Ordinary Least Squares Linear Regression to Estimate the Attributable Cost for Antimicrobial-Resistant Infection, 392 A20-6 Differences Between Original Cost and Sequential Cost Averages When Comparing Patients with Antimicrobial-Resistant Infection to Matched Controls, 394 A21-1 Proteoresistance Elements, 408 FIGURES WO-1 The relationship between antibiotic resistance development in Shigella dysenteriae isolates in Japan and the introduction of antimicrobial therapy between 1950 and 1965, 4 WO-2 Major classes of antimicrobials and the year of their discovery, 5 WO-3 Principal targets for antibiotic action, 10 WO-4 Common mechanisms of resistance in methicillin-resistant Staphylococccus aureus, 12 WO-5 Survey of 480 soil actinomycetes and their level of resistance to each antibiotic of interest, 13 WO-6 Vancomycin resistance distribution, 13

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xix TABLES, FIGURES, AND BOXES WO-7 Three connected antimicrobial ecosystems, 16 WO-8 Antibiotic-induced increase in mutation rate, 18 WO-9 Transfer of an integrative conjugative element, 19 WO-10 Economic burden of multidrug-resistant bacteria: nomogram for in- hospital costs, 22 WO-11 Danish experience after growth promoter ban, 27 WO-12 Conceptualized view showing the possible fates of antibiotic residues and mechanisms of antibiotic resistance gene acquisition and dissemination by bacteria, beginning with land application of animal waste as the source of entry of drugs, bacteria, and resistance genes into the soil environment, 30 WO-13 Systemic (i.e., non-topical) antibacterial new molecular entities approved by the FDA, per 5-year period, 36 WO-14 Modified bacteriophage enter and destroy the biofilm matrix, 41 WO-15 Synthetic tailoring is widely used to create successive generations of antibiotic classes, 42 WO-16 Surmounting resistance with scaffold alterations, 44 WO-17 Mining genes for drugs, 45 WO-18 Over-the-counter availability of antibiotics in the Cancun (Mexico) airport, 50 WO-4-1 Methicillin-resistant Staphlyococcus aureus, 58 WO-4-2 Vancomycin-resistant Staphlyococcus aureus, 59 WO-4-3 Multidrug-resistant tuberculosis, 60 WO-4-4 Vancomycin-resistant enterococci, 60 Detection of extended-spectrum b-lactamase production by the WO-4-5 double disk test on DSM-ES agar, 61 WO-4-6 Clostridium difficile, 62 WO-4-7 Klebsiella pneumoniae, 63 WO-4-8 False-colored scanning electron micrograph of a human phagocyte and gonococci, 63 A2-1 The four waves of antibiotic resistance in Staphylococcus aureus, 86 A2-2 An example of a multilocus sequence typing scheme and the designation of clonal complexes, 92 A2-3 Distribution of antibiotic-susceptible and -resistant Staphylococcus aureus among clonal complexes, 94 A2-4 Comparison of the methicillin resistance cassettes that are typical of hospital- or community-acquired methicillin-resistant Staphylococcus aureus, 95 A3-1 Low levels of bactericidal antibiotics increase mutation rate due to reactive oxygen species formation, 119

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xx TABLES, FIGURES, AND BOXES A3-2 Low levels of bactericidal antibiotics can lead to broad-spectrum increases in MIC due to ROS-mediated mutagenesis, 121 A3-3 Ampicillin treatment of E. coli results in heterogeneous increases in MIC for ampicillin and norfloxacin, 123 A3-4 Ampicillin treatment leads to the formation of norfloxacin-resistant isolates with mutations in gyrA, gyrB, or the acrAB promoter (PacrAB) and kanamycin-resistant isolates with mutations in rpsL or arcA, 126 A3-S1 Bactericidal antibiotics can lead to broad-spectrum increases in MIC, 137 A3-S2 Survival of E. coli following treatment with near-MIC levels of antibiotics, 138 A4-1 Antibiotic induced increase mutation rate in S. pneumoniae, 144 A4-2 Antibiotic promotes evolution of resistance in S. pneumoniae, 145 A4-3 Transfer of an integrative conjugative element (ICE), 146 A5-1 Phylogenetic tree of actinobacteria based on 1,500 nucleotides of 16S rRNA, 151 A6-1 Multidrug-resistant strains of these bacterial pathogens are on the rise, 162 A6-2 Synthetic tailoring is widely used to create successive generations of antibiotic classes, 164 A6-3 Between 1962 and 2000, no major classes of antibiotics were introduced, 165 A6-4 Surmounting resistance with scaffold alterations, 166 A6-5 The chemical structures of new and underexplored antibiotic scaffolds mentioned throughout the text are organized by type into three categories: synthetic, semisynthetic, and natural product, 168 A7-1 Shifting balance, 175 A7-2 Total antimicrobial use in food animal production, 179 A7-3 Danish laws limiting antimicrobial use in swine production resulted in a dramatic decline in non-therapeutic (NTA) use of these agents (dark gray) as well as an overall decline in antibiotic use per kilogram of meat produced, 182 A10-1 APUA chapter network, 223 A10-2 APUA Small Grants Program, 224 A10-3 Venezuela declaration of public health threat by antibiotic resistance (AMR), 225 A10-4 Effect of the need for a prescription on sale of antibiotics in Chile, 226 A10-5 Training journalists, 227

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xxi TABLES, FIGURES, AND BOXES A10-6 The APUA GAARD project reports a “shadow epidemic,” 228 A11-1 Dose-dependent killing with a bactericidal antibiotic reveals a small subpopulation of tolerant cells, persisters, 234 A11-2 Resistance and tolerance, 234 A11-3 A model of a relapsing biofilm infection, 235 A11-4 The two faces of recalcitrance, 237 A11-5 Candidate persister genes, 239 A11-6 The HipA toxin causes dormancy in E. coli by phosphorylating elongation factor Tu, which inhibits protein synthesis, 240 A11-7 Persister induction by antibiotic, 242 A11-8 The high-tech platform, 244 A11-9 A diffusion chamber for growing bacteria in situ, 247 A11-10 Understanding the mechanism of uncultivability, 248 A11-11 A high-throughput screen for antimicrobials in an animal model, 251 A12-1 Age pyramids for more and less developed regions, 1998 and 2050, 260 A12-2 Global population projection as percent urban, 2007, 2015, and 2030, 261 A12-3 Percentage of population at midyear residing in urban areas, by region, 1950–2030, 262 A14-1 Population-weighted, average proportion of resistant isolates among blood isolates of bacteria frequently responsible for bloodstream infections, EU Member States, Iceland and Norway, 2002–2007, 290 A14-2 New systemic antibacterial agents with a new target or new mechanism of action and in vitro activity based on actual data (dark color bars) or assumed in vitro activity based on class properties or mechanisms of action (light color bars) against the selected bacteria (best-case scenario), by phase of development (n = 15), 293 A17-1 The WHO/FAO food safety risk analysis framework, 322 A18-1 Change in deaths from infection in the United States following the introduction of antibiotics, 327 A18-2 Number of new systemic antibacterial agents approved by the FDA per 5-year period, 331 A18-3 Schema of the drug development process, 334 A18-4 Improvement in clinical response in patients with community- acquired bacterial pneumonia treated with sulfonamide antibacterial agents versus with standard background medical therapy without antibacterial agents, 344

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xxii TABLES, FIGURES, AND BOXES A18-5 Determination of noninferiority margins, 348 A21-1 Antibiotic discovery and resistance, 402 A21-2 The antibiotic resistome, 404 A21-3 Combinatorial resistance, 405 BOXES WO-1 Danish Experience Following Growth-Promoter Ban, 27 WO-2 FDA Trials for Antimicrobial Drugs: Plugging the Pipeline?, 38 WO-3 Legislation to Address AMR: The STARR Act and PAMTA, 52 WO-4 A Gallery of Antibiotic-Resistant Pathogens, 58 A2-1 Staphylococcus aureus Genotyping, 90 A9-1 The Dutch Experience with Controlling MRSA, 217