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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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
Washington, D.C.
www.nap.edu
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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
THE NATIONAL ACADEMIES PRESS
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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.
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Additional copies of this report are available from the
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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 hospitals 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: Implications for global health and novel intervention strategies. Washington, DC: The National Academies Press.
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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
—Goethe
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
Advising the Nation. Improving Health.
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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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. 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 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. 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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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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 responsibility 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.
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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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
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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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 endorse conclusions and recommendations. The responsibility for the content of the workshop summary rests with the authors and the institution.
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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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, evidence, 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, United Kingdom
Mary E. Wilson, Harvard School of Public Health
Although the reviewers listed above have provided many constructive comments 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.
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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 planning 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;
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Kate Skoczdopole, senior program associate; Katherine McClure, senior program associate; Collin Weinberger, research associate; and Robert Gasior, senior program 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 activity. 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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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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,
Arturo Casadevall
75
A2 Waves of Resistance: Staphylococcus aureus in the Antibiotic Era,
Henry F. Chambers and Frank R. DeLeo
83
A3 Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis,
Michael A. Kohanski, Mark A. DePristo, and James J. Collins
116
A4 Antibiotic-Induced Resistance Flow,
Patrice Courvalin
141
A5 Actinobacteria: The Good, The Bad, and The Ugly,
Vivan Miao and Julian Davies
149
A6 Antibiotics for Emerging Pathogens,
Michael A. Fischbach and Christopher T. Walsh
160
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A7 Averting a Potential Post-Antibiotic Era,
Shelley Hearne
174
A8 Antibiotic Effectiveness: New Challenges in Natural Resource Management,
Markus Herrmann and Ramanan Laxminarayan
190
A9 The Role of Health Care Facilities,
Ramanan Laxminarayan
206
A10 Responding to the Global Antibiotic Resistance Crisis: The APUA Chapter Network,
Stuart B. Levy
222
A11 Challenges and Opportunities in Antibiotic Discovery,
Kim Lewis
233
A12 Population Mobility, Globalization, and Antimicrobial Resistance,
Douglas W. MacPherson and Brian D. Gushulak
257
A13 Population Mobility, Globalization, and Antimicrobial Drug Resistance,
Douglas W. MacPherson, Brain D. Gushulak, William B. Baine, Shukal Bala, Paul O. Gubbins, Paul Holtom, and Marisel Segarra-Newnham
276
A14 The Bacterial Challenge: A Time to React, Executive Summary,
European Centre for Disease Prevention and Control and European Medicines Agency Joint Working Group—Dominique L. Monnet
287
A15 The Effects of Antibiotic and Pesticide Resistance on Public Health,
David Pimentel
294
A16 Clinical Issues and Outcomes Associated with Rising Antimicrobial Resistance,
Louis B. Rice
301
A17 World Health Organization Activities for Control of Antimicrobial Resistance Due to Use of Antimicrobials in Animals Intended for Food,
Jørgen Schlundt and Awa Aidara-Kane
308
A18 The Antibacterial Pipeline: Why Is It Drying Up, and What Must Be Done About It?,
Brad Spellberg
326
A19 Challenges in Antimicrobial Susceptibility Testing of Clinical and Environmental Isolates,
Fred C. Tenover
365
A20 Measuring the Cost of Antimicrobial-Resistant Infections:
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The Feasibility and Accuracy of Economic Analysis Using Electronic Medical Record Databases,
Rebecca R. Roberts, Linda M. Kampe, Ibrar Ahmad, Bala Hota, Edward K. Mensah, and Robert A. Weinstein
379
A21 The Antibiotic Resistome,
Gerard D. Wright
401
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
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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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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,
WO-4-2
Vancomycin-resistant Staphlyococcus aureus,
59
WO-4-3
Multidrug-resistant tuberculosis,
60
WO-4-4
Vancomycin-resistant enterococci,
60
WO-4-5
Detection of extended-spectrum β-lactamase production by the 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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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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Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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
OCR for page R22
Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies - Workshop Summary
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
