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WHO/CDS/CSR/DRS/2001.10 ORIGINAL: ENGLISH DISTRIBUTION: GENERAL A N T I B I O T I C R E S I S T A N Antibiotic resistance: C E : S Y synthesis of N T H E recommendations by S I S O F expert policy groups R E C O M Alliance for the Prudent M E N Use of Antibiotics D A T I O N S B Y E X P E R T P O L I C Y G R O U P S Copies can be obtained from the CDS Information Resource Centre World Health Organization World Health Organization, 1211 Geneva 27, Switzerland fax: +41 22 791 42 85 • email: [email protected] WHO/CDS/CSR/DRS/2001.10 ORIGINAL: ENGLISH DISTRIBUTION: GENERAL Antibiotic resistance: synthesis of recommendations by expert policy groups Alliance for the Prudent Use of Antibiotics JL Avorn, JF Barrett, PG Davey, SA McEwen, TF O’Brien and SB Levy Boston, MA, United States of America World Health Organization OR F MENT TEGY U A C R F O T O A BACTKHGE ROWFUHONO RD GCLDOOANBNTATAILI MSNIECMSIRESONTTB AINALCE R Acknowledgements The World Health Organization (WHO) and the Alliance for the Prudent use of Antibiotics (APUA) acknowledge the United States Agency for International Development (USAID) for their concern about the issue of antibiotic resistance and their support in producing this report. Stuart B. Levy, President of APUA, ensured that the report was accurate and comprehensive and that it would benefit both Ministers of Health and health care workers at the local level who can make a differ- ence. Kathleen Young, the Executive Director of APUA, recognized the contribution that APUA could make to support WHO’s Global Strategy through this project. She designed the initial format and assured the quality of the report. Barbara Souder, the Project Director, coordinated all aspects of this report and Margaret Kruse, a scientist and writer, acted as chief technical writer and production engineer. APUA gratefully acknowledges the assistance of its support staff: Sarann Bielavitz, for summarizing the reports by the expert policy groups; Brian Price for the graphics; Jennifer Mills-Knutsen for administrative coordination; and Ellen Wells for bibliographic and editorial assistance. Julia J. Chuang, from Scientific Information Resources, Bristol-Myers Squibb, United States, is gratefully acknowledged for her research work on Chapter IV. © World Health Organization 2001 This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organiza- tion. The document may, however, be freely reviewed, abstracted, reproduced and translated, in part or in whole, but not for sale or for use in conjunction with commercial purposes. The views expressed in documents by named authors are solely the responsibility of those authors. The designations employed and the presentation of the material in this document, including tables and maps, do not imply the expression of any opinion whatsoever on the part of the secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. Designed by minimum graphics Printed in Switzerland WHO/CDS/CSR/DRS/2001.4 DRUG RESISTANC IN MALARIA Contents List of acronyms v Executive Summary 1 Introduction Stuart B. Levy 11 Chapter I Improve and expand surveillance Thomas F. O’Brien 15 Chapter II Increase awareness: optimize patient and provider behaviour Jerry L. Avorn 33 Chapter III Strengthen sanitation, infection control, and regulatory measures Peter G. Davey 39 Chapter IV Encourage research and product development John F. Barrett 53 Chapter V Improve antibiotic use in animals Scott A. McEwen 65 Conclusion Stuart B. Levy 81 References 83 Some useful web sites 87 Appendix A Summaries of reports by expert policy groups (1987–2000) 89 Appendix B Local action around the world 125 Appendix C About the authors 153 iii WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS List of acronyms AHRQ Agency for Healthcare Research DTC Drug and Therapeutic Committee, and Quality, United States Viet Nam AIDS Acquired Immune Deficiency DVA Department of Veterans’ Affairs, Syndrome United States AIEPI Integrated Management of Child- EARS European Antimicrobial Resistance hood Diseases, Pan American Surveillance Health Organization EMEA European Medicines Evaluation APO Audit Project Odense Agency AR antimicrobial/antibiotic resistance ENT ear, nose, and throat ARM antimicrobial resistance manage- EPA Environmental Protection Agency, ment/manager/monitor United States ASM American Society for Microbiology ESBIC European Society for Biomodu- BBSRC Biotechnology and Biological lation and Chemotherapy Sciences Research Council, United ESCMID The European Society for Clinical Kingdom Microbiology and Infectious BSAC British Society for Antimicrobial Diseases Chemotherapy EU European Union CA-SFM Comite de l’Antibiogramme de la FDA Food and Drug Administration, Société Française de Microbiologie, United States France FESCI Federation of the European CDC Centers for Disease Control and Societies for Chemotherapy Prevention, United States GAARD Global Advisory on Antibiotic CEM/NET Centro de Epidemiologia Molecu- Resistance Data lar, Portugal/Network for Epide- GAO General Accounting Office, miological Tracking of Antibiotic United States Resistant Pathogens, United States GPs General Practitioners CISET Committee on International HACCP Hazard Analysis, Critical Control Science Engineering and Technol- Point, United Kingdom ogy, United States HCFA Health Care Financing Adminis- CMO Chief Medical Officer tration, United States CNS central nervous system HELICS Hospitals in Europe Link for CPD continuing professional develop- Infection Control through Surveil- ment, United Kingdom lance DANMAP Danish Integrated Antimicrobial HGOH Hospital Gynecology-Obstetric Resistance Monitoring and Hanoi, Viet Nam Research Program HIV Human Immunodeficiency Virus DDA Department of Drug Administra- HMG His/Her Majesty’s Government tion, Nepal HMO Health Maintenance Organization, DDD defined daily dose United States DHHS Department of Health and Human HRSA Health Resources and Services Services, United States Administration, Department of DoD Department of Defense, United Health and Human Services, States United States v ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10 ICARE Intensive Care Antimicrobial NNISS National Nosocomial Infections Epidemiology, Centers for Disease Surveillance System Control and Prevention, United OIE Office International des Epizooties States OTA Office of Technology Assessment, ICU intensive care unit United States Congress ID infectious disease OTC over the counter IDSA Infectious Diseases Society of PAHO Pan American Health Organiza- America tion IMF International Monetary Fund PCR polymerase chain reaction IND investigational new drug PHCP/GTZ Primary Health Care Project/ IOM Institute of Medicine, United Deutsche Gessellschaft für States Technische Zusammenarbeit ISC International Society of Chemo- PHLS Public Health Laboratory Service, therapy England and Wales KOL key-opinion-leader PHON Pharmaceutical Horizon of Nepal MDRTB multidrug-resistant tuberculosis PRP penicillin-resistant pneumonia MIC minimal inhibitory concentration, PRSP penicillin-resistant Streptococcus testing method pneumoniae MRC Medical Research Council, QC quality control England RCCDC Regional Center of Communicable MRSA methicillin-resistant Staphylococcus Disease Control, Malmo, Sweden aureus R&D research and development MSH Management Sciences for Health, RTI respiratory tract infection Boston, United States SIGN Scottish Intercollegiate Guideline NAO National Audit Office, United Network Kingdom SMA Scottish Microbiology Association NARMS National Antimicrobial Resistance SMAC Standing Medical Advisory Monitoring System, United States Committee, United Kingdom NATAC National Antibiotic Therapeutic SRH Smolensk Regional Hospital, Advisory Committee, Nepal Russia NCCLS National Committee for Clinical STD sexually transmitted disease and Laboratory Standards, Europe STRAMA Swedish Strategic Program for the NEPI Network for Rational Use of Antimicrobial Pharmacoepidemiology, Sweden Agents and Surveillance of NHS National Health Service, United Resistance Kingdom TB tuberculosis NIAID National Institute of Allergy and TIGR The Institute for Genomic Infectious Diseases, United States Research, Maryland, United States NIBSC National Institute for Biological TSN The Surveillance Network, Standards and Control, United California and Virginia, United Kingdom States NICE National Institute for Clinical USAID United States Agency for Interna- Excellence, Great Britain tional Development NICE Nosocomial Infection Control in USDA Department of Agriculture, United Europe States NIH National Institutes of Health, UTI urinary tract infection United States VRE vancomycin-resistant enterococci NINSS Nosocomial Infection National WB World Bank Surveillance Scheme WHO World Health Organization NISS Nosocomial Infection Surveillance WMA Welsh Microbiological Association System WP Working Party NME new molecular entity WTO World Trade Organization NSG National Steering Group vi WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS Executive Summary In the not too distant past, antibiotics could be APUA also collected information from their in- counted on to treat a bacterial infection. Those days ternational chapters about experiences at the local are almost gone, as bacteria have emerged that are level; these reports, reflecting the views of APUA resistant to each of the antibiotics currently on the Chapters and not necessarily reflecting national market. Deaths have occurred as a result of untreat- policy, are included in Appendix B. able bacterial infections. This trend is expected to After review, analysis and update, and with ad- continue unless the problem of antibiotic resist- ditional insights from the authors of the individual ance can be curbed. In response to this threat, the chapters of this review, the key recommendations World Health Organization (WHO) has worked emanating from the 25 expert reports are summa- with many partners, including the Alliance for the rized below under the following headings: Prudent Use of Antibiotics (APUA), to develop the • Increase awareness of the antibiotic resistance WHO Global Strategy for Containment of Anti- problem microbial Resistance (26). As part of the development process of the WHO • Improve surveillance of antibiotic resistance Global Strategy, WHO commissioned a series of • Improve antibiotic use in people technical reviews. APUA responded to WHO’s • Regulate antibiotic use in animals request to review reports on antibiotic resistance prepared by prestigious scientific and governmen- • Encourage new product development tal organizations over the last two decades. The pur- • Increase resources to curb antibiotic resist- pose of this review is to identify areas of consensus ance in the developing world in the experts’ recommendations in the selected reports, update the findings, consider the barriers • Increase funding for surveillance, research and to concerted action and suggest ways to move from education. recommendations to action. Under each heading recommendations have Twenty-five expert reports (1–25—see Table 1, been organized on the basis of the suggested level Table 3 and Appendix A) compiled by scientific of decision-making necessary for implementation and medical authorities were selected for this re- of the intervention i.e., “who can do what”. view by APUA because they are highly referenced A more detailed analysis of these recommenda- in the literature and reflect extensive deliberations tions is provided by the author of each chapter. by a wide variety of key expert policy groups. In developing this synthesis, APUA consulted five Increase awareness of the antibiotic medical and scientific experts on antibiotic resist- resistance problem ance who reviewed relevant sections of the reports. Their reviews are presented in Chapters I–V and For real reforms in the use of antibiotics to occur, cover the major areas of intervention, i.e., surveil- individuals in the general public and in public lance, education of patient and provider behaviour, health and provider groups at the international, prevention (including sanitary and infection con- national, and local levels must take ownership of trol), research and product development, and anti- the problem and provide leadership to reverse this biotic use in animals. Each author focused on those public health crisis. reports with extensive subject matter related to their area of investigation. In addition to summarizing International organizations findings from the expert policy reports, updated information, references and authors’ insights were • Obtain worldwide commitments to establish added. prudent antibiotic use policies. 1 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10 National and municipal organizations Health care workers • Publicize the outcomes of programmes from other • Educate the general public: countries: Communicate global trends in antibi- — Physicians: Discuss proper antibiotic use otic resistance with potential local impact, such with all patients. as the results of the European Union’s legisla- — Veterinarians: Discuss ways to minimize an- tion against use of antibiotics in growth promo- tibiotic use with animal owners, such as im- tion. Collect and publicize the economic proved farm hygiene and alternatives to consequences, or lack thereof, of Denmark and antibiotics as growth promoters. Sweden’s complete ban on growth promoters. • Educate the general public: The United Kingdom’s Improve surveillance of antibiotic campaign to “cherish and conserve your natural resistance flora” pointed out the beneficial aspects of bac- The urgent recommendation for surveillance of teria which can be obliterated by excessive anti- antimicrobial resistance and plans for performing biotic use. A campaign about proper antibiotic surveillance have been elaborated upon over the past use should be aimed at young children, the two decades. Over that same period a succession of parents of young children, workers in day care unexpected, new and life-threatening resistance centres, schoolteachers, those who work in agri- problems have emerged and spread throughout the culture, and policy-makers in all areas. world. These global outbreaks have had little • Promote communication: Facilitate communication monitoring to support their ultimately failed con- among academic institutions, government agen- tainment. Only inadequate and fragmentary cies, those who pay for health care, and pharma- surveillance systems exist today. ceutical manufacturers to reduce the extent to which such groups act at cross purposes in rela- National and municipal organizations tion to antibiotic use and infection control. Provide materials to support intervention pro- • Coordinate local surveillance networks: Public health grammes and utilize communication tools such departments can take the initiative to contact as the media and the Internet. medical centres and develop a surveillance net- work. If an existing privately-initiated network • Evaluate the curricula of universities: Undergraduate, exists, the public health department should sup- postgraduate and continuing education pro- port and help that network to grow. grammes at veterinary, medical, pharmacy, and nursing schools should be evaluated to ensure • Recruit leaders for surveillance networks: The public that prudent antimicrobial use and resistance are health department cannot pay for all the par- given high priority. Courses should make ticipants that a surveillance network requires. It students more aware of how to evaluate promo- has to find leaders within the network and use tional materials and what questions to ask dur- their help to motivate all the participants to work ing a sales presentation. together on the surveillance network. • Support a reference laboratory: The public health Health care institutions department should support a reference labora- tory, hitherto lacking in many surveillance net- • Use effective teaching methods for educating pre- works. The network initiator’s laboratory may scribers: become the reference laboratory. With proper sup- — Use group problem-solving sessions, role port, the reference laboratory can appreciably im- playing, lectures. prove the performance of the network’s laboratories — Focus on clinical issues one at a time. and connect, integrate, and interpret their data. — Use an educational outreach worker for train- • Share results of surveillance with international organi- ing at the office. zations. — Use opinion leaders or district-level staff as trainers. • Monitor resistance in food animals: Undertake regu- —Repeat sessions to reinforce message. lar monitoring for resistant bacterial pathogens — Apply community-based case management and commensals in food-producing animal interventions. populations and animal-based food products. 2 WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS • Monitor sentinel human populations: Evaluate the ers and detractors; how to reach goals, and usefulness of monitoring sentinel human ways to build on existing audit systems. populations (e.g. farm and abattoir workers) and • Update guidelines based on surveillance data: Regu- people in the community for infection and/or larly update guidelines for antimicrobial use colonization with resistant bacteria. based on resistance surveillance data. • Eliminate financial incentives that promote the misuse Health care institutions of antibiotics: In countries where governments • Develop local surveillance networks: Medical centres subsidize the purchase of antimicrobial drugs, can support data gathering within their centre legislative or regulatory changes in these subsi- and join or start a local surveillance network. dies could lead to a decline in the use of the drugs. Governments could investigate the effect • Maintain a laboratory with adequate quality assurance of changes in reimbursement on the prudent use and trained technicians. of antibiotics and on surveillance of prescribing or resistance; for example, the United States Health care workers Congress Office of Technology Assessment • Initiate a local surveillance network: A microbiologist (OTA) identified a potential problem with Med- or infectious disease specialist can initiate an icaid and Medicare reimbursement policies. antimicrobial resistance surveillance network; • Monitor advertising: Develop and enforce ethical most of the networks started in various coun- standards concerning advertising of antibiotics tries began in this way. The leadership and in- to the general public to counteract the strong terest of these individuals and their colleagues commercial pressures from manufacturers to in- can keep these networks functioning. crease utilization of antibiotics and antibacterials. • Consider the impact of new drugs on resistance during Pharmaceutical companies the drug approval process: Consideration of resist- • Undertake post-marketing surveillance to detect emer- ance issues should be required prior to drug gence of resistance to new antibiotics. approval for human, animal, or plant use. • Support surveillance networks: Support the work of • Limit general access to new drugs. a local surveillance centre through funding and/ • Establish post-marketing surveillance accords with or surveillance projects. producers to ensure early detection of emerging resistance to new drugs. Improve antibiotic use in people National and municipal organizations Health care institutions • Enforce the prudent use of antibiotics: For example, • Establish an Infection Control Committee for surveil- the United States federal government could lance of infection; identification of outbreaks; adopt a strategy making the implementation of implementation of effective control measures state policies to curb the misuse of antimicro- (e.g., hand washing); sterilization and disinfec- bial drugs mandatory before states could receive tion of equipment and supplies. federal funds earmarked for public health. • Establish a Drugs and Therapeutics Committee to evalu- • Create national and regional guidelines: National ate antibiotic use data, resistance patterns, standards and guidelines should be created for efficacy and cost; make recommendations for community infection control management with proper antibiotic use that are appropriate to a the following features: particular clinical setting and population. — A requirement that every district health • Establish guidelines for appropriate antibiotic use: For authority should have at least one commu- maximum benefit, such guidelines should be: nity infection control nurse. — The ability to be adapted at the local level. — Based on evidence. — An implementation protocol that includes — Relevant and appropriate to the clinical and who is being targeted; how to stage the im- microbiological issues of a given population. plementation; how to manage the support- — Developed with the involvement of the prac- 3

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World Health Organization 2001 the issue of antibiotic resistance and their support in producing this report. Stuart B. Levy, President of .. Antibiotics are used not only to combat bacterial . predictably poor selling, but medically.
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