Copies can be obtained from the CDS Information Resource Centre

World Health Organization, 1211 Geneva 27, Switzerland

fax: +41 22 791 42 85 • email: cdsdoc@who.int
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 A BACKGROUND DOCUMENT FOR

THE WHO GLOBAL STRATEGY

FOR CONTAINMENT OF

ANTIMICROBIAL

RESISTANCE
© World Health Organization 2001

This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organization. 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

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 difference.

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.
Contents

iii

WHO/CDS/CSR/DRS/2001.4 DRUG RESISTANC IN MALARIA

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

List of acronyms

AHRQ Agency for Healthcare Research

and Quality, United States

AIDS Acquired Immune Deficiency

Syndrome

AIEPI Integrated Management of Childhood Diseases, Pan American

Health Organization

APO Audit Project Odense

AR antimicrobial/antibiotic resistance

ARM antimicrobial resistance management/manager/monitor

ASM American Society for Microbiology

BBSRC Biotechnology and Biological

Sciences Research Council, United

Kingdom

BSAC British Society for Antimicrobial

Chemotherapy

CA-SFM Comite de l’Antibiogramme de la

Société Française de Microbiologie,

France

CDC Centers for Disease Control and

Prevention, United States

CEM/NET Centro de Epidemiologia Molecular, Portugal/Network for Epidemiological Tracking of Antibiotic

Resistant Pathogens, United States

CISET Committee on International

Science Engineering and Technology, United States

CMO Chief Medical Officer

CNS central nervous system

CPD continuing professional development, United Kingdom

DANMAP Danish Integrated Antimicrobial

Resistance Monitoring and

Research Program

DDA Department of Drug Administration, Nepal

DDD defined daily dose

DHHS Department of Health and Human

Services, United States

DoD Department of Defense, United

States

DTC Drug and Therapeutic Committee,

Viet Nam

DVA Department of Veterans’ Affairs,

United States

EARS European Antimicrobial Resistance

Surveillance

EMEA European Medicines Evaluation

Agency

ENT ear, nose, and throat

EPA Environmental Protection Agency,

United States

ESBIC European Society for Biomodulation and Chemotherapy

ESCMID The European Society for Clinical

Microbiology and Infectious

Diseases

EU European Union

FDA Food and Drug Administration,

United States

FESCI Federation of the European

Societies for Chemotherapy

GAARD Global Advisory on Antibiotic

Resistance Data

GAO General Accounting Office,

United States

GPs General Practitioners

HACCP Hazard Analysis, Critical Control

Point, United Kingdom

HCFA Health Care Financing Administration, United States

HELICS Hospitals in Europe Link for

Infection Control through Surveillance

HGOH Hospital Gynecology-Obstetric

Hanoi, Viet Nam

HIV Human Immunodeficiency Virus

HMG His/Her Majesty’s Government

HMO Health Maintenance Organization,

United States

HRSA Health Resources and Services

Administration, Department of

Health and Human Services,

United States

v

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

vi

ICARE Intensive Care Antimicrobial

Epidemiology, Centers for Disease

Control and Prevention, United

States

ICU intensive care unit

ID infectious disease

IDSA Infectious Diseases Society of

America

IMF International Monetary Fund

IND investigational new drug

IOM Institute of Medicine, United

States

ISC International Society of Chemotherapy

KOL key-opinion-leader

MDRTB multidrug-resistant tuberculosis

MIC minimal inhibitory concentration,

testing method

MRC Medical Research Council,

England

MRSA methicillin-resistant Staphylococcus

aureus

MSH Management Sciences for Health,

Boston, United States

NAO National Audit Office, United

Kingdom

NARMS National Antimicrobial Resistance

Monitoring System, United States

NATAC National Antibiotic Therapeutic

Advisory Committee, Nepal

NCCLS National Committee for Clinical

and Laboratory Standards, Europe

NEPI Network for

Pharmacoepidemiology, Sweden

NHS National Health Service, United

Kingdom

NIAID National Institute of Allergy and

Infectious Diseases, United States

NIBSC National Institute for Biological

Standards and Control, United

Kingdom

NICE National Institute for Clinical

Excellence, Great Britain

NICE Nosocomial Infection Control in

Europe

NIH National Institutes of Health,

United States

NINSS Nosocomial Infection National

Surveillance Scheme

NISS Nosocomial Infection Surveillance

System

NME new molecular entity

NSG National Steering Group

NNISS National Nosocomial Infections

Surveillance System

OIE Office International des Epizooties

OTA Office of Technology Assessment,

United States Congress

OTC over the counter

PAHO Pan American Health Organization

PCR polymerase chain reaction

PHCP/GTZ Primary Health Care Project/

Deutsche Gessellschaft für

Technische Zusammenarbeit

PHLS Public Health Laboratory Service,

England and Wales

PHON Pharmaceutical Horizon of Nepal

PRP penicillin-resistant pneumonia

PRSP penicillin-resistant Streptococcus

pneumoniae

QC quality control

RCCDC Regional Center of Communicable

Disease Control, Malmo, Sweden

R&D research and development

RTI respiratory tract infection

SIGN Scottish Intercollegiate Guideline

Network

SMA Scottish Microbiology Association

SMAC Standing Medical Advisory

Committee, United Kingdom

SRH Smolensk Regional Hospital,

Russia

STD sexually transmitted disease

STRAMA Swedish Strategic Program for the

Rational Use of Antimicrobial

Agents and Surveillance of

Resistance

TB tuberculosis

TIGR The Institute for Genomic

Research, Maryland, United States

TSN The Surveillance Network,

California and Virginia, United

States

USAID United States Agency for International Development

USDA Department of Agriculture, United

States

UTI urinary tract infection

VRE vancomycin-resistant enterococci

WB World Bank

WHO World Health Organization

WMA Welsh Microbiological Association

WP Working Party

WTO World Trade Organization
1

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Executive Summary

APUA also collected information from their international chapters about experiences at the local

level; these reports, reflecting the views of APUA

Chapters and not necessarily reflecting national

policy, are included in Appendix B.

After review, analysis and update, and with additional insights from the authors of the individual

chapters of this review, the key recommendations

emanating from the 25 expert reports are summarized below under the following headings:

• Increase awareness of the antibiotic resistance

problem

• Improve surveillance of antibiotic resistance

• Improve antibiotic use in people

• Regulate antibiotic use in animals

• Encourage new product development

• Increase resources to curb antibiotic resistance in the developing world

• Increase funding for surveillance, research and

education.

Under each heading recommendations have

been organized on the basis of the suggested level

of decision-making necessary for implementation

of the intervention i.e., “who can do what”.

A more detailed analysis of these recommendations is provided by the author of each chapter.

Increase awareness of the antibiotic

resistance problem

For real reforms in the use of antibiotics to occur,

individuals in the general public and in public

health and provider groups at the international,

national, and local levels must take ownership of

the problem and provide leadership to reverse this

public health crisis.

International organizations

• Obtain worldwide commitments to establish

prudent antibiotic use policies.

In the not too distant past, antibiotics could be

counted on to treat a bacterial infection. Those days

are almost gone, as bacteria have emerged that are

resistant to each of the antibiotics currently on the

market. Deaths have occurred as a result of untreatable bacterial infections. This trend is expected to

continue unless the problem of antibiotic resistance can be curbed. In response to this threat, the

World Health Organization (WHO) has worked

with many partners, including the Alliance for the

Prudent Use of Antibiotics (APUA), to develop the

WHO Global Strategy for Containment of Antimicrobial Resistance (26).

As part of the development process of the WHO

Global Strategy, WHO commissioned a series of

technical reviews. APUA responded to WHO’s

request to review reports on antibiotic resistance

prepared by prestigious scientific and governmental organizations over the last two decades. The purpose of this review is to identify areas of consensus

in the experts’ recommendations in the selected

reports, update the findings, consider the barriers

to concerted action and suggest ways to move from

recommendations to action.

Twenty-five expert reports (1–25—see Table 1,

Table 3 and Appendix A) compiled by scientific

and medical authorities were selected for this review by APUA because they are highly referenced

in the literature and reflect extensive deliberations

by a wide variety of key expert policy groups. In

developing this synthesis, APUA consulted five

medical and scientific experts on antibiotic resistance who reviewed relevant sections of the reports.

Their reviews are presented in Chapters I–V and

cover the major areas of intervention, i.e., surveillance, education of patient and provider behaviour,

prevention (including sanitary and infection control), research and product development, and antibiotic use in animals. Each author focused on those

reports with extensive subject matter related to their

area of investigation. In addition to summarizing

findings from the expert policy reports, updated

information, references and authors’ insights were

added.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

2

National and municipal organizations

• Publicize the outcomes of programmes from other

countries: Communicate global trends in antibiotic resistance with potential local impact, such

as the results of the European Union’s legislation against use of antibiotics in growth promotion. Collect and publicize the economic

consequences, or lack thereof, of Denmark and

Sweden’s complete ban on growth promoters.

• Educate the general public: The United Kingdom’s

campaign to “cherish and conserve your natural

flora” pointed out the beneficial aspects of bacteria which can be obliterated by excessive antibiotic use. A campaign about proper antibiotic

use should be aimed at young children, the

parents of young children, workers in day care

centres, schoolteachers, those who work in agriculture, and policy-makers in all areas.

• Promote communication: Facilitate communication

among academic institutions, government agencies, those who pay for health care, and pharmaceutical manufacturers to reduce the extent to

which such groups act at cross purposes in relation to antibiotic use and infection control.

Provide materials to support intervention programmes and utilize communication tools such

as the media and the Internet.

• Evaluate the curricula of universities: Undergraduate,

postgraduate and continuing education programmes at veterinary, medical, pharmacy, and

nursing schools should be evaluated to ensure

that prudent antimicrobial use and resistance are

given high priority. Courses should make

students more aware of how to evaluate promotional materials and what questions to ask during a sales presentation.

Health care institutions

• Use effective teaching methods for educating prescribers:

— Use group problem-solving sessions, role

playing, lectures.

— Focus on clinical issues one at a time.

— Use an educational outreach worker for training at the office.

— Use opinion leaders or district-level staff as

trainers.

 — Repeat sessions to reinforce message.

— Apply community-based case management

interventions.

Health care workers

• Educate the general public:

— Physicians: Discuss proper antibiotic use

with all patients.

— Veterinarians: Discuss ways to minimize antibiotic use with animal owners, such as improved farm hygiene and alternatives to

antibiotics as growth promoters.

Improve surveillance of antibiotic

resistance

The urgent recommendation for surveillance of

antimicrobial resistance and plans for performing

surveillance have been elaborated upon over the past

two decades. Over that same period a succession of

unexpected, new and life-threatening resistance

problems have emerged and spread throughout the

world. These global outbreaks have had little

monitoring to support their ultimately failed containment. Only inadequate and fragmentary

surveillance systems exist today.

National and municipal organizations

• Coordinate local surveillance networks: Public health

departments can take the initiative to contact

medical centres and develop a surveillance network. If an existing privately-initiated network

exists, the public health department should support and help that network to grow.

• Recruit leaders for surveillance networks: The public

health department cannot pay for all the participants that a surveillance network requires. It

has to find leaders within the network and use

their help to motivate all the participants to work

together on the surveillance network.

• Support a reference laboratory: The public health

department should support a reference laboratory, hitherto lacking in many surveillance networks. The network initiator’s laboratory may

become the reference laboratory. With proper support, the reference laboratory can appreciably improve the performance of the network’s laboratories

and connect, integrate, and interpret their data.

• Share results of surveillance with international organizations.

• Monitor resistance in food animals: Undertake regular monitoring for resistant bacterial pathogens

and commensals in food-producing animal

populations and animal-based food products.
3

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• Monitor sentinel human populations: Evaluate the

usefulness of monitoring sentinel human

populations (e.g. farm and abattoir workers) and

people in the community for infection and/or

colonization with resistant bacteria.

Health care institutions

• Develop local surveillance networks: Medical centres

can support data gathering within their centre

and join or start a local surveillance network.

• Maintain a laboratory with adequate quality assurance

and trained technicians.

Health care workers

• Initiate a local surveillance network: A microbiologist

or infectious disease specialist can initiate an

antimicrobial resistance surveillance network;

most of the networks started in various countries began in this way. The leadership and interest of these individuals and their colleagues

can keep these networks functioning.

Pharmaceutical companies

• Undertake post-marketing surveillance to detect emergence of resistance to new antibiotics.

• Support surveillance networks: Support the work of

a local surveillance centre through funding and/

or surveillance projects.

Improve antibiotic use in people

National and municipal organizations

• Enforce the prudent use of antibiotics: For example,

the United States federal government could

adopt a strategy making the implementation of

state policies to curb the misuse of antimicrobial drugs mandatory before states could receive

federal funds earmarked for public health.

• Create national and regional guidelines: National

standards and guidelines should be created for

community infection control management with

the following features:

— A requirement that every district health

authority should have at least one community infection control nurse.

— The ability to be adapted at the local level.

— An implementation protocol that includes

who is being targeted; how to stage the implementation; how to manage the supporters and detractors; how to reach goals, and

ways to build on existing audit systems.

• Update guidelines based on surveillance data: Regularly update guidelines for antimicrobial use

based on resistance surveillance data.

• Eliminate financial incentives that promote the misuse

of antibiotics: In countries where governments

subsidize the purchase of antimicrobial drugs,

legislative or regulatory changes in these subsidies could lead to a decline in the use of the

drugs. Governments could investigate the effect

of changes in reimbursement on the prudent use

of antibiotics and on surveillance of prescribing

or resistance; for example, the United States

Congress Office of Technology Assessment

(OTA) identified a potential problem with Medicaid and Medicare reimbursement policies.

• Monitor advertising: Develop and enforce ethical

standards concerning advertising of antibiotics

to the general public to counteract the strong

commercial pressures from manufacturers to increase utilization of antibiotics and antibacterials.

• Consider the impact of new drugs on resistance during

the drug approval process: Consideration of resistance issues should be required prior to drug

approval for human, animal, or plant use.

• Limit general access to new drugs.

• Establish post-marketing surveillance accords with

producers to ensure early detection of emerging

resistance to new drugs.

Health care institutions

• Establish an Infection Control Committee for surveillance of infection; identification of outbreaks;

implementation of effective control measures

(e.g., hand washing); sterilization and disinfection of equipment and supplies.

• Establish a Drugs and Therapeutics Committee to evaluate antibiotic use data, resistance patterns,

efficacy and cost; make recommendations for

proper antibiotic use that are appropriate to a

particular clinical setting and population.

• Establish guidelines for appropriate antibiotic use: For

maximum benefit, such guidelines should be:

— Based on evidence.

— Relevant and appropriate to the clinical and

microbiological issues of a given population.

— Developed with the involvement of the prac-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

4

titioners (and potentially the patients) who

will be using them.

— Disseminated not simply via printed memoranda, but rather through the use of interactive strategies oriented to change

behaviour.

• Appoint an antimicrobial resistance monitor to:

— Serve as a local resource to follow the current literature on antibiotic resistance.

— Analyse local data.

— Propose and implement strategies for control and resistance.

— Work with clinicians on the care of specific

patients.

• Reduce the spread of infection: Adopt Centers for

Disease Control and Prevention (CDC) recommendations for isolation of patients colonized

with resistant bacteria.

• Create pharmacy reports: Hospitals should produce

regular reports about pharmacy supplies to wards

or clinics in the format of defined daily dose

(DDD) per 1000 beds. Review the pharmacy

reports periodically with the laboratory results

to detect problems of resistance early.

• Establish and disseminate essential drugs lists: Based

on those such as the World Health Organization Model List of Essential Drugs, to help

simplify antibiotic choices for practitioners as

well as make them more clinically appropriate

and cost-effective.

• Educate employees: Promote education about the

antibiotic resistance problem through:

— Providing ongoing supervision and monitoring of practice.

— Instituting regular audit and feedback of

prescribing patterns.

— Teaching through the development of group

processes.

— Developing standardized treatment guidelines.

— Using problem-oriented training.

— Providing targeted in-service training of

health workers.

• Maintain a laboratory: with adequate quality assurance and trained technicians. Use sterile supplies and sterile procedures: Gloves and gowns

are important pieces of protective equipment.

Health care workers

• Prescribe antibiotics prudently through:

— Avoiding antibiotics for simple coughs and

colds.

— Avoiding using antibiotics for the treatment

of viral sore throat.

— Limiting antibiotic use in uncomplicated

cystitis in healthy women to three days.

— Limiting telephone prescription of antibiotics to exceptional cases only.

— Avoiding using broad-spectrum antibiotics

when narrower-spectrum agents would work

as well.

— Basing the antibiotic prescription on microbiological culture results whenever possible.

— Modifying the regimen over time as required.

— Considering cost-effectiveness in choosing an

antibiotic regimen.

• Improve hygiene: Perform regular hand washing.

Failure to cleanse hands after each patient contact spreads infection.

Improve antibiotic use in animals

Antibiotics are used not only to combat bacterial

infections in animals but also as growth promoters

in animals raised for meat (referred to as food animals). In some countries, about 50% of total antimicrobial production by weight is used in animal

agriculture. As in people, the excessive antibiotic

use in animals provides intensive training in

survival-of-the-fittest to the resident bacteria. A

reservoir of antibiotic resistance is building in the

bacteria associated with animals which may be

transferred to the bacteria living in humans.

National and municipal organizations

• Increase awareness of the antibiotic resistance problem:

Make veterinarians and animal owners aware of

antibiotic resistance impact on humans, and of

the costs of resistance to themselves, their families and animals, and to the public. People need

good reasons to modify their behaviours and

these should be provided to them.

• Regulate antibiotic prescriptions for animals: Evaluate

the impact of making all systemic veterinary

antimicrobials available by prescription only. If

sufficient evidence exists that profits from sales

negatively impact on prescribing, take appropriate countermeasures. Address the reluctance or

inability to regulate prescribing practices of

veterinarians at the national level.
5

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• Restrict growth promoter use in animals: Stop using

antimicrobials of a similar class to those used

for treating humans as growth promoters in

animals.

• Regulate antibiotic use in animals: Establish a regulatory system to oversee the authorization, distribution, sale and the use of antimicrobials in

food-producing animals. Establish a system to

monitor the type and quantity of antimicrobials

given to food animals, similar to that for

humans.

• Set a risk standard for resistance: Identify the public

health risks from antibiotic resistance that are

acceptable to society. If acceptable levels for

microbial risks (or “risk standards”) can be agreed

upon internationally, quantitative risk assessment could be used to identify resistance thresholds, beyond which public health impacts

become unacceptable. If antibiotic resistance

increases above levels of concern, then incremental interventions up to withdrawal of the drug

from the market should be considered.

• Consider human and non-human uses simultaneously:

A single, multidisciplinary government committee should oversee the regulation of antimicrobials in both human and non-human

fields.

• Monitor advertising: Advertising and promotion of

animal health products should comply with

national guidelines and codes of practice.

Veterinarians

• Promote the prudent use of antibiotics in animals, in

accordance with similar strategies for humans.

Recommended dosages should be optimal for

therapy and minimize the development of

resistance. Prophylactic use should be regularly

assessed for effectiveness and need.

• Develop local guidelines for antibiotic use: Locally derived treatment guidelines should include a list

of antimicrobials for conditions commonly presented in various species, and offer a rational

treatment choice based on scientific data. These

guidelines should address the use of antibiotics

important to humans such as fluoroquinolones.

Food animal producers

• Improve farm hygiene: Develop and implement

standards of practice to ensure that antimicrobials are not used as a substitute for good farm

hygiene.

• Reduce use of antibiotics as growth promoters: Reduce

exposure of animals to low doses of antimicrobials for long periods of time (i.e., growth

promoters and prophylactics) if such uses select

for resistance to drugs used in human medicine.

• Improve animal husbandry: Encourage farming

practices that reduce the need for prophylactic

and therapeutic use of antibiotics. Alternative

ways to reduce infectious disease in animals, such

as improved vaccination programmes, enhanced

biosecurity measures, and reduced housing

density should be promoted when appropriate.

This could, however, increase the cost of food

production in some countries.

Researchers

• Risk-benefit analysis of growth promoter use: Evaluate the nature and magnitude of the impact of

antimicrobial growth promoters and use the information to assist in risk-benefit assessments

of each use.

• Environmental impact: Conduct pilot studies to

assess the extent of environmental contamination by antimicrobial residues and resistant

organisms that enter the soil or water from

human and animal waste.

• Food processing and distribution methods: Evaluate

the effect of current food processing and distribution methods on the emergence and spread

of resistant organisms.

Encourage new product development

As the current tools used against bacteria become

less effective, protecting the public from bacterial

infections requires new tools. Pharmaceutical companies and related industries must be encouraged

to pursue research and development of new preventative and curative measures (such as vaccines

and antibiotics) and new screening and surveillance

methods.

National and municipal organizations

• Provide incentives to industry:

— Create policies that give pharmaceutical

companies an extended patent life in exchange for increased restrictions on the sales

of antimicrobials.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

6

— Provide incentives to companies to invest in

research and development so as to remove

the need to re-coup their investment in a

predictably poor selling, but medically

needed agent.

— Streamline the regulatory process for drugs

and products that are critically needed or

which address infection solutions without

undermining resistance solutions.

— Provide a mechanism for a government or

not-for-profit organization to assume the

leadership (and risk) in developing an essential infectious disease therapy product

(vaccine or drug or diagnostic test) if pharmaceutical industries choose not to do so.This

would be analogous to the strategy of industry licensing-in from academia by establishing the option for the reverse process to occur

(license from the industrial concerns).

— Encourage pharmaceutical companies that

had developed antibiotics but never commercially exploited them to pursue more antimicrobial research and development if their

earlier antibiotics (now without patent protection) were given extra legal protection,

either under patent law or a legal regime like

the Orphan Drug Act.

— Introduce joint funding arrangement

schemes for research work between governmental agencies and industry.

• Protect intellectual property rights: International law

should provide intellectual property protection

rights and enforcement to encourage industry

to invest in antibiotic research, development, and

delivery in developing countries.

• Facilitate networking: Encourage partnerships between industry, academia, and government to

better exploit existing and new technologies to

combat antimicrobial resistance (drugs, vaccines,

diagnostics).

Pharmaceutical companies

• Increase research and development in several areas:

— Vaccine research and drug discovery.

— Pharmacokinetics, pharmacodynamics, and

dosage regimens in relationship to antimicrobial resistance emergence probability.

— Basic research into the identification and

function of novel genes to provide industry

with new, defined targets for therapeutic intervention.

— Screening methods.

— Surveillance tools, including computer programs for data management and reporting.

Increase resources to curb antibiotic

resistance in the developing world

Antibiotic-resistant bacteria are found in industrialized and developing countries alike and with international travel, can pass easily from country to

country.

International organizations

• Share results of surveillance internationally: International cooperation is needed to disseminate the

results of surveillance among all countries, so

that even those without the infrastructure can

use the results to conduct risk assessment, make

policy and manage risk.

• Secure technical and financial support for developing

countries: Investigate methods for mandating

technical or financial support from industrialized countries to developing countries.

• Invest in a worldwide vaccine strategy to reduce antibiotic use and combat antimicrobial resistance by

preventing infectious diseases in humans.

• Ensure the availability of vaccines and quality drugs:

— Initiate major worldwide programmes relating to formulation and delivery of vaccines.

— Strengthen national and international capacity to ensure the availability and quality of

anti-infective drugs.

• Facilitate communication among the countries of the

world:

— Introduce a global alert system requiring

national governments to inform worldwide

health authorities about outbreaks of resistant infections.

— Develop a global web site similar to the

Nosocomial Infection Control in Europe

web site at http://helics.univ-lyon1.fr.

• Safeguard privacy and human rights: International

human rights law must be taken into account

to set effective public health policies.

• Promote appropriate international laws: Consultations with experts in international law is important when devising a global strategy for curbing

antibiotic resistance.
7

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

National and municipal organizations

• Decrease risk of infectious disease by:

— Improving the quality of life and health with

widespread immunizations.

— Improving sanitation and water supply

systems.

— Emphasizing alternate methods of infection

control, such as bednets in areas at risk for

malaria.

• Ensure antibiotic availability: Availability of appropriate antibiotics for treatment of infections will

contain the spread of infection in general and

resistant strains in particular.

• Share resources with other countries: Industrialized

countries should help developing countries build

a quality infrastructure to address health needs

in the long term, including investment in

research and development.

— Provide support to invest in diseases in the

developing world.

— Assist in implementing preventive strategies

through improving social infrastructure and

improving sanitation and water supply systems in developing countries.

— Support developing countries in creating

reliable supply systems.

Increase funding for surveillance, research

and education

Increasing understanding of the bacterial response

to antibiotics and increasing operational research

into interventions to deal with the antibiotic resistance are two major recommendations to help

curb the antibiotic resistance problem.

National and municipal organizations

• Increase funding for a surveillance network: Public

health departments need funding to build a surveillance network.

• Increase funding for research: Basic and clinical

researchers need funding to identify new antibacterial targets and to better understand antibiotic resistance mechanisms.

• Increase funding for education: Health care providers and the general public need to be educated

about the antibiotic resistance problem.

TABLE 1. REPORTS BY EXPERT POLICY GROUPS (1987–2000)

Year Study nature, location,

(ref no.) Document title Organization and time Conclusions

1987 Reviews of Infectious National Institutes Six Task Forces, comprised of A global, standardized surveillance system is

(1) Diseases Antibiotic Use of Health (NIH), representatives from different recommended as the best way to track

and Antibiotic Resistance Fogarty Center disciplines and countries, studied emerging resistance patterns. Expanded

Worldwide Sponsored by (USA) various aspects of antibiotic studies of the mechanisms of multidrug

the Fogarty International resistance between 1983 and resistance are supported. The authors also

Center, NIH 1986. encourage the expansion of central

surveillance systems and the development

of vaccines and more rapid diagnostic tests.

1990 Healthy People 2000: Public Health Convened consortium in 1987 The keys to meeting the government’s

(2) National Health Promotion Service (PHS) with 300 national organizations. objectives on infectious diseases include

and Disease Prevention. (USA) The 2000 Consortium was public education about hygiene and

Full Report, With facilitated by the National infection control, education of health care

Commentary Academy of Sciences and the providers about disease epidemiology and

Institute of Medicine to assist disease prevention, research on the

the PHS to convene 8 regional improvement of immunizations, diagnostic

hearings and take testimony techniques and therapies, as well as

from over 750 individuals. Over immunization and efforts to maintain safe

10,000 people responded to the food and water supplies.

review and comment period.

1992 Emerging Infections: Institute of Between February 1991 and Surveillance is crucial to the detection and

(3) Microbial Threats to Health Medicine (IOM) July 1992, a multidisciplinary control of infectious diseases. Coordinated

in the United States (USA) committee convened to identify efforts of public and private organizations,

significant emerging infectious individuals and government agencies must

diseases and develop recom- be expanded and improved.

mendations on how to deal with

them.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

8

Year Study nature, location,

(ref no.) Document title Organization and time Conclusions

1994 Addressing Emerging Centers for Disease Plan developed by CDC in The creation of a comprehensive strategy is

(4) Infectious Disease Threats: Control and partnership with representatives necessary to address the threat of emerging

A Prevention Strategy for Prevention (CDC) from public and private health infectious diseases. To be most effective,

the United States (USA) organizations at the local, state, such a strategy should be integrated with

national and international plans for reform of the larger health care

levels. system.

1995 WHO Scientific Working World Health Summary of International Heavy usage of antimicrobial agents, poor

(5) Group on Monitoring and Organization Workshop held by WHO, Geneva, infection control standards, and

Management of Bacterial (WHO) Switzerland Nov. 29-Dec. 2, 1994. environmental contamination with

Resistance to Antimicrobial antimicrobial-resistant pathogens are key

Agents areas of concern.

1995 Impacts of Antibiotic- Office of Review of scientific literature, Infection control, the optimal use of existing

(6) Resistant Bacteria Technology exploration of biological antibiotics, and the development of new

Assessment (OTA) mechanisms behind ABR, and antibiotics should be the primary

(USA) research into availability of new approaches to antibiotic resistance.

 antibiotics.

1995 Infectious Disease – National Science Report from the CISET Working In order for a global surveillance network to

(7) A Global Health Threat and Technology Group on Emerging and Re- be realized, it is necessary to coordinate,

Council (USA) emerging Infectious Diseases strengthen and link existing systems.

Convened December 1994. Electronic links would enhance the surveillance capabilities of the US government’s

field stations.

1995 Report of the ASM Task American Society Report of a workshop held on The Task Force stresses the immediate need

(8) Force on Antibiotic for Microbiology July 6, 1994. for surveillance of resistance in humans and

Resistance (ASM) animals. They also advise the more prudent

use of antibiotics in human and veterinary

medicine; improved hospital infection

control and guidelines; improvement of

infection control curricula for all health care

professionals; better consumer education;

and more basic research.

1997 The Medical Impact of the World Health Report of WHO Meeting When creating any public health policies

(9) Use of Antimicrobials in Organization Berlin, Germany regarding the use of antimicrobials in

Food Animals (WHO) Oct. 13–17, 1997. livestock production, it is necessary to take

into account the benefits to production

versus the potential risks to human health.

More prudent use of antibiotics is the key

recommendation, especially when viable

alternatives exist.

1997 America’s Vital Interest in Institute of Report of a workshop conducted The improvement of global health, security

(10) Global Health Medicine (IOM) in November of 1995. and economic viability depends on

(USA) collaborations among US government health

agencies, as well as partnerships with US

industry, academia and non-governmental

organizations, other governments and NGOs.

1997 New and Reemerging American Society Analysis of documents on The report recommends increased funding

(11) Infectious Diseases: A Global for Microbiology emerging infectious diseases. for research efforts to develop improved

Crisis and Immediate Threat (ASM) diagnostic tests, new antibiotics, and

to the Nation’s Health. The vaccines.

Role of Research.

1997 Resistant Organisms: Global Royal Society of Proceedings of a conference The abatement of the problem of antibiotic

(12) Impact on Continuum Medicine sponsored by 3M Health Care resistance can only be achieved through

of Care (UK) and Regent Medical, London cooperation of prescribers, patients,

September 27, 1996. government, pharmaceutical, and

agricultural industries. Surveillance, infection

control, and improved prescribing practices

are all important components of any

collaborative effort.
9

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Year Study nature, location,

(ref no.) Document title Organization and time Conclusions

1997 Joint Committee on the Society for Health Publication in Infection Control Antibiotic resistance must be considered a

(13) Prevention of Antimicrobial Care Epidemiology and Hospital Epidemiology, global health problem. Responsibility lies

Resistance: Guidelines for of America and Vol.18, No.4, pp. 275–291. with all hospital personnel to control

the Prevention of Antimi- Infectious Diseases infections and use antibiotics properly, to

crobial Resistance in Society of America help prevent its further spread.

Hospitals

1997 Antibiotic Resistance: CIBA Foundation Proceedings of a Symposium Reversal of antibiotic resistance and return of

(14) Origins, Evolution, (International and (#207) held at the Ciba susceptible organisms are possible. These

Selection, and Spread Scientific Charity) Foundation, London goals can be achieved through the

July 16–18, 1996. implementation of rational use guidelines for

new antimicrobials and through the

cooperation of prescribers and consumers.

1998 The Current Status of Anti- World Health Report of WHO Workshop (held Europe’s disparate surveillance networks

(15) microbial Resistance Organization in collaboration with the Italian would benefit from a pan-European

Surveillance in Europe (WHO) Associaizone Culturale Microbio- coordinating group. Such a group could help

logia Medica) Verona, Italy, to standardize surveillance methodologies

December 12, 1997. at the local, national and international levels.

1998 Emerging Infectious Centers for Peer-review Journal: Proceedings Basic research is crucial to the control of

(16) Diseases Special Issue Disease Control of the International Conference emerging and reemerging infectious

and Prevention on Emerging Infectious Diseases, diseases. Improvements in hygiene and

(CDC) (USA) Atlanta, GA, March 1998. immunization can be very effective methods

of infection control, although often difficult

to implement because of human nature.

1998 Preventing Emerging Centers for An evaluation and update of Implementation of guidelines from

(17) Infectious Diseases: Disease Control Preventing Emerging Infectious Preventing Emerging Infectious Diseases

A Strategy for the and Prevention Diseases. resulted in decreases in the prevalence of

21st Century (CDC) (USA) certain infectious organisms. The authors

expect this follow-up plan to be successful in

preparing the US public health infrastructure

to respond to infectious diseases, whether

they are familiar, of unknown origin, or the

result of bioterrorist attacks.

1998 Antibacterial Drugs in Food and Drug The criteria are suggestions for The criteria are meant to keep the

(18) Animal Feeds. Human Administration complying with regulations agricultural industry within what are thought

Health Safety Criteria, (FDA) (USA) mandated by Congress and the to be safe levels of antimicrobial use in foodGuideline 18. Food and Drug Administration. producing animals.

1998 The Path of Least Department of Review of case studies, review The prescription of antibiotics often depends

(19) Resistance Health (UK) of the basis and impact of on the attitudes and expectations of patients;

resistance, commission of an the practitioner’s decision must take into

independent review of evidence. account the greater effect of the prescription,

in terms of increased selection for resistance.

A combined approach of practitioner and

public education is recommended.

1998 Antimicrobial Resistance British Medical Peer Review Journal Cooperation on the part of medical

(20) (Entire Journal for Journal (7 editorials and 4 papers). professionals, politicians, the pharmaceutical

September 5, 1998 devoted industry, and patients is necessary to improve

to Antimicrobial Resistance) the problem of antibiotic resistance.

1998 Resistance to Antibiotics House of Lords Between July 1997 and March The problem of antibiotic resistance must be

(21) and other Antimicrobial (UK) 1998, Sub-Committee members more widely recognized as a serious threat

Agents conducted interviews at the in order to be adequately addressed.

Public Health Laboratory Service Continuing professional education would

and with individual experts in help to achieve such recognition. Locallythe US and UK. They also created antibiotic formularies and

gathered evidence from the guidelines, and improved access to microagricultural and pharmaceutical biological testing, when practical, are other

industries, international and important tools for practitioners. The authors

regional health organizations urge caution in the use of antibiotic classes

and professional medical and that are prescribed in both human and

scientific societies. veterinary medicine.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

10

Year Study nature, location,

(ref no.) Document title Organization and time Conclusions

1998 Antimicrobial Resistance: Institute of Report of a workshop conducted The participants stress the need for national

(22) Issues and Options Medicine (IOM) in July of 1997. and global surveillance of antibiotic

(USA) resistance in animals and humans; for more

prudent use of antibiotics, especially in the

area of food production; improved hospital

infection control and guidelines; patient

education; continuing education for

practitioners; and more basic research for

new antibiotics and diagnostic tests.

1998 Protecting the Crown Center for Science Compilation of statistics and The authors recommend changes on the part

(23) Jewels of Medicine: in the Public information from other of public and private institutions, as well as

A Strategic Plan to Preserve Interest scientific sources. consumers, to prevent the further spread of

the Effectiveness of (USA) antibiotic resistance. Prevention of infectious

Antibiotics diseases is emphasized over the development of new drugs.

1999 The Agricultural Use of General Review consisting of interviews Despite 20 years of discussion among

(24) Antibiotics and Its Accounting with representatives from govt government agencies, consensus on the

Implications for Human Office (GAO) agencies, agricultural industry subject of antibiotic use in agriculture has

Health (USA) and agricultural associations; not been reached. The report recommends

also scientific review, and restriction of antibiotics as growth promoters

consultations with experts. in animals.

May 1998–April 1999.

1999 The Use of Drugs in Food National Research The Committee reviewed major The committee’s greatest concern is the

(25) Animals: Benefits and Risks Council classes of drugs used in food potential for development of resistance to

(USA) animals; reviewed scientific antibiotics used in human medicine due to

literature; heard testimony on misuse of antibiotics in food animals. To

animal drug-related issues and avoid any increase in such development, the

reviewed relevant federal committee recommends the development of

regulations. new antimicrobials, with possible restrictions

of their use to either human or animal

medicine.
11

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Introduction

Stuart B. Levy

tion, rapid increases in vancomycin-resistant enterococci and the emergence of vancomycin-resistant Staphylococcus aureus have raised concerns that

even industrialized countries may be losing this antibiotic of last resort (Figure 1).

In addition to considering the problem on local

and global levels, one must think of resistance in

The introduction of antibiotics into medical practice in the 1940s revolutionized man’s ability to cure

infectious diseases. Now, over fifty years later, health

practitioners around the world can no longer expect their choice of antibiotic to work. Multidrug

resistance has become common in clinical settings.

While some antibiotic resistance is a natural consequence of antibiotic use, resistance as a clinical

threat to patient care can be prevented. More

prudent use of these agents will restore and maintain a bacterial environment where susceptible

strains can flourish.

The cavalier use of antibiotics has resulted in

the progressive depletion of cost-effective agents

from our medical armamentarium. A dangerous

pattern has emerged in which, as a new antibiotic

is introduced, there is rampant overuse or misuse

resulting in accelerated development of resistance

(Table 2). In the last quarter of the century, respiratory organisms, including Haemophilus

influenzae, and agents of sexually-transmitted infections, such as Neisseria gonorrhoeae, have emerged

as worldwide multidrug-resistant threats. In addiFIGURE 1. PROPORTION OF ISOLATES ASSOCIATED WITH A NOSOCOMIAL INFECTION AMONG ICU (SOLID LINE) OR NON-ICU

(DOTTED LINE) PATIENTS WHO WERE INFECTED WITH ENTEROCOCCI RESISTANT TO VANCOMYCIN.

Source: Fridkin S, Gaynes R. Antimicrobial resistance in intensive care units. Clin Chest Med 1999;20:306. Reproduced with permission.

1989 1990 1991 1992 1993 1994 1995 1996 1997

25

20

15

10

5

0

Percent resistance

Year

TABLE 2. ANTIBIOTIC DISCOVERY AND RESISTANCE

DEVELOPMENT

Antibiotic Discovered Introduced Resistance

into clinical use identified

Penicillin 1940 1943 1940

(methicillin 1965)

Streptomycin 1944 1947 1947, 1956

Tetracycline 1948 1952 1956

Erythromycin 1952 1955 1956

Vancomycin 1956 1972 1987

Gentamicin 1963 1967 1970

Source: CIBA Foundation (14). Reproduced with the permission.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

12

terms of the broader environment in which

microbes live. Antibiotic resistance is an ecological

problem reflecting the fact that antibiotics are

societal drugs. Antibiotic use affects not only the

individual, but also the individual’s environment

of microorganisms, which is shared with the rest of

society. Susceptible strains are removed and resistant

strains replace them. Thus, any national or local

strategy to curb antibiotic resistance must stress the

prudent use of antibiotics so as to allow restoration

of the susceptible flora in a particular community.

Recognizing the role that microbial ecology plays

in housing and propagating resistant pathogens and

commensal organisms will help enormously in

developing guidelines for antibiotic use. The microbiologist and clinician, working together as a team,

can determine appropriate use in their facility or

community.

Selection of reports for this review

As part of the process of development of the WHO

Global Strategy for Containment of Antimicrobial

Resistance (26), a series of technical reviews were

commissioned. The Alliance for the Prudent Use

of Antibiotics (APUA) responded to WHO’s

request and reviewed reports on antibiotic resistance

prepared by prestigious scientific and governmental

organizations over the last two decades. Twentyfive expert reports (1–25), compiled by scientific

and medical authorities, were selected for this review

by APUA because they are highly referenced in the

literature and reflect extensive deliberations by a

wide variety of key expert policy groups. There are

other excellent policy reports which have not been

reviewed but which could supplement those

considered here, such as those from Canada,

Australia, Finland and Denmark.

The review process

In developing this synthesis, APUA consulted

five medical and scientific experts on antibiotic

resistance who reviewed relevant sections of the

selected expert reports. Their reviews are presented

in Chapters I–V and cover the major areas of

intervention: Chapter I. Improve and Expand

Surveillance; Chapter II. Increase Awareness:

Optimize Patient and Provider Behaviour; Chapter

III. Strengthen Sanitation, Infection Control, and

Regulatory Measures; Chapter IV. Encourage

Research and Product Development; and Chapter

V. Improve Antibiotic Use in Animals. Each author

focused on those reports with extensive subject

matter related to their area of investigation (see

Table 3). For example, only McEwen (Chapter V)

reviewed those reports written specifically on

antibiotic use in animals and plants. O’Brien

reviewed additional reports (27,28,29,30,31)

because they were exclusively about surveillance and

introduced important data and principles revisited

in later reports. In addition to summarizing findings from the expert policy reports, updated

information, references and the author’s insights

were added where considered appropriate and

relevant by the author. The Summary of Reports,

with key conclusions from each, is presented in the

Executive Summary Table 1 together with the Key

Recommendations synthesized under a series of

headings:

• Increase awareness of the antibiotic resistance

problem

• Improve surveillance of antibiotic resistance

• Improve antibiotic use in people

• Improve antibiotic use in animals

• Encourage new product development

• Increase resources to curb antibiotic resistance in the developing world

• Increase funding for surveillance, research and

education.

Each set of recommendations is categorized by

the levels of decision-making necessary to initiate

action. A resumé of each of the expert reports reviewed, prepared by APUA, is contained in Appendix A.

In addition, APUA collected information from

their international chapters about a number of current national and local initiatives, as an illustration

of the power of local movements. Each of these

programmes chose a particular feature of the antibiotic use and resistance problem and put together

a team to address it. Their reports, reflective of

APUA Chapters but not necessarily reflecting national policy, are included in Appendix B.

Conclusion—A manageable approach at

the local level

Although concerned scientists and prestigious study

groups have met to document the problem of antimicrobial resistance and suggest solutions, the key

players who can impact the problem have somehow not been engaged. This review highlights the
13

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

TABLE 3

General review Control & prevention

Public health

Reference Trends in Causes & Antimicrobial Economic promotion & Public

No. (year of publication) diseases & mechanisms use in animals cost of prevention policy

Short title resistance of resistance & plants resistance strategies strategies Surveillance

1. (1987) Antibiotic use and antibiotic resistance worldwide:

report of a study sponsored by

the Fogarty International Center

of the National Institutes of

Health, 1983–1986 x x x x x

2. (1990) Healthy People 2000:

National Health Promotion and

Disease Prevention x x x

3. (1992) Emerging Infections:

Microbial Threats to Health in

the United States x x x x

4. (1994) Addressing emerging

infectious disease threats: A

prevention strategy for the

United States x

5. (1995) WHO Scientific Working

Group on Monitoring and

Management of Bacterial Resistance to Antimicrobial Agents x x

6. (1995) Impacts of Antibioticresistant bacteria x x x x x x x

7. (1995) Infectious Disease–

A Global Health Threat x x x

8. (1995) Report of the ASM Task

Force on Antibiotic Resistance x x x

9. (1997) The Medical Impact of

the Use of Antimicrobials in

Food Animals x

10. (1997) America’s vital interest

in global health: Protecting our

people, enhancing our economy,

and advancing our interests x

11. (1997) New and Re-emerging

Infectious Diseases: A Global

Crisis and Immediate Threat to

the Nation’s Health x x

12. (1997) Resistant organisms :

Global Impact on Continuum

of Care x x

13. (1997) SHEA Position Paper on

Prevention of Antimicrobial

Resistance in Hospitals x x x

14. (1997) Antibiotic Resistance:

Origins, Evolution, Selection

and Spread x x x x x x x

15. (1998) The Current Status of

Antimicrobial Resistance

Surveillance in Europe x
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

14

need for action at the national and local levels to

break this pattern and to reverse increasing rates of

resistance in communities and countries worldwide.

It also identifies a number of barriers to be overcome including:

• The complex, and somewhat invisible, nature of the problem;

• Financial incentives which foster misuse of

antibiotics;

• Lack of necessary coordination among many

disciplines;

• Lack of adequate funding, leadership, and

accountability at the national level;

• The complexity and vast number of possible

interventions, making prioritization difficult.

Despite these formidable barriers, it is the local

nature of the problem which provides optimism

that resistance can be contained and curbed if susceptible microbes can be re-established within defined areas. Individual institutions and health

practitioners that use antibiotics more prudently

will restore bacterial equilibrium in favour of susceptible bacteria and thereby preserve the effectiveness of antibiotic therapy in their communities.

While the WHO Global Strategy (26) provides

a thorough and comprehensive foundation, it is up

to each nation, local institution and local provider

to tailor specific initiatives to their particular resistance problems, resources, and practices.

General review Control & prevention

Public health

Reference Trends in Causes & Antimicrobial Economic promotion & Public

No. (year of publication) diseases & mechanisms use in animals cost of prevention policy

Short title resistance of resistance & plants resistance strategies strategies Surveillance

16. (1998) Papers from the International Conference on

Emerging Infectious Diseases x x x x x

17. (1998) Preventing Emerging

Infectious Diseases: A Strategy

for the 21st Century x x x x x

18. (1998) Human Health Safety

Criteria Guideline 18 x

19. (1998) The Path of Least

Resistance x

20. (1998) British Medical Journal

special edition on Antimicrobial

Resistance x x x x

21. (1998) Resistance to antibiotics

and other antimicrobial agents x

22. (1998) Antimicrobial Resistance:

Issues and Options x x x

23. (1998) Protecting the Crown

Jewels of Medicine: A Strategic

Plan to reduce the spread of

antibiotic resistance x x

24. (1999) The Agricultural Use of

Antibiotics and its implications

for human health x x x

25. (1998)The Use of Drugs in Food

Animals: Benefits and Risks x
15

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

CHAPTER I

Improve and expand surveillance

Thomas F. O’Brien

The groups made generally similar recommendations over the two decades, although some of their

more recent reports have commented on how little

these recommendations have been implemented.

An obstacle may be that surveillance of resistance,

as noted, requires an unusual degree of cooperation and integration between the efforts of caregivers and public health workers. Caregiving

institutions are the predominant producers and

users of resistance surveillance data, but public

health leadership and support is needed to integrate the data into larger systems and to collaborate in understanding and containing resistance.

Synthesis and summary

Do we need surveillance of antimicrobial resistance?

The groups were nearly all emphatic about the need

for surveillance of antimicrobial resistance, as

reflected in their statements:

• “without reliable information ... it would be

impossible to find solutions”(2)

• “more systematic surveillance on a much larger

scale is needed to provide explanations or

remedies”(4)

• The US should “take the lead in promoting the

development and implementation of a comprehensive global infectious diseases surveillance

system.”(5)

• “Distribute ...software in laboratories to enable

them to monitor their own results for test quality, for infection control problems and for local

trends in resistance, and to enable them also to

merge their results into same-format, isolatebased databases for detailed national and international surveillance of resistance.”(6)

• “There is an urgent need for effective domestic

surveillance of antibiotic resistance in animals

and humans.”(7)

• “A surveillance system is essential for understanding the spread of antibiotic-resistant bacteria and

Abstract

Expert groups advising on control of antimicrobial

resistance have repeatedly emphasized the need for

surveillance of resistance. This chapter reviews the

discussions and recommendations on surveillance

of resistance in reports issued by sixteen such groups

over the past two decades.

The problem of antimicrobial resistance is enormous because of the magnitude of the interconnecting global bacterial populations it involves. It

is intricate because of the diversity of resistance

genes and genetic vectors responding to differing

usage of antimicrobial agents on different parts of

those populations in different parts of the world. It

is also peculiarly circular since an attempt to cure

one patient may eventually prevent cure of another.

For these reasons, as reflected in these reports,

resistance presents different problems to a remarkably wide range of caregivers, policy-makers, and

researchers, and they need different kinds of information from surveillance. The reports identify

needs for local information to guide local selection

of agents for individual patients, infection control

in the hospital, public health in the community,

and local antimicrobial usage strategy. Different

analyses are needed at the national level to overview resistance epidemiology and to set drug policy.

Global detection and tracing of emerging problems

are also needed.

The reports recognize that information for surveillance of resistance must ultimately begin with

data from microbiology laboratories and that these

laboratories need to be increased and improved.

They look to advancing information technology to

link clinical laboratories in networks guided by

reference laboratories that would work to both

generate and improve the data. They also seek to

integrate this information with additional patient

information, including patient antimicrobial usage,

in order to make better systems for the management of local resistance. Such data from multiple

centres would also provide more detailed understanding of the relationship of antimicrobial use to

the spread of resistance.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

16

planning interventions so as to preserve the

efficacy of currently available antibiotics.”(9)

• “Establish a system for monitoring bacterial

resistance and antibiotic usage.”(10)

• “Redressing these deficits”[in surveillance] “is

crucial in global and national public health terms,

and the most powerful case possible must be

made for urgent and substantial response.”(12)

• “Systematic collection of epidemiological data

on resistance should be initiated immediately...The costs to the NHS are likely to be

modest compared with many other actions.”(13)

• “Comprehensive surveillance is required to measure the public health impact of antimicrobial

resistance and of interventions (including those

proposed in this report) to minimize antimicrobial usage.”(14)

• “A critical elemental in addressing the environmental impact of antimicrobial resistance is

effective surveillance...With respect to antimicrobial impact on the environment, surveillance

involves not only data on bacterial pathogens,

but also data on other microorganisms that are

part of the affected ecosystem.”(15)

• “Surveillance of antibiotic resistance (AR) is critical to provide early warning of emerging problems, monitor changing patterns of resistance,

and target and evaluate prevention and control

measures.”(16)

What kind of surveillance do we need?

Systems for surveillance of antimicrobial resistance

have many common and interrelated elements,

which are mentioned frequently in the reviewed

reports. Any one system will be a blend of and a

balance between these elements. Report numbers

referenced below for each element do not cite all of

the reports that touched upon that element, but

only some that are representative or most pertinent.

Antimicrobial resistance is an enormously complex subject, dealt with by microbiologists, clinicians, epidemiologists, pharmacists, basic research

scientists, infection control workers and public

health workers, etc. They see the problem in different ways and, as members of these expert groups,

have wanted different kinds of information from

surveillance of it. Nonetheless, a general consensus

about the elements of surveillance emerges from

these reports, and their differences often seem complementary.

Clinical microbiology laboratory information

The essential basic element of surveillance is information from microbiology laboratories. Antimicrobial resistance is ultimately about different kinds

of bacteria and their susceptibility to different

antimicrobial agents. Microbiology laboratories are

the only source of such information, and most of it

is generated by routine clinical microbiology laboratories.

The immediate users of such data from any

microbiology laboratory are health care workers in

the hospital and the community it serves. They need

this level of surveillance information to treat individual patients, to update local treatment guidelines, to observe effects of their local interventions

and to detect, monitor, and contain local spread of

resistant strains (3,6,12,14,15).

The most direct, responsive, and useful way of

providing local health care workers with the surveillance information they need is to file the data

from their clinical microbiology laboratory in a

user-friendly, local electronic database, which they

can query instantly, repeatedly, and in specific detail, as problems arise. The World Health Organization (WHO) provides free software for such a

database (WHONET) and additional software

(BACLINK) to translate data into the database

from existing local computerized laboratory reporting systems that lack database capability (6,7,15).

The need for antibiotic use data. In addition to resistance data there is need for health institutions and

governments to collect and review antibiotic use

data. This would allow more precise analyses of

relationships between antibiotic use and resistance.

Much of the antibiotic use data reside within pharmaceutical companies which should be encouraged

to share this information with public health agencies. Also, governments could set up their own systems and requirements to collect the use data from

health care providers and institutions. In addition,

post-marketing resistance surveillance should be

routine to detect resistance trends.

Problems with quality of clinical microbiology laboratory

information. Several of the groups recognized problems with the existing quality of clinical microbiology laboratory data. Quality of testing may be

uneven in many laboratories, and there is often no

programme for quality assurance. These limitations

may represent lack of funding, supplies, training

or oversight. Many regions lack microbiology labo-
17

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

ratories altogether, and where they do exist their

services may be underutilized or improperly

utilized. Information is further diminished if a

laboratory reports only the interpretations of susceptibility tests without their actual measurements

(12,16).

Recognition of these limitations has prompted

recommendations in the reports reviewed for

development, support, training, improvement and

quality assurance oversight of clinical microbiology laboratories, and for more of them in some

places. Their improvement is seen as essential for a

comprehensive surveillance system and, not incidentally, to improve care for the many patients

whose individual treatment is being directly affected

by tests done in those laboratories (6,12).

Problems with analysis of clinical laboratory information.

Another limitation of using only clinical microbiology laboratory reports, cited by several of the

reports, is that it relates to an uncertain population

base. Prevalence of resistance is commonly expressed

as a percentage derived from the number of resistant isolates as the numerator with the number of

both resistant and susceptible isolates as the

denominator.

This is adequate for many practical uses of surveillance information, including many at the local

level such as infection control. It can, however,

allow a sampling bias that overstates resistance by

ignoring susceptible strains obscured by successful

treatment without culture, or by more culturing in

places where there is more resistance. It also limits

more formal epidemiological studies of resistance

and its contribution to disease burden (14).

The reports that mention this need for more

appropriate denominators do not specify how to

get them. Presumably, the microbiology databases

would have to be linked to other databases containing demographics, diagnoses, etc., which could

better characterize the patients. The microbiology

databases could also be linked with pharmacy

databases in order to identify those patients who

were treated for infection without being cultured

before treatment. Advances in informatics are now

beginning to make this a real possibility (14).

Members of some groups wanted to specify in

advance which bacterial pathogens should be included in surveillance, presumably to minimize

work or data storage costs. We have been repeatedly surprised in recent decades, however, by

resistance problems emerging in species where they

had not been expected (e.g., enterococci). We have

also come to recognize the importance of early

detection of such new problems (called “alert organism surveillance” or “exception reporting” in one

report). Over the same period, moreover, the costs

of data storage and management have plummeted

to near trivial levels (7,14).

A similar question about what to include in the

database further illustrates differences in viewpoint.

Those investigating the evolution or ecology of

antimicrobial resistance see resistance as epidemics

of resistance genes through vast populations of bacteria that rarely infect. They want surveillance to

elucidate and trace how resistance genes emerge,

get into vectors and become linked under selection

and co-selection in reservoirs of environmental or

colonizing bacteria before finally entering a pathogenic strain that may infect someone. Their

denominators are bacterial populations. They think

that everything important for resistance happens

in the bacteria before the infection begins and the

epidemiologists start to count people for their

denominators.

Advancing information technology has the potential to accommodate such diverse views. It can

facilitate entry of data that is well characterized, so

the database can be broadly inclusive at little cost

and still allow subsequent analyses of any selected

subsets of the data to be sharply defined. Your

pathogens need not interfere with my commensals,

and we may both learn how they interact (4,12,15).

The roles of microbiology reference

laboratories

The reviewed reports identified multiple roles in

resistance surveillance for microbiology reference

laboratories (6,14,15).

Surveillance by the reference laboratory. Reference laboratories can themselves do surveillance of antimicrobial resistance. The usual way is for a network

of clinical laboratories to collect designated types

of bacteria from among those they routinely isolate and ship them to the reference laboratory. The

reference laboratory then retests the susceptibility

of those isolates and may also repeat their identification.

Reference laboratory surveillance has the potential to test the isolates by more uniform methodology and against more agents. Testing against more

agents can distinguish fine differences between

agents and discriminate more resistance phenotypes. Having all of the isolates in one laboratory
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

18

also makes it easier to use newer methods to investigate their genetic relatedness and the molecular

bases of their resistance phenotypes.

The limitations of this model of reference laboratory surveillance is that it is expensive and therefore can sample only a tiny fraction of a network’s

clinical isolates. It is best at answering selected questions or providing general overviews of specific

problems. Its information on population denominators for the isolates it tests is no greater and may

be less than that of the network clinical laboratories that contributed them. It also lacks the detail

needed for surveillance at the local level. Local

infection control needs to know the locations of

the last hundred patients who had methicillinresistant Staphylococcus aureus (MRSA), and not just

of the two whose isolates were sent to the reference

laboratory.

It would be valuable, however, for local surveillance to know both the locations of their last hundred patients with MRSA, from their own local

database, and also how their local testing of the

two MRSA isolates sent to the reference laboratory

compared to its testing of them. It would additionally be useful for them to know how their two isolates related to the MRSA sent in from other centres.

Conversely, it would be useful for the reference laboratory to know whether the two isolates they tested

from that centre represented only a few such isolates at that centre or an extensive outbreak.

For such reasons, the value of integrating the

data from routine clinical laboratories and the data

from reference laboratories on the isolates they have

both tested was recognized by several of the groups

reviewed, and characterized as “cross-validating” by

one of them. It does not appear to have been much

exploited yet (14). Most existing reference laboratory surveillance has been proprietary, its large

budgets supported mostly by pharmaceutical companies seeking information on particular issues.

Cross-validation has thus not been a priority.

It would seem easy, however, to extend the analyses of databases of such proprietary systems to crossvalidation and to other questions framed by public

health concerns. There will undoubtedly be a need

also to develop antimicrobial resistance reference

laboratories in the public health sector, not only to

do some specialized or “cross-validating” surveillance, but to also have multiple other roles in coordinating multi-centre surveillance networks, as

discussed below.

Reference laboratory roles in coordinating multi-centre surveillance networks. Organizing networks of medical

centres and merging their individual susceptibility

test databases can generate a national resistance

surveillance database without great expense. The

organized network can then serve as a base for collaborative programmes that use continuing quality

control and benchmarking analyses of the shared

data to improve its quality, use, and interpretation

both locally and nationally.

Several of the groups discussed the roles that a

central reference laboratory could play in organizing and coordinating such a surveillance network.

It could take the initiative in recruiting and setting

up the network. It could train participants in use

of the network software. It could develop or be the

network distribution point for proficiency testing

and other quality assurance programmes for network laboratories. It could give network laboratories training courses shaped, in part, by problems

seen in the results of such quality testing results

and in the analyses of the data flowing through the

network (6,14).

To the extent that a network reference laboratory also conducted surveillance projects on the

reference laboratory model sketched above, it would

have the opportunity to further improve routine

network data by the kind of cross-validation mentioned above. Finally, the reference laboratory

would take the lead in the continuing analysis of

total network data and in improving the local analyses ongoing at each centre in the network (14).

Active surveillance. “Active surveillance” is a term

sometimes used in descriptions of epidemiological

studies. Within the context of studies of resistance

the term may be applied at a number of levels, for

example: the identification and recruitment of a

patient or study population; the collection of

screening or diagnostic specimens; the performance

of non-routine testing; and/or the in-depth analysis of data. Used in this sense, active surveillance

can often be accomplished within, and be a valuable complement to, routine clinical practices. For

some purposes, however, it may also require

special studies.

Special studies. Special studies to provide more

surveillance information than is in routine clinical

isolate data usually undertake to obtain additional

designated specimens for culture, or additional categories of patient information, or to perform more

elaborate isolate testing or data analysis.
19

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Such studies might, for example, survey resistance of E. coli from stools of untreated healthy

people, of S. pneumonia in nasopharyngeal swabs

from children in a day-care centre, or the urinary

isolates of all untreated women presenting with

symptoms of urinary tract infection.

Alternatively, they might seek to record all diagnoses, or extensive demographic data or all antimicrobial therapy in a given population of patients.

They might also perform extensive analyses of the

genotypes of isolates of one species or of the linkages of different antimicrobial resistance phenotypes

in different bacterial species in various collections

of isolates.

Because such special studies have usually been

labour intensive, requiring extra effort and funding, they have tended to be fragmentary and difficult to sustain. They do, however, have the potential

to enhance the information obtained from surveillance and improve its epidemiological foundation,

especially if they can be linked to one another and

to more routine surveillance to develop new kinds

of cross-validation (14).

Advancing information technology has the potential to eliminate the extra effort required for some

of these studies and so make them more widely

utilized. Data on patients’ demographics and use

of antimicrobials are increasingly being filed in electronic reporting systems, along with their microbiology test results. Downloading all three into a

common database would routinize and so make

widely available analyses previously kept rare by the

need for tedious chart review.

Participants interconnected in existing surveillance networks may also be better organized, if not

already self-selected, to collaborate in ongoing

projects requiring collection and culturing of additional specimens.

Information systems for surveillance

Many of the reviewed reports emphasized how

essential for the surveillance of antimicrobial resistance are computerized information systems, but

few explored their specifications. The needs seem

obvious and advancing information technology

should be making it easier to meet them

(3,5,6,7,13,14).

Software exists now, as mentioned above, to put

any laboratory’s susceptibility test results and some

basic demographics of the cultured patients into a

database dedicated to that application. If software

with the same or easily matched codes and file format is used by all the laboratories in a network,

merging their databases, after ‘hashing’ for confidentiality, into a database network costs almost

nothing.

Further development of such software could

increase its usefulness for infection control data

management. Downloading discharge data on each

patient’s diagnoses and pharmacy data on each

patient’s antimicrobial usage into additional fields

in the same database would make it possible to

analyze what kinds of isolates preceded or followed

what kinds of antimicrobial therapy in patients with

what kinds of diagnoses (7,14).

Downloading pharmacy data on antimicrobial

usage by each patient at each medical centre in a

multi-centre resistance network would also allow

the network to capture that data for the whole network, as it does the resistance data, by merging the

databases of all the centres. This could be one component of a national system for surveillance of antimicrobial usage. Such surveillance has been

strongly recommended in several of the recent reviewed reports, but none of them has offered much

detail on how to do it (12,16).

Information technology now makes it easier to

implement such integrated information systems. A

type of software called a data conversion utility facilitates matching of data fields and translation of

codes between the various electronic systems that

report and store relevant data sets in different medical centres and a common database that can analyze

all of their interrelationships. An example would

be BACLINK, which facilitates translations of data

from various microbiology reporting systems into

common WHONET files.

Research on surveillance data

We can picture how resistance genes may emerge,

insert into genetic vectors and spread under selection in one or many strains and species through

the world’s interconnecting bacterial populations.

The picture we have, however, is projected largely

from expectations based on the well-studied molecular details of those genes and vectors. Plasmids

can transfer, and resistance genes should move in

and out of integrons, etc., but only rarely have we

been able to observe them actually doing those

things in the real world. The microbes’ resistance

system is operating all around us, but we cannot

observe its workings or the rates at which changes

occur. If we could, we might manage it better.

The kind of systematic surveillance of resistance
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

20

recommended by many of these reports, coupled

with advancing molecular technology, should make

it possible to do at least some surveillance at the

molecular level. We should be able to trace lineages of resistance genes, genetic vectors, and strains

of bacteria in different circumstances and under

differing selection. The goal would be to improve

our ability to predict what will happen and to

intervene and avert problems (3,4,6).

Research and surveillance are each recommended

in nearly all of the reviewed reports, but only a few

make a connection between them. We need research

on how best to do surveillance. We need further

development of surveillance software and research

on how to use it fully. We also need to develop

surveillance linked to molecular technology as a

research tool to elucidate the real world population biology and detailed epidemiology of antimicrobial resistance.

What have been the barriers to the implementation

of surveillance?

The urgent recommendation for surveillance of

antimicrobial resistance and basic plans for how to

do it were made nearly two decades ago (2,3). Its

urgency has been reemphasized and elaborated

upon by each of the expert groups that has met

since. Over that same period, a succession of unexpected, new, and very damaging resistance problems have emerged and spread throughout the

world. These global outbreaks, one after another,

have had only the sketchiest of monitoring to support the ultimately failed attempts at containment.

As nearly all of the recent reports agree, only inadequate and fragmentary surveillance systems exist

today.

The reports reviewed do not examine the

reasons why prior reports’ recommendations for

surveillance of antimicrobial resistance had been

so little implemented, except for one that discusses

barriers and resources in one country (13). The

nature of antimicrobial resistance, the types of recommendations made, and the experiences of those

surveillance systems that have been started may,

however, suggest some of the barriers.

Compared to other medical problems being

brought to the attention of the public and public

health officials, antimicrobial resistance is an extremely diffuse subject and difficult to describe. It

is not in one organ or one type of patient but carried by all of us and in the environment. It is not a

disorder in people as much as it is a disorder of the

world’s huge but invisible bacterial populations.

Attempts to cure people drive a process that ultimately prevents cure of other people. The fact that

it is confusing may have been a barrier to focusing

attention on recommendations to contain resistance.

The recommendations for surveillance made in

these reports require perhaps unprecedented cooperative activity in any country between a small

number of public health officials and large numbers of diverse groups of health care workers. Antimicrobial resistance is a public health problem.

Most of the people who are causing it, trying to

cope with it, and generating nearly all of the information on it, however, are providing services to

individual patients. They produce, own, and have

the most immediate and varied uses for the data

that will have to be recycled into public health surveillance if there is to be any.

The two parties need to help each other. The

public health official on whose desk the recommendations arrive may not have a detailed grasp of the

workings of the microbiologists, pharmacists, infection control workers, and clinicians in the medical centres and the communities they serve.

Conversely, it may not occur often to these busy

multi-specialty local health care providers that they

are in part public health workers.

Most of the antimicrobial resistance surveillance

networks that have gotten started in various countries over the last decade or so were initiated by a

microbiologist or infectious disease specialist. He

or she began to file and analyse local susceptibility

test results in a database in his or her own medical

centre, then persuaded colleagues at other centres

to do the same. Occasional funds and/or occasional

surveillance projects from pharmaceutical companies helped. The leadership and interest of these

individuals and their colleagues have kept many of

these networks functioning, and some have grown

to include thirty or more centres.

Less often, a public health department has taken

the initiative to contact medical centres and begin

development of a surveillance network. What seems

to have worked best has been when a public health

department has established a relationship with one

of the beginning privately-initiated networks. In

two such examples some relationship had existed

from the beginning, and the public health division

had later expanded its support when it came to

realize the value of the growing network.

When a public health department has come to

support a surveillance network, substantial im-
21

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

provements have followed. Presumably two things

have happened. The first is that the network had

been built with participants who were motivated,

in that they had been self-selected by their interest

and belief that a network could help their work

locally.

The second is that the public health department

could begin to support a reference laboratory, hitherto lacking in those networks. In each of these two

cases the network initiator’s laboratory became the

reference laboratory. With this support, it could

begin to perform the reference laboratory functions

described above, and the networks improved appreciably.

Each of the two parties has its own barrier. The

public health department needs to be given funding and accountability to build a surveillance network. The public health department, however,

cannot begin to pay all the participants that a network needs. Therefore, it has to exercise real leadership in finding leaders within the network, and,

with their help, motivate all the participants to work

together on the network.

Similarly, none of the participants in the network would be able to fully support a reference laboratory. Yet, the improvements in the network from

such a laboratory can enhance the work of the participants. Cooperative mutual barrier removal

between public health and local health care may be

the most important process in implementing

surveillance of antimicrobial resistance.

Governments and their public health agencies

need to take the lead in removing these barriers

and in encouraging clinical laboratories to participate fully in surveillance networks. They have rarely

done this because they have been slow to see the

epidemic nature and the menace to health of antimicrobial resistance and thus slow to see it as a

public health responsibility, deserving priority and

adequate support.

Authors’ notes on reports

(27) WHO International Collaborative Study of

Antibiotic Sensitivity Testing (1968–1970)

This study, carried out in 16 laboratories in different parts of the world, was set up in response to a

recommendation of the WHO Expert Committee

on Antibiotics.(1961) It was sponsored by WHO,

initiated at a meeting in Geneva and coordinated

by the Karolinska Institute in Stockholm, with

financial support for meetings and administrative

work provided by WHO.

The study compared, in multiple countries in

great quantitative detail, both broth dilution and

agar diffusion methods for antimicrobial susceptibility testing. It essentially began the development

of the framework for standardizing and interpreting test results and comparing results from different countries, which are essential prerequisites for

surveillance of resistance, especially for international

surveillance of resistance.

Its 90 page report, published as a supplement to

ACTA Pathologica et Microbiologica Scandinavia

(Section B 1971, Supplement No. 217) did not use

the word “surveillance” which may not then have

been applied to antimicrobial resistance, but for

which the study began to build a foundation. It did,

however, begin by listing as one of three purposes for

standardizing the measurement of the sensitivity

of microorganisms to antibiotics (along with

rational use and evaluation of new agents) as “for

epidemiological studies.”

(28) WHO Scientific Working Group on Antimicrobial

Resistance, Geneva, 23–27 November 1981.

WHO/BVI/PHA/ANT/ 82.1

The Working Group outlined the current situation

of antimicrobial resistance. It emphasized that the

increasing frequency of acquired resistance to antibiotics among bacteria of medical importance is a

worldwide health problem that demands international attention. Its report concluded that without

reliable information about the susceptibility to

antibiotics of important bacteria, it would be impossible to find solutions to the problems created

by antibiotic resistance.

The Working Group therefore recommended

promotion of surveillance activities at both national

and international levels and suggested that WHO

could play an important role in promoting these

activities. It stressed the necessity of extending the

WHO activities in establishing a system for surveillance of antibiotic resistance, and concluded that

there was a need for unification of methodology

used for the surveillance.

(29) WHO Consultation Group for Surveillance of

Antimicrobial Resistance, Geneva, 22–26

November 1982. WHO/BVI/PHA/ ANT/ 82.5

This meeting was convened to respond to the recommendations on surveillance of the previous year’s

Scientific Working Group (above). Its purpose was

to discuss the approaches to and objectives of national and international surveillance of antibiotic
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

22

resistance, and to make recommendations as to how

such a surveillance programme might be designed

and implemented on a global scale.

The plan proposed was to:

1. Develop systems to produce reliable data on

resistance in all parts of the world.

2. Develop systems to ensure that the data are

of good quality and comparability.

3. Analyse the resulting data in many different

useful ways on a continuing basis.

4. Use the analyses to monitor, understand and

control the spread of resistance.

The Consultation Group identified three general sources of data for surveillance. One was the

susceptibility test result data generated in enormous

volume by the world’s clinical microbiology laboratories. A second was the more specialized data

generated by reference laboratories. A third would

come from special studies with epidemiologically

planned sampling not just of selected patient

populations but also of healthy people in different

settings and of the environment. The group emphasized that planning in advance to integrate

analyses of data from these three general sources

would allow cross-referencing enhancement of the

value of each.

The report made general recommendations for

methods of susceptibility testing, and also for quality control of that testing and for what antimicrobials to test, drawing upon an earlier WHO

report on “Guidelines for Antimicrobial Testing

(WHO, Ref, LAB/79.3 in Annex)”. It pointed out

the need to record the actual measurements of susceptibility, such as diameters of zones of inhibition

around susceptibility test discs or minimal inhibitory concentrations, rather than the interpretive

categories derived from them.

The Consultation Group also examined in some

detail the management of the data from such

surveillance. It recognized that nearly a dozen categories of data, such as type of sample, date of

sample, and the identified species and susceptibility measurements of each isolate were recorded in

most laboratories.

Planning in advance a common software format

for filing the data in these categories and common

codes for the terms and measurements of that data

would thus greatly simplify the merging, managing and analysis of data from many laboratories and

sources.

The report noted also that once such data are

electronically filed, it is easy and cheap to analyse and reanalyse it in many ways to fully extract

from it practical understanding of the emergence

and spread of resistance. For illustration, it sketched

out nine different types of such analyses. It went

on to explain how results from these analyses could

be extrapolated to insights about prevalence or

resistance in different places and different subpopulations, about prevalence of resistance genes

and about the evolution and epidemiology of

resistance plasmids. It summarized this with a

table (below) offering three examples of the kinds

of observations that might be made from such

Level Observation Use

Local Frequency of resistance to each antibiotic Aid selection of antibiotics for individual patients

Frequency of resistance to each combination Identify cross-infecting strains, locally endemic resistance plasmids

of antibiotics

Local trends in resistance Aid re-evaluation of local antibiotic usage and infection control

practices

National More resistance to one antibiotic than usual Decrease use of the antibiotic, introduce alternative agents

in other countries

Variation in antibiotic resistance in different Seek regional differences in usage, vehicles of resistance spread,

regions of the country e.g., food or water, hygienic practices

General level and trend of national resistance Review, revise national antibiotic usage strategy to increase its

overall in comparison with other countries effectiveness, reduce resistance

Global Global trends in resistance to various antibiotics, Guide development, use of new antibiotics, ways of preserving

prevalence of different genera older ones. Compare countries’ practices

Early detection of new resistance to an antibiotic Global warning to detect, contain, treat the emerging strain,

in a particular strain in a particular area examine circumstances preceding emergence

Global trends in prevalence of distinctive Detection, prevention of international spread of particular resistance

combinations of resistance or resistance genes plasmids of resistant strains
23

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

surveillance at each of three levels, local, national,

and global, and then of the kind of corresponding

practical responses that might be made by caregivers

and policy-makers at each level.

Even though this Consultation Group was meeting within about a year after the introduction of

the IBM personal computer (PC), at a time when

applications of the PC were only beginning, the

group noted its potential significance. “Now, however, rapid improvement and reduced costs of small

computer technology may soon make it possible

to enter the data directly on cassette tape or disc at

the testing laboratory.” They further observed that

this would make possible local analysis of the data

for local management of resistance at each medical

centre in addition to the more centralized multicentre analysis, which was all that had been practical previously with the big, expensive mainframe

computers.

(1) Antibiotic Use and Antibiotic Resistance

Worldwide, A study sponsored by the Fogarty

International Center of the National Institutes of

Health, 1983–1986

Nearly all reference to surveillance of antimicrobial resistance in this study performed by five task

forces comprised of international experts was in the

report of Task Force 2, entitled “Resistance of Bacteria to Antibacterial Agents.” The 13 members of

that Task Force came from 5 continents, with only

2 of its members from the same country. Many of

the members brought available data on resistance

from their own medical centres, from colleagues in

their countries, or from published literature. Data

were also presented from a computerized and isolate-based international surveillance system supported by the US Food and Drug Administration

(FDA), which was then ongoing but discontinued

later when FDA found an international study inappropriate.

The work of Task Force 2 was to piece together

from this available information an overview of the

current distribution and apparent trends of antimicrobial resistance throughout the world. Their

particular emphasis was to try to integrate what data

they had with growing understanding of the molecular basis of resistance and of its spread, so as to

be able to interpret one in terms of the other. Their

report attempts to do this by examining resistance

to agents grouped according to their being inactivated by the same families of resistance mechanisms.

The first recommendation of Task Force 2 was:

“The available data on global prevalence of resistance to antibacterial agents were barely adequate

to sketch ranges and suggest trends. More systematic surveillance on a much larger scale is needed

to provide explanations or remedies. The World

Health Organization has developed detailed recommendations for such surveillance and is now

beginning integrated surveillance programmes in

several regions of the world...This initiative should

be exported and expanded.”

Their second recommendation began by noting

the growing understanding of the genetic elements

of resistance. It then stated: “What are particularly

needed now are broadly based studies of the deployment of these genetic elements in natural

populations of bacteria that will provide an explanation of the phenomena observed in surveillance

and suggest practical strategies for containment and

reduction of resistance.”

(3) Emerging Infections. Microbial Threats to Health

in the United States. Report of the Institute of

Medicine. National Academy Press (1992)

This report called attention to a whole group of

recently observed or recently worsening infectious

disease problems by creating a new category for

them, Emerging Infections, and setting forth their

special features and similarities and the growing

seriousness of their threat to human health. It amplified the perceived importance of antimicrobial

resistance by including it in this category of Emerging Infections.

The report repeatedly emphasizes the importance of surveillance for the control of all emerging

diseases. They constitute such a large and diverse

set of problems, however, that the report did not

attempt to delineate the special needs for the surveillance of each, let alone for antimicrobial resistance, which probably differs most from the others

in surveillance methodology. Surveillance of resistance is, however, mentioned in several places.

1. Additional resources are recommended for the

Centers for Disease Control and Prevention

(CDC) to enhance its National Nosocomial Infections Surveillance System (NNISS) in five

ways. The first is to “include data on antiviral

drug resistance.” The fifth is “to determine the

reliability of antimicrobial susceptibility testing

performed in NNISS member hospitals.” No

description is given of the current status of

NNISS data on antimicrobial resistance.

2. Under “Agricultural Conditions and Practices”

is the somewhat tentative sentence: “It is con-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

24

ceivable that surveillance of feedlot animals for

the development of resistant organisms might

be a means of early warning for the emergence

of newly drug-resistant pathogens.”

3. In a section on Access to Surveillance Information, emphasizing that access to surveillance

databases is needed by many types of health care

workers and researchers, it is noted that there

are now no such databases for many problems,

including antimicrobial resistance.

4. In a later section is a recommendation that the

US Public Health Service develop a comprehensive, computerized infectious disease database

that includes all of these components and

ensure appropriate access to it.

5. It later recommends that the US “take the lead

in promoting the development and implementation of a comprehensive global infectious

diseases surveillance system.” Another sentence

later in the report says that: “Should a global

infectious diseases surveillance system be put in

place, such as the one suggested in this report,

tracking antimicrobial resistance worldwide may

be possible.”

(5) WHO Scientific Working Group on Monitoring

and Management of Bacterial Resistance to

Antimicrobial Agents. Geneva (1994).

WHO/CDS/BVI/ 95.7

This Working Group added several new insights.

Meeting at this time, they were able to look back

and recognize that resistance had worsened greatly

over the previous decade due to an array of surprising new problems, which they reviewed in detail.

They warned also that this was happening at a time

when pharmaceutical companies, represented at the

meeting, appeared to have under development few

new antimicrobials to address these new problems.

For surveillance of resistance, a particular insight

and emphasis of this group was the primary importance of local surveillance linked to local management of resistance for each medical centre and

its community. The group introduced the idea of a

local antimicrobial resistance management (ARM)

team comprised, to the extent available, of infection control workers, microbiologists, pharmacists

and infectious disease clinicians. They would work

together, applying their diverse skills to the ongoing analyses of local resistance data, to treat patients

and retard spread of resistance optimally within the

special circumstances of their time and place.

The report noted that such local monitoring and

management was now possible because local resistance databases could be maintained on local

personal computers. Previously, local results had to

be sent to a single remote centre for multi-centre

analysis on a mainframe computer, with standardized printed overview results returned to the centre

later. In contrast, local databases can be queried

locally, frequently and very specifically on an ad

hoc basis as specific local problems arise. The technology was seen capable of inverting the older “topdown” surveillance into a “bottom-up” model. In

this newer “grass roots” model, actively used local

databases could, if they shared common file formats and codes, be easily merged without loss of

detail to produce higher level regional, national or

international databases, as an inexpensive byproduct.

Software dedicated to supporting such local but

combinable antimicrobial resistance databases was

demonstrated for the Group. This shareware, called

WHONET, had been developed to meet the needs

set forth by the WHO Consultation Group for

Surveillance of Resistance of 1982 (see above).

Another emphasis of this Scientific Working

Group relating to surveillance was the need to build

professional infrastructure to support the monitoring and management of resistance. Well-trained

microbiologists in adequately supported microbiology laboratories were essential because they were

the ultimate source of all of the surveillance data

and its quality, and of the information for treating

individual patients. The microbiologists, in addition to infection control workers, infectious disease clinicians and pharmacists, would constitute

the ARM teams.

The report made separate recommendations for

each of three levels of organization. Those related

to surveillance of resistance are quoted verbatim

below.

Recommendations for WHO

Improve systems for surveillance of antimicrobial

resistance.

• Assist nations in assessing status and specific

needs of their laboratories for performing adequate identification and susceptibility testing

of bacterial pathogens.

• Distribute and facilitate the installation of

WHONET software in laboratories to enable

them to monitor their own results for test quality, for infection control problems, and for local
25

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

trends in resistance, and to enable them to merge

their results into same-format isolate-based

databases for detailed national and international

surveillance of resistance.

• Assist laboratories, through WHO Regional

Offices, in the development of quality control

and quality assurance programmes to help improve the accuracy of antimicrobial susceptibility testing methods.

• Provide support and facilitate coordination

between reference laboratories for better strain

typing and other specialized procedures in

order to better characterize the epidemiology of

resistance.

• Encourage the prompt reporting of culture and

resistance data and analyses to clinicians, infection control personnel, and public health

authorities, and prompt transmission of selected

isolates to reference laboratories when appropriate.

• Call attention to patterns of resistance in

species of bacteria that may represent emerging

epidemics, such as vancomycin-resistant

enterococci, penicillin-resistant pneumococci,

fluoroquinolone-resistant Shigella, multi-resistant Salmonella typhi, and others less obvious.

• Develop an action plan for appropriate response

to outbreaks of resistant organisms.

• Identify funding sources to help implement the

above recommendations.

Recommendations for individual countries

Same as for WHO plus:

• Encourage medical centre laboratories to develop

isolate-based computer databases of their susceptibility test measurements in a common file

format, such as WHONET, which can easily be

monitored at each centre and aggregated into a

national surveillance database.

• Designate one or more laboratories to help other

laboratories install and use the common software, to provide them with test strains and other

support for improving their testing, and to manage and share with them their shared surveillance database.

• Assess the quality, geographic distribution and

professional microbiological support of existing

microbiology laboratories, improve them where

needed, and open new laboratories in

underserved areas.

• Integrate the work and data of reference laboratories with that of other laboratories monitoring the spread of resistance.

Recommendations for local hospitals and reference

laboratories

• Develop a plan to monitor and control resistance.

• Implement a user-friendly, multi-analysis isolatebased computer system, such as WHONET,

which allows detailed monitoring of local resistance and flags isolates or clusters of isolates that

may represent emerging outbreaks of resistant

strains.

• Appoint an antimicrobial resistance manager

(ARM) responsible for monitoring and interpreting local resistance and local antimicrobial

use and for alerting and working with infection

control, pharmacy, administrators and clinicians

to refine and optimize antimicrobial therapy and

to focus containment efforts.

(8) Report of The ASM Task Force on Antibiotic

Resistance (1995)

This report emphasized the need for surveillance

of resistance in the US. It pointed out that: “There

is currently no national or global surveillance system for monitoring antibiotic resistance in animals

or humans. In fact, the amount being expended is

totally inadequate.” It reviewed available figures

from 1992 and could find, outside of private-sector investment in proprietary systems, only $55,455

from all sources dedicated to antibacterial and antiviral drug resistance, out of a total of $76.4 million of federal, state and local funds for surveillance

activities of all kinds.

The first recommendation of the report is for a

National Antimicrobial Surveillance System. It begins with a list of things the surveillance system

should do. The first block of suggestions includes

focus on prevalent pathogens from clinical disease

cases and routine isolates, attention to upward

“creep” of minimal inhibitory concentration (MIC)

levels, monitoring of animal products at the supermarket level, inclusion of Salmonella as reflecting

antimicrobial usage in the animal world and Shigella usage in the developing world, and monitoring of soil waste on farms.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

26

The list further includes use of concurrent

patient demographic profiles, the ability to flag

organisms with certain phenotypic or genotypic

resistance patterns for further study at reference

laboratories and for molecular typing, and the use

of surveillance to target areas for intervention or

epidemiological investigation, mostly at the local

but also at national or international levels. It also

suggests devising different benefits for different sets

of participants, making data available to pharmaceutical companies and having a system that could

be modified to address new areas of concern.

Under “monitoring of organisms”, the report

discusses how to update the list of pathogens to

monitor, frequency of analyses, the need for

significant numbers of isolates, and the need to

include species that may not be pathogens but may

be a source of transfer of resistance genomes to

prevalent human pathogens.

Sections on geographic representation discuss

choosing participant laboratories by US population

distribution, suggesting one site per one to two

million people with stratification by medical centre size, type, and services, and with supporting help

from local and state laboratories, possibly in coordinating data from laboratories supporting community practices.

A section on methods recommends following

Europe’s National Committee for Clinical and

Laboratory Standards (NCCLS) documents, using

where possible the disc-diffusion method with alternative special tests including molecular testing,

some at reference laboratories, guided by expert

advisory panels and with rigid quality control. It

also states that: “all data should be expressed as

quantitative endpoints regardless of method. This

dictates measurement of disc diffusion tests by

calipers to the nearest whole millimeter and the use

of MIC endpoints in micrograms per millimeter

for dilution methods.” “Qualitative interpretations

shall be applied objectively by computer programs

based on current NCCLS tables. Similarly, quality

control guidelines found in the NCCLS tables

should also establish the validity of each participant’s/ referee’s data.”

A section on data entry and analyses emphasizes

that all surveillance systems need well-structured

computer systems. It cites the CDC’s NNISS and

the WHO’s WHONET as examples of such software used for resistance surveillance, available and

modifiable. It also suggests that networks using such

systems or others such as CDC’s sexually transmitted disease programme, Veteran Administration

(VA) networks, or SCOPE (Surveillance and Control of Pathogens of Epidemiologic Importance,

Medical College of Virginia and University of Iowa)

might serve as working models and that these international programmes might provide possible

collaborations. Another section sketches guidelines

for analysis of and access to the data, which would

be audited by the oversight panel or study administrators.

A section on organization of the surveillance

system recommends that funding should be sought

from all parties that would benefit from the system, including CDC, FDA, NIH, USDA, VA,

DoD, pharmaceutical and health supply industries,

drug and health care delivery companies, academic

institutions, professional societies, and university

medical centres. An oversight panel should include

representatives of the organizations plus members

of the scientific community who are experts on

antimicrobial resistance, specialists in infectious

diseases and in vitro susceptibility testing or experienced in multi-laboratory surveillance, hospital/

health care epidemiologists, and computer and

statistical analysts conversant with antimicrobial

issues. Location of the programme within CDC

would allow integration with other surveillance

activities.

A final section on immediate recommendations

calls for an expert panel to develop a surveillance

protocol and establish an annual budget, for which

the ASM outline might serve as a preliminary or

tentative plan. Federal funding should be immediately identified, with federal agencies and other

sources involved in funding decisions. It calls also

for appropriate expertise in statistical and computer support and for an immediate search for earlier

resistance surveillance databases from the US or

worldwide surveillance, if available.

(7) Report of the US National Science and

Technology Council Committee on International

Science, Engineering, and Technology Working

Group on Emerging and Reemerging Infectious

Diseases. Washington (1995)

This US government interagency Working Group,

chaired by the Undersecretary for Global Affairs of

the Department of State and established under the

aegis of the Committee on International Science

Engineering and Technology (CISET) of President

Clinton’s National Science and Technology Council, had members representing more than 17 different Government agencies and departments. Its
27

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

charge was to review and make recommendations

on the US role in detection, reporting and response

to outbreaks of new and re-emerging infectious

diseases.

The Working Group considered the entire range

of emerging infections and emphasized the important role of surveillance for the whole group. The 2

of its 19 recommendations that mention surveillance for antimicrobial resistance specifically are

reproduced below.

• Assisting WHO to establish surveillance of antibiotic

resistance and drug use, as a first step towards the

development of international agreements on antibiotic usage.

WHONET, an international reporting system

for antibiotic resistance, provides WHO with a

starting point for this significant work. Taking

advantage of its overseas networks US Agency

for International Development (UASID) can

provide support for surveillance of drug resistance that hinders the treatment of internationally important diseases. In addition CDC can

contribute technical support and data management resources (5).

• Identifying and strengthening WHO Collaborating

Centres that serve as unique reference centres for

diseases whose re-emergence is feared.

WHO Collaborating Centres operated in the

United States by Government agencies or by

American universities require support to build

or rebuild their capacity to serve as reference

laboratories within a larger, more active infectious diseases network (8).

(6) Report of the Office of Technology Assessment of

the Congress of The United States on Impacts of

Antibiotic Resistant Bacteria (1995)

The report does not use the word “recommend”,

that presumably being the prerogative of the Congress, but instead presents “issues and options”,

usually expressed as “the Congress could.” Under

the first of these in its summary (A. Surveillance) it

says that “Congress could support the establishment

of a national surveillance system, including providing funding.”

It goes on to explain: “A surveillance system is

essential for understanding the spread of antibioticresistant bacteria and planning interventions so as

to preserve the efficacy of currently available antibiotics. Because of these public health considerations, and the likelihood that a surveillance system

would decrease medical costs, including costs to

medicare, Congress could consider funding a

nationwide surveillance system.”

“The features of the current, limited systems can

be incorporated and combined to produce a system of desired size, complexity and cost. It may be

advantageous to begin with a less complex system

(such as some of the operating systems described

in this report), and then add more features. Any

system must have a strong advisory group that includes diagnostic laboratory and computer experts,

clinicians, hospital administrators, pharmaceutical

company researchers, academic scientists, and federal and state regulatory and health officials. The

advisors could work to assure that the surveillance

system collects and disseminates the information

in the forms for its best use.”

(13) Society for Healthcare Epidemiology of America

and Infectious Disease Society of America Joint

Committee on the Prevention of Antimicrobial

Resistance: Guidelines for the Prevention of

Antimicrobial Resistance in Hospitals. (SHEA

Position Paper) (1997)

The first two of the report’s seven recommendations for hospitals large and small are: “Establish a

system for monitoring bacterial resistance and antibiotic usage” and “Establish practice guidelines and

other institutional policies to control the use of

antibiotics, and respond to data from the monitoring system.”

(15) WHO Workshop on the Current Status of

Antimicrobial Resistance Surveillance in Europe.

Verona (1997). WHO/EMC/BAC/98.1

Participants in resistance surveillance networks in

Europe filled out questionnaires in advance, and

their responses constitute the descriptions printed

in this report. Twenty-nine surveillance activities

or networks are described, approximately half of

which targeted a single bacterial species. In the

workshop the participants reviewed, elaborated

upon and discussed these systems.

They found need to improve communication

of results to decision-makers; to improve and harmonize quality assurance standards throughout

Europe; to have adequate support for microbiology and epidemiology training, laboratory infrastructure, data analysis and communication; and

to provide adequate funding for regional partnerships. Lack of funding was the principal obstacle

for existing systems. They concluded that further
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

28

discussions were necessary to develop collaboration

between existing programmes.

(22) Antimicrobial Resistance: Issues and Options.

Institute of Medicine Workshop Report (1998)

The report’s section on surveillance begins by stating that its purpose is to provide information for

action and that the information is “for several purposes at every level where health care is provided.

Each level has different needs and all are critical.”

Examples are given of the many kinds of questions

that need to be asked and a review of the problems

that have historically restricted efforts to monitor

antimicrobial resistance.

The report makes the statement in its summary

that: “No country, including the United States, has

a reliable, longitudinal, full-service antimicrobial

resistance surveillance programme with comprehensive focus, nor is there a comprehensive database

for monitoring trends in antimicrobial usage.”

A section on characteristics of an ideal resistance surveillance system indicates that it should be

prospective, active, timely and affordable, with the

broadest possible access. It should also provide

accurate incidence and prevalence rates, exclude repeat isolates, distinguish infecting and colonizing

organisms, and categorize data by location as well

as by hospital or community, urban or rural. In

addition, it should gather information on antimicrobial use and treatment outcomes (especially failure); detect new resistance markers; and use reliable,

standardized test methods on appropriate specimens

with validation. It should be a national network

representing inpatients and outpatients in all

regions with all participating laboratories computerized to collect, process, and report electronic data

continuously, with all such databases integrated

nationally, and regional and local data made available to practitioners. A separate section reemphasizes the need for local-level surveillance.

A section follows which describes several existing national surveillance systems, including: CDC’s,

The Surveillance Network (TSN), Canada’s, Iceland’s, and as international systems CEM/NET,

WHO initiatives, and SENTRY. This partially overlaps with a lengthier inventory added as Appendix

A.

Another section points out that surveillance data

are laboratory-dependent. It proceeds to give an

overview, based on extensive experience with quality control surveying largely in the US, of the kinds

of problems encountered in laboratory susceptibility testing. It emphasizes that there are few laboratories, even when central laboratories are included, where testing cannot stand improvement,

and an alarming number where improvement is

essential. The need to improve is not just for surveillance, but for the patients whose therapy is being guided by these tests.

In addressing what is needed the report summarizes why no single global or national antimicrobial resistance surveillance system has the

qualities outlined here. Few of the multiple existing surveillance activities have been longitudinal

and as a group they are almost totally uncoordinated and unstandardized, so the magnitude and

impact of resistance remain poorly understood and,

“...the most powerful case possible must be made

for urgent and substantial response.”

The report refers to the ASM Task Force of 1995

(see above), the recommendations of which it includes as Appendix B. It comments that even

though those recommendations are straightforward,

their elaboration and implementation will require

much coordination and compromise. “No single

system is likely to be able to perform the full range

of necessary surveillance, so that harmonization of

multiple systems and guidelines for the production

of comparable data will be ongoing challenges.”

“Real partnerships will be essential as people and

institutions with varying priorities try to achieve

goals that may be similar in many ways but divergent in others.”

(21) The British House of Lords Select Committee on

Science and Technology Report on Resistance to

Antibiotics and Other Antimicrobial Agents.

London (1998)

Chapter 5 of the report is on surveillance. Its first

9 paragraphs are on general reporting requirements

for infections and on liaison between agencies. Paragraphs 10–13 emphasize importance of information technology, citing NNISS and Intensive Care

Antimicrobial Epidemiology (ICARE). Paragraphs

14–17 discuss recent problems with professional

infrastructure and its funding in the UK, including declining financial support for the Public Health

Laboratory Service (PHLS).

The last 5 paragraphs cover a national strategy

for surveillance. Many groups agree that there is

no adequate systematic surveillance of resistance in

the UK now. Costs for such a system would be

modest but no source has provided funding. There

needs to be a consensus with PHLS, NHS,
29

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

academia and clinicians. The British Society for

Antimicrobial Chemotherapy (BSAC) has set up a

Working Party on Resistance Surveillance, which

has proposed a multi-level approach and is seeking

collaborative arrangements. The Minister for Public Health said, “We support a strategic approach

to this,” but was unable to make any commitment

as to resources.

In concluding their report, the Committee declares surveillance of resistance to be vital to the

fight against resistance. It makes multiple recommendations for surveillance, most of which are addressed to specific agencies or organizations in the

UK about resource allocation rather than to elements of system design. It does, however, stress the

importance of information technology in speeding

up exchange of compatible data locally, nationally,

and internationally. It also expresses approval of the

UK’s NNISS system, hopes that it can acquire data

on use of antimicrobials, and suggests it consider

the ICARE model.

(19) Report of the British Department of Health

Standing Medical Advisory Committee Subgroup

on Antimicrobial Resistance: The Path of Least

Resistance (1998)

This incisive and comprehensive report visualizes

a multi-level surveillance system that integrates

multiple methods of surveillance, “each cross-validating the other.” It summarizes and critiques what

exists at each level in the UK now and makes realistic suggestions about their improvement. It is extracted, at times nearly verbatim, below.

“Alert organism surveillance,” the detection of

organisms with significant new features, has a role

as an early warning system. It is in place now only

to the extent that such isolates find their way to

reference laboratories.

Reference laboratory elaboration of species or

of resistance mechanisms is often elegant now, but

interpretations of epidemiological significance are

beset by sampling problems and lack of a denominator.

Sentinel laboratory monitoring, meaning the

prospective collection of selected organisms for testing with standard methodology by a central laboratory, offers a high level of control but also lacks a

denominator population and can test only small

numbers of isolates.

Special surveys are a good tool, particularly if

they have prospective selection with a clinical case

definition in a defined population, but cannot be

performed for every organism and the costs are

considerable.

Compilation of routine susceptibility testing

data can be a measure of public health impact because these data do have a population denominator, but there remains the problem of non-standard

testing methodology. Such routine data represent

a huge untapped source of inexpensive, accessible

results, which could be analyzed at local, national,

and regional levels to give a measure of the public

health impact of antimicrobial resistance. The system envisaged is one fed by regular downloads from

laboratory computers of routine susceptibility data

on a wide range of organisms and specimen types.

The aim would be to encompass the whole; an

essential facet would be linking the data to population denominators. Although this is a new area of

work, the burden on individual laboratories would

be relatively low. Electronic downloading of data

directly from microbiology computer systems is the

ideal, and has been done in other places.

(30) Report from the American Academy of

Microbiology: Antimicrobial Resistance, An

Ecological Perspective (1999)

This report seeks to take a broad, ecological view

of antimicrobial resistance and its distribution in

the environment. This emphasis is given to much

of the discussion and to most of the recommendations for future scientific research. The ecological

approach is reflected in the section on surveillance

by the statements that “with respect to antimicrobial impact on the environment, surveillance

involves not only data on bacterial pathogens but

also data on other microorganisms that are part of

the affected ecosystem.” The report also states “Different types of surveillance are needed for each component of the biosphere.”

In discussing different existing types of surveillance it mentions sentinel surveillance for detecting

rare or important events. An ecological dimension

might be added to this if instead of noting only

strains categorized resistant by existing clinical

breakpoints resistance could also be defined by

lower “thresholds” of change in susceptibility that

would “provide a selective advantage to a microorganism or risk for evolution toward greater resistance.”

The report continues its discussion of resistance

surveillance methods by recognizing that special

studies conducted with prospectively defined

populations, e.g., surveying pharyngeal carriage of
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

30

pneumococci in a defined group of children, is

desirable but expensive because the survey has to

pay for the culturing.

The same is true for surveillance of clinical isolates by sending them to a remote reference laboratory for uniform testing.

It acknowledges that the bulk of surveillance data

will thus come from clinical isolate susceptibility

test results downloaded from routine clinical laboratory files. This approach has the potential disadvantage of variable test quality, but it costs little, is

rich in local epidemiological detail, and so supports

local management of resistance while being a component of regional or national surveillance. Analysis of the resulting stream of test results, moreover,

“can serve to continuously improve the quality of

the laboratory sampling and testing.”

Implicit, but not stated in this discussion, are

two ways to enhance the value of such clinical

isolate data for generating ecological or environmental insights. One would be to not screen out

non-pathogens from surveillance databases, as is

sometimes suggested, but only exclude them from

particular analyses. The other, as supported above

for many other reasons, would be to file only full

range measurements of isolate susceptibility (inhibition zone diameters or full-range MICs) rather

than just the interpretive categories derived from

those measurements. This would allow continuous

monitoring of the small increments in resistance

(e.g., creeping resistance by accumulating mutations

to fluoroquinolones) that may “provide a selective

advantage....or risk evolution toward greater resistance.”

(31) US Interagency Task Force for a Public Health

Action Plan to Combat Antimicrobial Resistance

(2000)

Based on a public meeting held in Atlanta, Georgia, in July 1999, with representatives of CDC,

FDA, NIH, AHRQ, USDA, DoD, DVA, EPA,

HCFA, and HRSA and many other groups, the plan

lists issues, goals and actions that apply mostly to

human (as opposed to non-human, such as agricultural) antimicrobial resistance (AR) issues. For

each action item “coordinator” and “collaborator”

agencies/departments are specified. Its Executive

Summary lists under 4 major headings 11 top

priority action items to combat antimicrobial resistance. The first of the 4 headings is “Surveillance”,

with 2 priority items under it:

“With partners design and implement a national

AR surveillance plan that defines, national, regional,

state and local surveillance activities; the roles of

clinical, reference, public health, and veterinary

laboratories; and is consistent with local or national

surveillance methodology and infrastructure that

currently exist or are being developed”.

“Develop and implement procedures for monitoring patterns of antimicrobial drug use in human

medicine, in agriculture, and in consumer products.”

The section on surveillance in the report states:

“At present the United States lacks a coordinated

national plan for AR surveillance” and “Improved

AR surveillance depends upon enhanced epidemiologic and laboratory capabilities at local, state and

national levels, use of standardized and reliable laboratory testing methods, and enhanced use of

informatics.”

The remainder of the section is an extensive

outline of the general needs for developing and

implementing such a comprehensive system. The

first block deals largely with allocation of general

categories of tasks to specific coordinators and collaborators.

The second block is on the development of

standards and methodologies. It includes “standardized laboratory methodologies and data elements

that allow susceptibility test results and AR surveillance data to be compared across geographic

jurisdictions. Similarly, use standardized definitions

and methodology to create an electronic surveillance system that health care institutions can use

to compare AR data from other local facilities.”

It also calls for development of “standards for

reporting quantitative data (e.g., MICs or zone diameters) in ways that will detect decreased susceptibility.” This is necessary because numerical AR

test results reported non-quantitatively (e.g., as susceptible, intermediate or resistant) as “susceptible”

may mask an emerging AR problem (i.e., microbes

with a small decrease in susceptibility may still be

classified as susceptible).

A block is devoted to the need, little mentioned

in previous reports, to allow the data within such a

surveillance system to comply with patient confidentiality policy. Subsequent sections recommend

work to ensure that this is possible and to develop

new policy if needed.

Other recommendations follow, such as: “Link

human drug-use data to clinical information (e.g.,

diagnosis, severity of illness and outcome). “Work

with accrediting agencies to address antimicrobial
31

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

drug-use monitoring as part of quality control assurance in health care delivery systems.” “Evaluate

the performance of licensed, automated AR testing devices in the context of changing resistance

patterns and update their labeling where appropriate (e.g., changes in quantitative resistance that may

make a test result invalid).”

Under a section on state health and agricultural

agencies is the recommendation that they “maintain the capacity to test the drug-susceptibility patterns of resistant organisms of public health

importance, especially for drug-microorganism

combinations for which testing methods are not

routinely available at hospital and commercial laboratories.”

A section on dissemination of surveillance data

recommends: “Provide an accessible, centralized

source of AR data from major surveillance systems

involving animal and human populations. In consultation with stakeholders determine how to report AR data in a way that is useful to interested

parties (e.g., clinicians, public health officials,

veterinarians, and researchers). Include sufficient

detail in surveillance reports to permit local analysis and comparison with trends in drug use and

medical and agricultural practices.”

A final section on monitoring AR in agricultural

settings recommends expansion of the National

Antimicrobial Resistance Monitoring System

(NARMS) and extension of its sampling to monitor transmission of resistant infections. It also recommends monitoring of fruit and vegetable

production and of environmental contamination

by antimicrobial drug residues and drug-resistant

organisms that enter the soil from human and animal waste.

CHAPTER II

Increase awareness: optimize patient

and provider behaviour

Jerry L. Avorn

• Minimal or nonexistent training of children at

all levels of education in relation to health habits

• Aggressive marketing of antibiotics and

antibacterials to both physicians and patients

• Inadequate or nonexistent continuing education

requirements concerning infection control and

antibiotic utilization for most health professionals.

This chapter reviews the barriers for changing

physician and patient behaviour and suggests

effective intervention strategies.

Disincentives and barriers to overcome

A number of specific problems have been identified that present obstacles to the development and

dissemination of effective programmes of prescriber

and patient education concerning the prudent use

of antibiotics (7,21,22,39). These include:

• Inadequate support for publicly financed educational programmes for either professionals or

lay people

• Strong commercial pressures from manufacturers to increase utilization of antibiotics and

antibacterials

• Low levels of literacy in the developing world,

limiting the impact of verbally-based public education messages

• Fear of litigation in the United States which encourages the practice of “defensive medicine”,

often leading to prescription of an antibiotic

when one may not be necessary

• Pressures to shorten the length of a physician

visit, which in turn increases pressure for antibiotic utilization as a time-efficient means of

ending the visit

• Poor regulation in the developing world of claims

made in promotional materials for antibiotics

• Physicians’ desire for autonomy, which can make

Abstract

Considerable evidence points to widespread problems in knowledge, attitudes, and behaviour relating to antibiotic use among both patients and

prescribers in the industrialized and the developing worlds (19,32,33,34). Such evidence is drawn

from numerous sources:

• Inappropriate patterns of antibiotic use for a

variety of specific clinical conditions:

— Use of antibiotics to treat symptoms that are

clearly viral in nature

— Reliance on excessively broad-spectrum antibiotics when narrower-spectrum agents

would be more appropriate

— Errors in the timing and duration of antibiotic prophylaxis at the time of surgery

— Poor adherence by patients to prescribed

antibiotic regimens, including premature

cessation of therapy and “hoarding” antibiotics for future unsupervised use

• In the developing world, widespread use of antibiotic injections when not clinically indicated

• Erroneous responses by patients and physicians

to surveys concerning antibiotic knowledge and

attitudes

• Under-use by physicians and consumers of

proven non-antibiotic means of infection control, such as hand washing

• Growing consumer demand for “antibacterial”

cleaning preparations which can actually increase

bacterial resistance

• Low levels of use of products that can provide

safe, effective alternatives to antibiotic use to

combat infection, such as condoms, bednets in

malaria-prone areas, vaccines.

The causes of such educational and behavioural

deficits have also been well identified (8,35–38).

They include:

• Inadequate training of health professionals in

rational antibiotic use (and non-use)

33

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

34

them disinclined to accept guidelines or antibiotic restrictions.

Educational strategies which have been

shown to be ineffective

One approach stands out as having remarkably little effect in altering antibiotic use. This approach,

the simple dissemination of printed guidelines or

educational messages, without other reinforcement,

is unfortunately among the most commonly used.

This has now been studied in a variety of

randomized controlled trial settings with strikingly

consistent results: physicians who are mailed printed

information on proper prescribing, but who do not

receive any other kind of intervention, in general

do not change their practice any more than physicians randomized to a control group (40). The fact

that this finding has been so consistently reported

makes it even more disturbing that this approach

is probably the single most frequently employed

strategy for changing antibiotic prescribing.

Another common approach, that of having an

expert lecture a passive audience with minimal

opportunity for interaction, has also been reportedly shown to result in little or no change in medication use behaviour.

Fortunately, other methods of improving antibiotic utilization have been well studied and found

to reliably improve the appropriateness of prescribing. These are described in the section that follows.

While the term “appropriate antibiotic use” will be

used consistently, it should be pointed out that such

broadly-defined education would also include such

topics as the appropriate use of vaccines and the

use of alternative methods of infection control, such

as hand washing.

Strategies which have been demonstrated

to be effective in improving the

appropriateness of antibiotic use

Most studies and published recommendations have

considered education and behaviour change interventions separately by the audience targeted:

patients, prescribers, or (in the developing world)

non-physician drug vendors. These categories will

be used in the sections which follow. However, it is

evident that the ideal approach would constitute a

combination strategy aimed at both the prescribers and the users of antibiotics. In fact, some

recent research has shown that such a “doublebarrelled” targeting of both audiences can produce

a synergistic effect much greater than that achieved

by addressing either audience separately.

Another overarching principle evident in many

studies and policy recommendations on improvement of medication use is the concept that education/behaviour change interventions should be

tailored to the specific circumstances and needs of

the audience, rather than presenting a “one size fits

all” formula which may not resonate with the individual experience of the targeted prescriber or

patient.

Ideally, programmes to change behaviour of

patients, physicians, or lay caregivers should be

grounded in solid behavioural science theory and

experience, as well as (equally practically) the theory

and experience of marketing (41). Specific theories relevant to the reduction in antibiotic misuse

include the PRECEDE model, which considers

factors that encourage or prevent behaviour change,

and the Transtheoretical Model, which takes into

account the various cognitive and behavioural stages

associated with adopting changes in a specific area

(42,43).

While it is not easy to reduce inappropriate antimicrobial use, some encouraging data exists about

the efficacy of some programmes in improving

problematic practices. Overall, there is good news

about the efficacy of such programmes in improving drug use. In a review of 59 studies of interventions to improve medication use (primarily

antibiotics) in the developing world, Ross-Degnan

(44) found that among studies which had an evaluation design adequate to permit comparison of

outcomes, 43% of studies had an impact classified

as “large” (>25% improvement compared to controls), and 36% had a moderate impact (10–25%

improvement compared to controls). Only 21% of

the studies had low or no impact (<10% improvement). The most common approach in this latter

group of minimal impact was the dissemination of

printed materials recommending rational utilization.

Interventions directed at prescribers

In that review (44), the following types of interventions were found to produce significant improvements in prescribing, as measured in

randomized intervention trials:

• Multiple training modalities applied together

(group problem-solving, role playing, lectures,

opportunity to practice skills)

• Focusing on one clinical issue at a time
35

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• Training at the work site

• Use of opinion leaders or district-level staff as

trainers

• Repeated sessions focusing on reinforcement of

the message

• Community-based case management interventions (their use in acute respiratory infections

and diarrhoea was so effective that a mortality

benefit could be demonstrated).

Administrative interventions were found to work

well in improving antibiotic utilization if they had

the following attributes:

• Were based on group process

• Involved ongoing supervision and monitoring

of practice

• Provided regular audit and feedback of prescribing patterns.

In a similar evaluation, Laing and Hogerzeil (unpublished) reviewed the experience of a number of

programmes in the developing world and concluded

that the following strategies had strong records of

success in improving prescribing of antibiotics and

other drugs:

• The development and effective dissemination of

lists of essential drugs and standardized treatment guidelines

• The creation and empowerment of pharmacy

and therapeutics committees in hospitals

• Problem-oriented training

• Targeted in-service training of health workers.

In addition to these observations about effective strategies, consensus has also developed concerning the clinical content of programmes to

improve antibiotic use. Some of these are quite

straightforward, such as the basic British recommendations advocated as a simple starting-point

for reducing inappropriate antibiotic use (20):

• Avoid antibiotics for simple coughs and colds

• Do not use antibiotics for the treatment of viral

sore throat

• Limit antibiotic use in uncomplicated cystitis in

healthy women to three days

• Limit telephone prescription of antibiotics to

exceptional cases only.

Other recommended content areas for such antibiotic education programmes are equally straightforward, and contain messages such as the following:

• Do not use broad-spectrum antibiotics when

narrower-spectrum agents would work as well

• Base the antibiotic prescription on culture

results whenever possible

• Modify the regimen over time as required

• Consider cost-effectiveness in choosing an antibiotic regimen.

In the industrialized world, computers have been

put to good use in guiding choices of antibiotics

for hospitalized patients. In one system, a computer “consultant” is given all pertinent facts concerning a patient’s infection and clinical condition, and

then offers antibiotic recommendations. These have

been found to have a very high degree of clinical

accuracy when compared with the “gold standard”

recommendations of infectious disease specialists

(45).

The ordering of all medications, including antibiotics, on computer terminals will become common in many institutions in the industrialized

world over the next few years. Initial experience

with such systems in hospitals where they are already in place indicates that they can be used to

good advantage in reducing antibiotic utilization

by reminding the ordering physician at the time the

order is being written that such a choice is not in

conformance with available evidence and/or institutional guidelines, and offering more reasonable

alternatives. Such systems can also be used to flag

orders which require further consultation or approval by an infectious disease consultant (46,47).

Other educational approaches less dependent on

technology have also been demonstrated to be

effective in improving antibiotic use. In the 1980s,

researchers in the United States began to apply the

powerful behaviour change interventions employed

by the pharmaceutical industry, but put in the service of restrained prescribing rather than promotion

of sales of a given product. In this approach, which

came to be known as “academic detailing,” clinician/educators were trained from a medical school

base to become expert in the drug therapy required

for specific conditions, and also received training

in strategies of “social marketing” and behaviour

change. These educational outreach workers were

then sent to visit with physicians in their offices at

a convenient time, much as industry sales representatives do. They presented the need for appro-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

36

priate prescribing in terms which were concise,

clinically relevant, and behaviourally appropriate;

the presentation was supplemented by engaging,

well-designed, graphic print materials. Initially, such

educational outreach workers were primarily pharmacists, but this role has also been filled effectively

by physicians, nurses, and—in the developing

world—by lay people as well. The communication

is designed to be interactive rather than didactic,

which offers the educator an opportunity to understand the specific informational and attitudinal

situation of the targeted prescriber and to modify

the educational session accordingly. Following its

initial demonstration in the United States, this

approach has spread throughout the world, and has

been found to be equally effective in both industrialized countries and the developing world. In April

1997, a four-day conference in Chiang Mai, Thailand, focused on improving medications in the

developing world; a number of such successful programmes were described in detail. Cost-benefit

analyses have demonstrated that such programmes

can save more than twice their expenses in terms of

reduction of unnecessary prescribing (44).

Education of students in the health

professions

Current training about rational antibiotic use is

widely regarded as inadequate in most pre-professional settings throughout the world. More relevant

and critical education about infection control and

treatment has been called for not just for medical

students, but also for students of nursing, pharmacy, and veterinary medicine. Beyond the specific scientific content in pharmacology and

microbiology that must be taught, students also

need to be taught to critically evaluate promotional

materials for medications to become more “media

savvy” in evaluating printed advertisements and

prepared to ask the right questions during sales presentations for antibiotics. Problem-based education

has been found by many health professions educators to be a useful and powerful method of communicating such information.

Interventions directed at patients,

families, and consumers

The patient is a vital link in the pathway of antibiotic utilization; it is often patient demand which

triggers inappropriate antibiotic prescribing in the

first place. Because of this, and because of the central role played by the patient (or parent of a

pediatric patient) in the implementation of antibiotic regimens, strategies directed at consumers can

be of particular importance in reducing antibiotic

use (48). Such education can take numerous forms:

• In pediatrics, caregivers can be educated to recognize patterns of symptoms that can indicate

whether a child should be brought in for medical care and potentially for an antibiotic prescription. Such education encourages appropriate

utilization and discourages inappropriate use.

• Better recognition of the symptoms of malaria

can allow for earlier referral to a health care professional, earlier diagnosis, and treatment.

• Education about the non-drug management of

routine diarrhoea in children (e.g., with oral rehydration solutions) can replace unnecessary referrals to scarce medical resources, as well as

inappropriate requests for antibiotics.

• In adults, conditions susceptible to such education about appropriate health-seeking behaviour

include viral upper respiratory symptoms, vaginitis, and recognition of the early symptoms of

Human Immunodeficiency Virus (HIV), among

others.

Public education programmes have focused on

broad themes, such as the lack of utility of antibiotics in viral conditions and the need to adhere

carefully to the prescribed regimen if an antibiotic

is ordered, rather than starting or stopping therapy

on an as-needed basis.

A particularly interesting approach has been

taken in the United Kingdom to encourage the

public to “cherish and conserve your natural flora,”

pointing out the beneficial aspects of bacteria which

can be obliterated by excessive antibiotic use. Other

groups have advocated the education of the public

concerning the risks of unnecessary antibiotic use

in animals and agriculture as well as humans; the

Alliance for the Prudent Use of Antibiotics (APUA)

has been particularly active in this regard.

Other audiences for interventions

Beyond the obvious targets of physicians and patients, other important groups have been identified as appropriate audiences for education about

antibiotic use, including workers in day care centres, schoolteachers, those who work in agriculture,

and policy-makers in all these areas as well as health

care.
37

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

System-wide interventions

In addition to strategies directed at prescribers and

patients, a number of effective educational strategies have targeted the health care delivery system

itself, whether in the form of governmental health

care services or private sector health practices or

systems. This section will not deal with regulatory

approaches to improve the antibiotic use, which

are discussed elsewhere in this report (See Chapter

III). Rather, it will focus on means of educating

the participants and leaders of such systems in order to encourage them to adopt more enlightened

policies at a systems level (31,49).

• The creation of drugs and therapeutics committees (or pharmacy and therapeutics committees)

can be a very useful strategy at the level of individual health centres as well as at the level of

national health care programmes. Such groups

can evaluate all available evidence concerning

utilization data, resistance patterns, efficacy, and

cost, in order to make recommendations for

proper antibiotic use which are appropriate to a

particular clinical setting and population.

• Dissemination of essential drug lists, such as

those promulgated by the World Health Organization (WHO), can help simplify antibiotic

choices for practitioners as well as make them

more clinically appropriate and cost-effective.

• Facilitation of communication among academic

institutions, government agencies, those who pay

for health care, and pharmaceutical manufacturers can sometimes reduce the extent to which

such entities act at cross purposes in relation to

one another in relation to antibiotic use and

infection control.

• Beyond the drug lists themselves, guidelines for

the use (or non-use) of antibiotics in particular

situations can improve the rationality of prescribing. For maximum benefit, such guidelines

should be:

— Evidence-based

— Appropriate to the clinical and microbiological issues relevant to a given population

— Developed with the involvement of the practitioners (and potentially the patients) who

will be using them

— Disseminated not simply via printed memoranda, but rather through the use of interactive strategies oriented to changes in behaviour,

as described elsewhere in this section.

A number of strategies for improving the knowledge base of physicians and the public concerning

antibiotic use have pointed to the need for capacity building on a number of fronts to make such

programmes possible. Such infrastructure requirements fall into several categories. First among these

is the capacity to devise, validate, and modify evidence-based guidelines on rational antibiotic use,

since this is necessary to provide the content needed

to drive any educational programme. These programmes can be governmentally sponsored, as is

the case with the British National Institute for Clinical Excellence (NICE), or the guidelines development process of the US Agency for Health Care

Policy and Research before it was disbanded under

political pressure several years ago. Similar activities have been conducted by the US Centers for

Disease Control and Prevention as well as WHO,

and antibiotic guidelines have been widely disseminated in Australia. In addition, professional societies have also developed their own evidence-based

guidelines for appropriate antibiotic use. These have

included the American Society for Microbiology,

and a variety of specialty societies (e.g., the American Heart Association guidelines for the use of prophylactic antibiotics in patients with valvular heart

disease, or the American College of Gastroenterology recommendations concerning regimens for the

eradication of H. pylori infection).

WHO has identified a number of other infrastructure-related issues that bear directly on the

capacity to mount successful educational programmes concerning antibiotics. These include:

• Control of the promotional activities of drug

manufacturers

• Training of a new category of health professional,

the antimicrobial resistance manager/monitor

(ARM), to serve as a local resource to follow the

current literature on antibiotic resistance,

analyse local data, propose and implement strategies for control and resistance, and work with

clinicians on the care of specific patients

• Development and enforcement of ethical standards concerning advertising of antibiotics

• Analysis of data on local resistance patterns

• Communication of global trends in antibiotic

resistance with potential local impact

• Development of information systems to monitor and feed back data on utilization and resistance patterns.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

38

Similarly, the US Agency for International

Development (USAID) (39) has also focused on

the need to build local capacity in developing countries to provide the infrastructure needed to encourage rational antibiotic use. This includes training

of personnel and creation of systems to:

• Perform surveillance

• Manage data

• Conduct educational programmes

• Choose which antibiotics to purchase

• Develop policies concerning regulation, reimbursement, and financing of antibiotic purchases

• Provide unbiased drug information

• Establish field sites for innovative demonstration projects (e.g., tuberculosis surveillance and

control)

• Train microbiology laboratory personnel

• Prepare training and advocacy materials for

local government officials on the burden of

disease related to resistance and the need for

specific programmes to combat it

• Develop and enforce quality control standards

for drug manufacturing and microbiology laboratories.

Internet access makes it possible for patients and

practitioners throughout the world to have instantaneous access to current information about medications, patterns of resistance, and other data

relevant to appropriate antibiotic use. One such

guide has been made available on the Internet

through WHO (http://www.who.int). For other

relevant web sites see the section, Some Useful Web

Sites.

Conclusions

Just as considerable progress has been made in

microbiology and clinical infectious diseases in the

last two decades, similar progress has been made

during this period in understanding why antibiotics are misused by prescribers and by patients, and,

equally important, which strategies are most effective in preventing such misuse. Rigorous data are

available describing the effect of such innovative

programmes in patient and caregiver education,

computer-based prescribing guidelines, academic

detailing of prescribers, and community-oriented

educational programmes; such studies have amply

demonstrated their utility and, for some, even their

cost-effectiveness. Similarly consistent data are available describing the poor track record of many conventional practices in changing practice patterns,

such as the mailed transmission of expert guidelines. It is unfortunately true that such older, conventional practices remain the norm, while more

innovative programmes, though becoming more

widely adopted each year, still form the minority

of intervention programmes. This is probably the

combined result of habit and tradition, as well as

the lower costs required to conduct programmes

that are print-only in nature, and skepticism concerning the cost-effectiveness of more interactive

person-based programmes. As the stakes become

higher each year in terms of the clinical and economic consequences of antibiotic misuse, it is to

be hoped that educational interventions in this

arena are subjected to the same critical evaluation

and evidence-based use as are the medications

whose utilization they attempt to improve.
39

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

CHAPTER III

Strengthen sanitation, infection control,

and regulatory measures

Peter G. Davey

• Failure to cleanse hands after each patient contact

• Limited use of gloves and gowns

• Lack of sterile supplies and poor sterilization

practices

• Increased movement of patients within and between hospitals.

There is a broad consensus among the expert

policy groups (see Table B) on the need to establish

an infection control programme in order to more

effectively control hospital infections. Elements of

such a programme identified in the reports are:

• Surveillance of infection

• Identification of outbreaks

• Implementation of effective control measures

(e.g., hand washing, gowns)

• Sterilization and disinfection of equipment and

supplies.

Most of the reports reviewed recommended

some form of a committee or programme to be responsible for the improvement of infection control. The general statements about infection control

improvements within hospitals need to be supplemented by the specific recommendations for improvement of infection control which were

addressed in some of the previous expert reports

(see Tables C and D). Developing countries in particular face the challenge of improving their public

health infrastructure, community sanitation and

health education in order to decrease the emergence

and spread of infections. This is a priority need in

order to decrease the spread of resistant organisms.

All countries could improve education of health care

and day care workers (5,49). The previous expert

reports also make strong recommendations about

mandating hospital infection control within purchasing and commissioning agreements (see Tables

C and D).

Abstract

Governmental and private health management systems, at national, regional, and local levels provide

the basis for the delivery of health care. These systems are critical to the curtailment of antimicrobial resistance because they help determine the

availability and usage of antimicrobials. They also

play a role in developing and enforcing programmes

to reduce the spread of microbial infections,

whether in hospitals or in the community.

Limiting microbial infections is a key step towards the goal of reducing the current prevalence

of antimicrobial-resistant organisms. The responsibility of carrying out the daily routines of infection control and sanitation programmes falls to

hospital management and health care providers.

These routines range from proper hand washing to

reporting surveillance data.

This chapter reviews the expert groups’ (1,5,6,7,

11,13,19,20,21,22,24) findings and strategies relating to 1) sanitation and infection control, and

2) government and health system regulation. This

review outlines what is covered in previous expert

policy reports, and provides guidelines from the

expert policy groups on a global strategy. The review also designates specific programme components and models that countries might consider in

developing their national strategies for infection

control and regulation of antibiotics. Areas of concern from previous reports and additional recommendations from the expert policy reports are

noted.

I. Sanitation and infection control

Control and prevention of microbial infections and

improved sanitation in the health care setting are

imperative to decrease the spread of resistant

organisms and minimize the need for antibiotics.

As cited in the expert reports reviewed (1,5,6,7,

11,13,19,20,21,22,24) (Table A), the major factors contributing to the spread of infection and

antibiotic resistance transfer in health care settings

are:
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

40

Other national models for antibiotic resistance

intervention

Several programmes and guidelines related to health

care management and the control of infections have

been developed after most of the policy reports were

published. Since infection control is a key strategy

in containing antibiotic resistance, local governments and professional societies could consider

adapting the following programmes to their own

needs, within the limits of available resources (other

examples of local initiatives are outlined in Appendix B).

• The epic project: Developing National EvidenceBased Guidelines for Preventing HealthcareAssociated Infections. The epic project has

developed guidelines, approved by the UK

Department of Health, which include the following topics: standard principles (hospital environmental hygiene, hand hygiene, the use of

personal protective equipment, and the use and

disposal of sharps); short-term indwelling urethral

catheters in acute care; and central venous catheters. The guidelines are targeted at the United

Kingdom and are thought to be practical and

affordable within that context. However, the

structure of the guidelines would facilitate

adaptation to other countries, including developing countries. The second phase of the epic

programme will concentrate on control of infection in the community. More information can

be found at the following web site: http://

www.epic.tvu.ac.uk/

• The HELICS project: (Hospitals in Europe Link

for Infection Control Through Surveillance).

HELICS has produced infection control recommendations for hospitals in the European

Union (EU), annexes describing various national

infection control programmes, and the current

national policies concerning antibiotic resistance

from each EU member state. This information

can be found at the Nosocomial Infection Control in Europe web site (http://helics.univlyon1.fr).

Summary and conclusions: infection control

experiences

The statements about hospital infection from the

various expert reports discuss important actions at

the local and national level to curb antibiotic resistance. This author suggests that they should be

followed by these specific actions:

• Adapt for local use the HELICS Methodology for Measuring the Status Quo for National Initiatives in Infection

Control

This is consistent with the recommendation

from the WHO Scientific Working Group (5):

“Develop methods and standards for evaluating

hospital infection and antimicrobial resistance

control programmes, leading ultimately to

national accreditation systems.”

• Adapt the epic Evidence Based Guidelines (http://

helics.univ-lyon1.fr) for implementation in other countries

The evidence reviewed in these guidelines is a

comprehensive review of the published world

literature. However, there may be existing local

guidelines that could be reviewed and incorporated into country-specific guidelines. These

would also need to take account of existing clinical practices and facilities.

• Encourage governments to accept accountability for

infection control at the national level by making hospital management accountable for local implementation

This direction is consistent with the recommendation from the WHO Scientific Working

Group (5): “Link the prevention and control of

antimicrobial resistant organisms in hospital to

national and local quality assurance efforts.”

The concept of clinical governance is having considerable impact in the United Kingdom. The

UK Government has put infection control and

antimicrobial resistance into the list of national

priorities for public health, and used initiatives

on clinical governance to make it clear to hospital management that they are responsible for

action in their hospitals. This approach is now

being extended to managers responsible for community health services.

• Emphasize the importance of infection control in the

community

In addition to the recommendations of the

WHO Scientific Working Group (5), development of related interventions to contain antimicrobial resistance in the community include

educational programmes and hygienic standards

for day care and extended-care facilities, and

promotion of hygiene in the community, including safe water and food hygiene.

As noted in the UK House of Lords report (21),

infection control beyond the hospital is an area

of particular weakness. Communities should
41

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

consider improvements in antibiotic use and

infection control in nursing and residential

homes, which can act as reservoirs of methicillin-resistant Staphylococcus aureus and other resistant organisms which are carried back and

forth between the hospital and the community.

II. Regulatory measures

The regulations developed and enforced by governmental and health organizations can have a very

large impact on the use of antibiotics and the prevalence of antibiotic-resistant bacteria. The need to

develop strong national health system regulations

is mentioned in many of the expert reports (see

TABLE 1. LAWS AND REGULATIONS PERTAINING TO ANTIBIOTICS (ADAPTED FROM 19)

Category and designation Basis for assignment

A. Comprehensive 1. No free sale allowed.

2. Professional limits placed on prescription practices by law.

3. Statutory control of advertising; no advertising allowed to lay public.

4. Content of advertising limited by law.

B. Partial 1. No free sale allowed.

2. At least one of controls 2-4 above.

C. Minimal 1. No free sale allowed.

2. None of controls 2–4 above.

D. None 1. Free sale allowed without any restrictions.

Application in practice and enforcement of compliance with regulation

A. Complete Tightly controlled availability; regulations rigorously enforced.

B. Partial Incomplete enforcement of controls, associated with limited availability of antibiotics to the

public for other reasons, such as economics and/or logistic factors.

C. Minimal Incomplete enforcement of controls, associated with widespread availability of antibiotics as a

result of failure to apply regulations in practice, and absence of other constraining factors.

D. None No restrictive legislation; widespread availability.

TABLE 2. GROUPING OF 35 COUNTRIESa BY LAWS/REGULATIONS AND ENFORCEMENT/COMPLIANCE ASSESSED BY

QUESTIONNAIRE IN 1986.

Laws/Regulationsb Enforcement/compliance 1986

1. Complete 2. Partial 3. Minimal 4. None

Comprehensive 11 (31.4%) 2 (0.6%) 5 (14.3%) 1 (0.3%)

Partial 2 (0.6%) 1 (0.3%) 3 (0.9%) 1 (0.3%)

Minimal 2 (0.3%) 1 (0.3%)

None 6 (1.7%)

Source: Levy SB, Burke JP, Wallace CK (1)

a Countries were selected from Eastern and Western Europe; North, Central and South America; Africa; Asia and Oceania. Data were reported

anonymously (locality within each category not reported).

b See Table 1 for an explanation of categories of Laws/Regulations and Enforcement/Compliance.

Table E). Major issues cited by the WHO report

(50) include the following:

• Lack of regulation and informal sector sales of

antibiotics

• Absence of lists of essential drugs

• Absence of national standard treatment guidelines

• Poor communication and implementation of

national policies

• Ineffective regulatory mechanisms.

A helpful classification of regulatory mechanisms

and their implementation is given in “Task Force

Reports on Antibiotic Use Worldwide.”(1). The
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

42

report reviewed policies about antibiotics in thirtyfive countries and found that only eleven (31%)

had comprehensive laws and regulations that were

completely enforced (Tables 1 and 2). This evidence

supports the need for more effective regulatory

mechanisms. The data in “Task Force Reports” are

nearly fifteen years old; nonetheless, there is broad

consensus among the experts on the need to address the five problems listed above (see Table E).

There is also broad historical consensus in support

of effective national regulation of antibiotic quality, dissemination, and promotion.

Elements of a national policy to combat antibiotic

resistance

Additional regulatory recommendations proposed

in the recent WHO report (50) are also repeatedly

suggested by previous expert reports (see Table F)

and suggest a basic framework that each country

should establish to minimize the emergence and

spread of antibiotic resistance in their country:

• Adopt the WHO model legal framework for

antimicrobial licensing, sale, supply, distribution,

and promotion

• Introduce legal requirements for collection of

data on antimicrobial production, distribution,

sales, and consumption in human, veterinary,

and agricultural use

• Introduce formal training for personnel in antimicrobial dispensing outlets and registration

schemes for such outlets.

Additionally, the WHO document (50) makes

the following recommendation: “identify and eliminate economic incentives (i.e., reimbursement practices) that encourage inappropriate antimicrobial

use.” This recommendation was apparently overlooked by the other expert policy groups and is only

endorsed by one of the other documents (6, Table

F). Nonetheless, it is an important global issue and

a key consideration for national governments

attempting to control antibiotic use.

Finally, the importance of involving international organizations is noted in the WHO

recommendation: “Target advocacy for action

encouraging prudent use of antimicrobials among

relevant organizations, such as the World Trade

Organization, the World Bank and the International Monetary Fund” (50).

Additional issues concerning government and health

management systems

Additional specific issues and recommendations

from individual expert reports fall into two main

areas (detailed in Tables G and H). The first area

concerns suggestions for additional legislation to

improve the prudent use of antimicrobials, for example, granting antimicrobial use licenses contingent upon implementing antimicrobial-use

monitoring programmes, or, where applicable,

adjusting subsidies for antibiotics to encourage a

more prudent use (20,51).

The second area concerns legal issues that may

impact implementation of infection control or antimicrobial use measures. One example is improving personal human rights laws, especially in

developing countries, so that they have a positive

impact on a population’s public health (19,51). The

document by Fidler (51), is a particularly rich source

of issues about legislation, encompassing trade regulations, patient rights, data privacy, and patent protection.

Another example is creating economic incentives

for pharmaceutical companies to develop new antimicrobial medications (51). The listed statements

also include good practice guidelines for antimicrobial use, such as assisting poorer countries to

gain supplies of appropriate antimicrobials, as well

as creating international alert systems concerning

antimicrobial resistance (7,49,51).

Conclusions: Regulatory measures

In the management of distribution, availability and

use of antimicrobials, several factors—legal, economic, and scientific—should be considered, as

summarized below:

• Development of guidance documents by government

and health systems on policies for antimicrobial use

Local ownership of guidelines adds to their success. Guidelines can be applied to infection control and can also be part of general antibiotic

policies, where local microbial epidemiology can

justify variations in prescribing and where there

are legitimate concerns about the selection pressures created by uniform national prescribing

policies. These guidance documents should be

readily adaptable for use in developing countries.

• Assessment of policies, laws, and regulations and their

implementation

The 1987 report by the US Department of

Health and Human Services (1) could be up-
43

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

dated. The original report did not reveal the

identity of the countries that submitted data.

This author would query whether secrecy about

such an important global issue either necessary

or justifiable.

• Review opportunities for improving prudent use of antibiotics by changing the licensing process

Extend patents in exchange for industry support

of programmes to limit the use of antibiotics

and support license extension of older drugs with

activity against resistant pathogens through fast

tracking or orphan drug programmes.

• Investigate the effect of changes in reimbursement policies on prudent use of antibiotics and on surveillance of

prescribing or resistance

This is an important recommendation in “Containing Antimicrobial Resistance”(50) but does

not appear in the other WHO documents. It is

endorsed by US Congress Office of Technology

Assessment (6), which identifies a potential

problem with Medicaid and Medicare reimbursement policies. This issue deserves wider

consideration in a global context. In addition to

considering reimbursement for prescribing, the

extent to which privatization of laboratories

threatens the surveillance of antibiotic resistance

or infection control should be investigated.

• Consider recommendations (51) about trade restrictions

against countries that systematically neglect recognized

principles and practices for antimicrobial use

In the context of environmental protection, trade

restrictions seeking to change a production process in another country, rather than to protect

against health dangers from a particular product, have been ruled incompatible with international trade law. As part of a general strategy to

combat antimicrobial misuse, legitimate trade

restrictions against countries that systematically

neglect recognized principles and practices for

antimicrobial use might be considered; such a

move would elevate the status of Codex’s Code

of Practice for Control of the Use of Veterinary

Drugs and Guidelines for the Establishment of

a Regulatory Program for Control of Veterinary

Drug Residues in Foods (52), in the same way

as the Sanitary Phytosanitary (SPS) Agreement has

elevated the importance of Codex’s Maximum

Residue Levels for Veterinary Drugs in Foods.

• Identify opportunities to link financial incentives to implementation of policies at the national or regional level

In the United States the most powerful strategy

would be to make implementation of state policies to curb the misuse of antimicrobial drugs

mandatory before states receive federal funds

earmarked for public health. Similar opportunities should be explored in other countries.

• Investigate methods for mandating technical or financial support from developed countries to developing

countries

Fulfilment of legal duties often hinges on sufficient resources. In many developing countries,

public health systems may be inadequate. Thus,

financial and technical leadership is needed from

national governments towards local authorities,

and from international organizations towards developing countries. A precedent can be found

in the proposed Convention on the Provision

of Telecommunication Resources for Disaster

Mitigation and Relief Operations, which obligates the parties, where possible, to lower or

remove regulatory barriers for using telecommunication resources during disasters.

• Investigate international law on personal control and

data protection issues relating to antimicrobial resistance

At a time when antimicrobial resistance may have

created a greater need for personal control measures for public health (e.g., with multidrugresistant tuberculosis), the status of international

law on the scope and nature of a government’s

power to undertake such measures should be

reviewed. Lessons from international environmental efforts suggest that international law

must play a major role in setting international

standards for implementation at the national

level, and creating the political, technical, and

financial conditions necessary to integrate international and national law.

• Build on experience in EU countries of legislation against

use of antibiotics in growth promotion

The EU has passed legislation to eliminate antibiotics that are used in humans from being used

as growth promoters in animal feeds. However,

Denmark and Sweden have banned growth promoters entirely. If other governments are to follow that lead, they will need to be reassured that

there are no adverse economic consequences.

Therefore, data about the impact of legislation

in Denmark and Sweden should be collected and

publicized (see also Chapter V).
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

44

TABLE A. SANITATION AND INFECTION CONTROL RECOMMENDATIONS FROM THE WHO REPORT “CONTAINING ANTIMICROBIAL

RESISTANCE”(50) AND ENDORSEMENT BY EXPERT POLICY GROUP REPORTS

Document Cleanse hands Movement of patients within and Correct the lack There are several Improve hand Additional issues

after each patient between hospitals is increasing and of sterile supplies proven methods washing and/ or raised by this

contact to prevent contributes to the spread of infection and poor for improving use of gloves and document

the spread of sterilization hand washing gowns to decrease

infection infection rates

(5) WHO 1995 Endorsed Endorsed Endorsed Endorsed Endorsed

(49) WHO 2000 Endorsed Endorsed; stresses international travel. Endorsed Endorsed Endorsed

(21) House of Lords Endorsed Endorsed Endorsed Endorsed Endorsed Yes

(UK)

(1) USA DHHS Endorsed Endorsed

(6) US Congress Endorsed Importance of coordinating infection Endorsed Endorsed Endorsed

Office of Technology control measures between acute

Assessment hospitals and long-term care facilities.

(20) Antimicrobial Endorsed Endorsed. Emphasizes blurred Endorsed Yes

resistance boundaries between community and

hospital and increased travel.

(51) Fidler While microbes move freely around

the world, unhindered by borders,

human responses to infectious

diseases are conditioned by

jurisdictional boundaries.

(19) UK Department These issues were outside the remit of this report. Nonetheless, there is strong endorsement of the critical role of infection control in the

of Health hospital and community in the containment of antibiotic resistance.

(13) Shlaes, et al. Yes

(24) USA General Endorsed; stresses international travel.

Accounting Office

TABLE B. SUGGESTED INFECTION CONTROL INTERVENTIONS FROM THE WHO REPORT “CONTAINING ANTIMICROBIAL RESISTANCE”(50) AND

ENDORSEMENT BY EXPERT POLICY GROUP REPORTS

Key components of an Infection Control Committee

Establish an Surveillance of Identification of Implementation Sterilization and

effective infection infection outbreaks of effective control disinfection of Additional issues

control measures (e.g., equipment and raised by this

Document programme hand washing) supplies document

(5) WHO 1995 Endorsed Endorsed Endorsed Endorsed Endorsed Yes

(49) WHO 2000 Endorsed

(21) House of Lords (UK) Endorsed Endorsed Endorsed Endorsed Endorsed Yes

(6) US Congress Office of Technology

Assessment Yes

(20) Antimicrobial resistance Endorsed Endorsed

(7) National Science and Technology

Council (USA)

(13) Shlaes, et al. Endorsed Endorsed Endorsed Endorsed Endorsed Yes

(31) Centers for Disease Control and

Prevention (USA) Yes
45

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

TABLE C. SANITATION AND INFECTION CONTROL: ADDITIONAL INSIGHTS AND RECOMMENDATIONS

BY EXPERT POLICY GROUP REPORTS

Document Additional issues raised

(49) WHO 2000 1. Emphasizes the importance of community sanitation for infection control in developing countries.

(21) House of Lords (UK) 2. Infection control beyond the hospital is an area of particular weakness (paragraphs 4.20–25). This is

especially true of nursing and residential homes, which can act as reservoirs of MRSA and other

resistant organisms, which are then carried back into hospitals.

(20) Antimicrobial resistance 3. Economic costs of infection control in the community (increased cost of hygienic production).

4. Importance of sanitation in developing countries.

(13) Shlaes, et al. 5. Adopt CDC recommendations for isolation of patients colonized with resistant bacteria.

TABLE D. SANITATION AND INFECTION CONTROL: ADDITIONAL SUGGESTED INTERVENTIONS

BY EXPERT POLICY GROUP REPORTS

Document Additional issues raised

(5) WHO 1995 1. Link the prevention and control of antimicrobial-resistant organisms in hospitals to national and local

quality assurance efforts.

2. Develop methods and standards for evaluating hospital infection and antimicrobial resistance control

programmes, leading ultimately to a national accreditation system.

3. Develop educational programmes and hygienic standards for day care and extended-care facilities.

4. Promote standards of hygiene in the community, including safe water and food hygiene.

(49) WHO 2000 5. Promote other means of infection control (such as bednets in malaria endemic countries), education,

and support for those living in developing countries.

(21) House of Lords (UK) 6. Purchasers and commissioning agencies for hospital services should put infection control and basic

hygiene where they belong, at the heart of good hospital management and practice, and should

redirect resources accordingly; such a policy will pay for itself quite quickly. NHS Executives should

assure themselves that every NHS hospital is covered by a properly trained infection control team, as

recommended in the Cooke Report (paragraph 11.26).

7. The NHS should draw up national standards and guidelines for community infection control

management, along the lines of the Cooke Report for hospitals. These should include a requirement

that every district health authority should have at least one community infection control nurse

(paragraph 11.28).

8. Those responsible for the review of the Public Health (Control of Disease) Act 1984 should consider

the shortcomings of the provisions for compulsory medical examination and detention in hospital,

and the case for a more humane regime, and for extending the legislation to provide also for

supervised treatment at home (paragraph 11.29).

(6) US Congress Office of 9. Hospitals should consider instituting antibiotic-use subcommittees in the infection control

Technology Assessment committees.

(13) Shlaes, et al. 10. Make hospital administration accountable for the implementation and enforcement of policies

adopted by hospital committees.

(31) Centers for Disease Control 11. Top priority action item: Support demonstration projects to evaluate comprehensive strategies that

and Prevention (USA) use multiple interventions to promote judicious drug use and reduce infection rates, in order to assess

how interventions found effective in research studies can be applied effectively on a routine basis, on

a large scale, and cost-effectively.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

46

TABLE E. WHO SUGGESTED RECOMMENDATIONS FOR GOVERNMENT AND HEALTH SYSTEMS AND ENDORSEMENT

BY EXPERT POLICY GROUP REPORTS

Items from “Containing Antimicrobial Resistance”(50)

Document End poor commu- Institute effective Regulate sales, Establish Essential Establish national Additional issues

nication and regulatory including informal Drugs Lists standard raised by this

implementation mechanisms sector sales treatment document

of national policies guidelines

(5) WHO 1995 Endorsed Endorsed Endorsed Endorsed

(49) WHO 2000 Endorsed Endorsed Endorsed Endorsed Endorsed

(21) House of Lords Endorsed Endorsed Not a problem in Endorsed WHO Endorsed need for Yes

(UK) the UK; efforts in national approach

condemned any developing on implementing

OTC availability of countries. prudent use of

antibiotics. antimicrobials.

(1) USA National Endorsed Endorsed Endorsed Endorsed

Institutes of Health

(6) US Congress Office Endorsed

of Technology

Assessment

(20) Antimicrobial Especially in Endorsed Endorsed Restricting access Yes

resistance developing to a specific drug

countries. leads to excessive

use of alternatives;

policies need to

address overall prescribing as well as

use of specific

drugs. Guidelines

will not be effective

unless they are

evidence-based.

(51) Fidler Endorsed Endorsed Yes

(19) UK Department Endorsed

of Health

(13) Shlaes, et al. Endorsed

(22) Institute of Endorsed Yes

Medicine (USA)

(11) American Society Comments on Comments on

for Microbiology developing developing

countries only. countries only.

(39) USAID This document is a statement of intent rather than a review of the literature or set of recommendations. One of the

statements of intent covers this current review and synthesis of information or recommendations.
47

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

TABLE F. WHO (50) ADDITIONAL SUGGESTED INTERVENTIONS FOR GOVERNMENT AND HEALTH SYSTEMS AND ENDORSEMENT BY EXPERT

POLICY GROUP REPORTS. SEE ADDITIONAL ISSUES LISTED IN TABLES G AND H.

Document Identify and eliminate Target advocacy for Adapt WHO model Introduce legal require- Introduce formal Additional issues

economic incentives action towards legal framework for ments for collection of training and raised by this

(i.e., reimbursement relevant license, sale, supply, data on production, registration schemes document

practices) that organizations distribution, distribution, sales and for dispensing outlets

encourage inappro- (WTO, WB, IMF) promotion consumption for human,

priate antimicrobial use veterinary and agricultural use

(5) WHO 1995 This document covers the same issues, but sets them out as a series of general recommendations rather than specific

suggestions for policy or implementation. For example it is suggested that countries should “develop information

systems” but a legal requirement is not suggested. Regulation of promotion of antimicrobials is endorsed, but a legal

requirement to monitor supply and distribution is not covered.

(50) WHO 2000 Endorsed Endorsed Endorsed

(21) House of Lords (UK) Focus was on the UK, but endorsed UK Endorsed, particularly Endorsed, supports Yes

support for WHO activities: “The Govern- emphasizes the more coordinated

ment’s exemplary support for the WHO inadequate data about approach in the UK.

Division of Emerging Diseases should be hospital or veterinary

maintained, and the United Kingdom use. Commends the work of

Government’s example should encourage the WHO in the

other nations and agencies to contribute to developing world

this vital work. “ (paragraph 11.10).

(6) US Congress Office Congress should review Yes

of Technology effects of Medicaid and

Assessment Medicare reimbursement policies on antibiotic prescription

patterns.

(51) Fidler Endorsed (especially Endorsed Yes

WTO)

(7) CISET (USA) Endorsed (p7, p26) Endorsed (p7, p26) Endorsed (p7) Yes

(24) USA General Most countries do not

Accounting Office have measures of total

antibacterial use.

(22) IOM (USA) Endorsed Endorsed (p64) Yes

(31) CDC (USA) Primarily concerned with surveillance, prevention and control of resistance in the US, where regulation of license and promotion already

exists. However, does not deal with legislation compelling manufacturers to measure and report sales and consumption data.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

48

TABLE G. GOVERNMENT AND HEALTH SYSTEMS: ADDITIONAL INSIGHTS AND RECOMMENDATIONS BY EXPERT POLICY

GROUP REPORTS

Document and levels of

responsibility Additional issues raised

(49) WHO 2000

International Cooperation Emphasizes the importance of making antibiotics available for treatment of infections in developing

countries as a means of containing spread of infection in general and resistant strains in particular.

(21) House of Lords (UK)

National and Local Governments The evidence is clear (paragraphs 2.26–30) that prudent use is much harder to achieve if antimicrobials

for internal use are available over the counter.

Hospitals It is notoriously difficult to manage what cannot be measured; and we have heard much about the

contrast between the excellent data on general practitioner prescribing, captured by both the Prescription

Pricing Authorities and general practitioners themselves, and the lack of data on antimicrobial use in

hospitals (paragraphs 10.4–7).

Doctors and Patients We acknowledge the dilemma facing doctors and patients alike (paragraph 2.9), that what is prudent

from the point-of-view of public health may be highly imprudent from the point-of-view of the individual

patient, and vice versa.

Animal Health Regulators The United Kingdom led the world in addressing the threat to human health posed by antibiotic use in

farming practices with the Swann Report in 1969. Unfortunately, some of the recommendations of Swann

were not acted upon and many believe that, had action been taken then, our present concerns would be

much less than they are now, at least as regards the situation in the United Kingdom.

The evidence that we have heard (paragraphs 3.7–13) strongly suggests that there is a continuing threat

to human health from imprudent use of antibiotics in animals.

(20) Antibiotic Resistance

National Government Limit general access to new drugs (e.g., fluoroquinolones).

Governments should make and provide materials to support intervention programmes (e.g., materials

available from CDC).

Grant licenses conditionally based on monitoring of resistance (especially in veterinary use).

Hospitals Limit general access to new drugs (e.g., fluoroquinolones).

(51) Fidler

International Cooperation Private initiatives are building global information-sharing networks on various disease issues through the

Internet and other information technologies; private companies are starting to monitor and test bacterial

resistance globally; and some for-profit companies gather and sell epidemiologically useful information.

These private efforts raise legal questions: privacy issues arise with the dissemination of epidemiologic

data by private companies; this dissemination is treated differently in different countries; jurisdictional

problems arise regarding legal regulation of information-sharing in cyberspace.

The notion of personal control measures against drug-resistant malaria patients in Africa seems farfetched, given the scale of the problem. Nevertheless, the importance of international human rights law to

effective public health policies (as seen in the context of HIV/AIDS) demonstrates that complacency

towards individual rights in any public health policy is dangerous legally and medically.

International legal harmonization of principles for prudent antimicrobial drug use must include

monitoring and enforcement, as well as financial, technical, and legal assistance provided by industrialized

countries to developing countries.

In the context of environmental protection, trade restrictions seeking to change a production process in

another country, rather than to protect against health dangers from a particular product, have been ruled

incompatible with international trade law.

To avoid losing trade restrictions as part of a general strategy to combat antimicrobial misuse, legitimate

trade restrictions against countries that systematically neglect recognized principles and practices for

antimicrobial use might be considered; such a move would elevate the status of Codex’s Code of Practice

for Control of the Use of Veterinary Drugs and Guidelines for the Establishment of a Regulatory Program

for Control of Veterinary Drug Residues in Foods, as the SPS Agreement has elevated the importance of

Codex’s Maximum Residue Levels for Veterinary Drugs in Foods.

International law on intellectual property protection is a critical piece of the overall strategy against

antimicrobial resistance.
49

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

TABLE G. CONTINUED

Document and levels of

responsibility Additional issues raised

National and Local Governments Especially in federal systems, countries often divide authority for public health among various levels of

government.

Privatization of laboratory services by state legislatures may compromise national surveillance of

emerging infectious diseases and investigation of outbreaks, because many surveillance systems rely on

data from state laboratories.

Increased surveillance for antimicrobial resistance may heighten privacy concerns with respect to other

diseases, such as multidrug-resistant tuberculosis (MDRTB).

In the United States, Congress could regulate use of antimicrobial drugs by monitoring interstate

commerce in these products. Congress probably does not have the authority to regulate antimicrobial

prescription practices directly; such authority rests with the states.

Perhaps the most powerful US federal strategy would be to make implementation of state policies to curb

the misuse of antimicrobial drugs mandatory before states receive federal funds earmarked for public

health.

National Government In countries where governments subsidize the purchase of antimicrobial drugs, legislative or regulatory

changes in these subsidies could lead to a decline in the use of the drugs.

Pharmaceutical companies that had developed antibiotics but never commercially exploited them might

pursue more antimicrobial research and development if their earlier antibiotics (now without patent

protection) were given extra legal protection, either under patent law or a legal regime like the Orphan

Drug Act.

(22) Institute of Medicine (USA)

National Government Existing antibiotics may have activity against resistant pathogens but have not undergone clinical trials;

advocates accept surrogate indicators of efficacy.

Explore the value of extending patents as an incentive to prudent use.

Animal Health Regulators Need to address ambiguities about registration of antibiotics in agricultural products and incorporate

antibiotic resistance into discussions of food safety and the regulation of imports.

TABLE H. GOVERNMENT AND HEALTH SYSTEMS: ADDITIONAL SUGGESTED INTERVENTIONS BY EXPERT POLICY GROUP

REPORTS

Document and levels of

responsibility Additional issues raised

(5) WHO 1995

National and Local Governments Support programmes to improve access to treatment and thus earlier detection and interruption of

outbreaks of resistant bacteria.

National Government and Prohibit the use for growth promotion in animals of any antimicrobial agents used in human therapeutics

Agricultural Industry or potentially selecting cross-resistance to antimicrobial agents used in human medicine.

Define acceptable levels of antimicrobial agent residues in food from animal sources and ensure

compliance with national standards.

(49) WHO 2000

International Cooperation Support countries in developing reliable supply systems.

International and National Make effective medicines accessible to the poor.

Governments

Strengthen national and international capacity to ensure the quality of anti-infective drugs.

All Levels of Government and the Increase the availability of essential drugs.

Pharmaceutical Industry
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

50

TABLE H. CONTINUED

Document and levels of

responsibility Additional issues raised

(21) House of Lords (UK)

International Cooperation We commend the Government and the ABPI for their firm stand against over-the-counter antibiotics, and

urge them not to give way. Since this is an area of EU responsibility, and the position in several other

Member States appears to be different, we recommend that the Government should engage in active

diplomacy to ensure that, should the issue be raised in the Council of Ministers, their position is

understood and their allies are in place; and, in the long term, to induce those Member States which are

currently more relaxed about over-the-counter antibiotics to introduce more controls.

National Government The Government and the health authorities must do more to educate the public about the proper use of

antimicrobials. In particular, we recommend a campaign targeted at mothers of young children.

The Education Committee of the General Medical Council and the medical Royal Colleges should review

the evidence that undergraduate curricula give insufficient emphasis to infectious diseases and

antimicrobial therapy, and the Royal Colleges should increase the attention paid to antimicrobial therapy

in their programmes of postgraduate education and vocational training (paragraph 11.6).

The Medicines Control Agency should consider whether the drug licensing system could be used more

effectively to encourage prudent use in the interest of public health (paragraph 11.9).

The Government should respond positively to the EU proposal for an “orphan drug” regime, and should

seek to ensure that the scheme gives the pharmaceutical industry a real incentive to work on novel

treatments for problem diseases, particularly diseases of the world’s poor, such as malaria (paragraph

11.40).

Local Government The NHS Executive must work towards the goal of compatible and interconnected information technology

for every general practitioner, every hospital ward and infection control team, and every clinical

microbiology laboratory. They must accept the considerable cost involved; and they must give a strong

lead from the centre to ensure compatibility (paragraph 11.51).

Hospitals All hospitals should install computer systems for patient-specific prescribing information at ward level.

Doctors We do not recommend that general practitioners should be required to establish antimicrobial

susceptibility before prescribing (paragraph 2.22). This, we believe, would at present be impracticable, and

would overload diagnostic services which are already stretched. But improved access to microbiological

testing clearly reduces uncertainty in prescribing.

Veterinarians The veterinary profession must address the use of potent agents important to human medicine (e.g.,

fluoroquinolones), by introducing rapidly a Code of Practice on when such compounds should be

prescribed (e.g., when other agents have failed) and how (e.g., for no longer than necessary); we

recommend self-regulation in preference to legislation.

(1) USA National Institutes of Health

National Government In countries with more restrictive legislation and more effective enforcement of antibiotics prescriptions,

studies should be carried out on the effects of such legislation on requirements for training of health-care

personnel and on economic and other consequences for patients and national health-care delivery

systems.

Legal restrictions on the use of antibacterial drugs may exert positive or negative effects on mortality and

morbidity, especially among children.

National Government and Hospitals Longitudinal studies must determine whether regulations and effective enforcement have any effect on

the emergence of resistance.

National Government and The public health consequences of restrictions on antibacterial use in food production and animal

Agricultural Industry husbandry should be investigated.

(6) US Congress Office of Technology Assessment

National Government Congress can provide FDA with authority to negotiate extended market exclusivity to manufacturers that

agree to restrictions on marketing of antibiotics.

Congress could authorize FDA to extend market exclusivity for “off-patent” antibiotics that are effective

against drug resistant bacteria.

Congress could provide research support for a federal programme to conduct clinical trials of antibiotics to

determine if they have uses against antibiotic resistant bacteria.
51

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

TABLE H. CONTINUED

Document and levels of

responsibility Additional issues raised

Veterinarians The document is skeptical about the possibility of reaching consensus about veterinary use of antibiotics

based on existing data, and about the value of additional studies.

(20) Antibiotic resistance

National Government Make assessment of resistance potential of new compounds part of their licensing.

(51) Fidler

International Cooperation The International Health Regulations mandate, for example, that Member States of the World Health

Organization (WHO) report outbreaks of plague, cholera, and yellow fever to WHO.

WHO has proposed including surveillance of antimicrobial resistance in the revision of the International

Health Regulations and requiring drug resistance reporting.

Creation of a legal duty does not ensure the success of a policy. WHO Member States have routinely

ignored required outbreak reporting of plague, cholera, and yellow fever.

Lessons from international environmental efforts suggest that international law must play a major role in

setting international standards for implementation domestically and creating the political, technical, and

financial conditions necessary to integrate international and national law.

The importance of Codex food safety standards to international trade law was seen in the Beef Hormones

Case, in which the WTO held that the EU violated the SPS Agreement for not providing scientific

justification for a beef hormone regulation stricter than the relevant Codex standards.

National Government Fulfilment of legal duties often hinges on sufficient resources. In many developing countries public health

systems may be inadequate. Thus, financial and technical leadership is needed from national governments

for local authorities, and from international organizations for developing countries.

A precedent can be found in the proposed Convention on the Provision of Telecommunication Resources

for Disaster Mitigation and Relief Operations, which obligates the parties, where possible, to lower or

remove regulatory barriers for using telecommunication resources during disasters.

The comprehensive statutory and regulatory system in the US that governs the acquisition, use, and

transfer of biological agents that pose a threat to public health might serve as a model for legislation in

other countries.

At a time when antimicrobial resistance may have created a greater need for personal control measures

for public health (e.g., with MDRTB), the status of US law on the scope and nature of the government’s

power to undertake such measures seems unsettled.

(19) UK Department of Health

National Government Licensing authorities should consider an antimicrobial agent’s potential to select for resistance in addition

to its safety and efficacy.

Pharmaceutical Industry Consider finding ways, through pricing and other mechanisms, of ensuring that investment in the

development of new antibiotics remains commercially viable.

(7) National Science and Technology Council (USA)

National and International Introduce a global alert system requiring national governments to inform worldwide health authorities

Governments about outbreaks.

National Government Establish a private sector subcommittee of the Interagency Task Force.

(22) Institute of Medicine (USA)

International Cooperation Explore International Conference on Harmonization (p59) as a forum for a global approach to rational

antimicrobial use.

Initiate dialogue, led by WHO with representation from WTO, EU and US Departments of State and

Commerce, about regulation of antibiotics in agricultural products.

CHAPTER IV

Encourage research and product development

John F. Barrett

and deterioration of public welfare as infectious

disease concerns continue to increase worldwide

(1,5,6,7,8,11,19,20,21,22,39,49,50,53). In addition, many reports address antibiotic resistance in

specific circumstances and microorganisms, and all

identify antibiotic resistance as a growing problem

(54–69).

The 1992 Institute for Medicine’s (IOM) report

on “Emerging Infections: Microbial Threats to

Health” (71) indicates that “changes in technology

and industry” are among those risk factors that have

contributed to the inability to prevent or control

microbial diseases. This IOM report (70) lists six

general factors leading to the emergence of infectious diseases and antimicrobial resistance:

• environmental change and land use;

• breakdown of public interest health measures;

• international travel (transporting infectious

diseases globally);

• changes in social behaviour;

• changes in technology and industry; and

• microbial adaptation and change (including

resistance development).

The world is no longer simply a matter of geographical division of diseases, as the spread of

infectious diseases continues to be demonstrated

with the emergence of “developing nation diseases”

in specific geographical centres in the industrialized world (e.g., tuberculosis, dysentery, etc.).

A practical way to look at emerging diseases is

that a disease in one geographical area could easily

be transmitted to the unaffected area, by simple

delivery of the infectious disease by human carrier.

Thus it is naive to believe that antimicrobial resistance in any part of the world is an “isolated problem”.

The industrialized countries, by virtue of

advanced technology and improved basic living

standards, are privileged to not be subject to the

massive outbreaks of infectious diseases that we see

in the developing world. Basic sanitation, basic eduAbstract

The areas of research and development offer

tremendous possibilities to have an impact on the

antimicrobial resistance crisis worldwide. A historical review of support for antimicrobial resistance

research and development, as a subset of infectious

disease research including tuberculosis research, has

determined a gross under-funding of this area, in

academic, governmental and industrial laboratories

over the past 10–15 years. There is a need to

encourage federal, university, and private sector collaboration in basic and applied research.

Consensus points by governing bodies reviewing antimicrobial resistance over the past five years,

consistent with current key-opinion-leader sentiment, show that the major needs include: basic

research is needed to delineate the genetic and metabolic pathways, microbial physiology, and the causes

of antimicrobial resistance; an increase in research

for the identification and development of new drugs

to fight antimicrobial resistance; and an increase in

basic and applied research for new vaccines and

other preventive measures.

In broader terms, research and development

needs to cover a more global effort to provide compelling evidence for the prudent use of antibiotics,

including the use in humans, animals and plants;

provide incentives for the discovery and development of agents to combat antimicrobial resistance;

facilitate innovative approaches to fight against resistance; and build worldwide alliances and partnerships to increase sensible access to antimicrobials

(1,5,6,7,8,11,19,20,21,22,39,49,50,53).

Introduction

There is significant consensus among research professionals that the US Surgeon General, William

Stewart, was wrong in 1969 when he was quoted

as saying that we (the US population) could

“...close the book on infectious diseases...” in addressing public concerns (from a health standpoint).

All position-piece documents reviewed for this

chapter make observations about the seriousness

53

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

54

cation on maintaining good health, and widespread

immunization against disease, provides a tremendous advantage to the occupants of the industrialized world. Short- and long-term gains are a matter

of basic education and building a foundation so

the next generation of developing countries’ children have the same advantages as industrialized

countries’ children in sanitation and health care.

However, research and development in the developing countries is virtually non-existent, and the

short-term possibilities for changing this are remote.

This chapter reviews the expert reports (1,5,6,7,

8,11,19,20,21,22,39,49,50,53,54) and other relevant literature from the viewpoint of research

(basic and applied) and product development and

attempts to summarize their recommendations.

Basic and applied research

Identification of research needs

All the expert reports reviewed made at least some

mention of research and many had extensive sections devoted to research needs both to improve

the understanding and management of antimicrobial resistance and to develop new drugs, vaccines

and diagnostic tools. Recommendations from Wise

and colleagues in the British Medical Journal’s

special (1998) issue on antimicrobial resistance

include the need for increased understanding of antimicrobial resistance processes; and for encouragement to the pharmaceutical industry to increase its

commitment to antimicrobial research (71,72).

Huovinen and Cars (73) emphasize research [both

basic and applied] as “...a cornerstone in the fight

against bacterial resistance.” From a better understanding of the microbiology and genetics of our

endogenous flora, we may better understand the

collateral damage of normal antibiotic usage in facilitating the evolution of resistance and the mechanism of transmissibility of resistant bacteria. More

prudent use of antibiotics will be attained by the

development of diagnostic technologies to enable

rapid identification of bacterial versus viral pathogens.

A synthesis of the key research needs identified

in the expert reports reviewed (1,5,6,7,8,11,

19,20,21,22,39,49,50,53,54) follows:

Infrastructure and training

• Improvement in basic and applied research infrastructure (academic and industrial);

• Improvement in basic research training in

academia to ensure a critical mass of researchers

in the antimicrobial resistance field of research.

Infectious disease and microbial pathogenicity

• Improvement in understanding of how to prevent the infectious disease state and to treat new

infectious diseases; basic research related to new

and re-emerging pathogens/infections and

better understanding of the infectious disease

link to chronic diseases

• Basic research in molecular pathogenesis, including:

— the evolution of pathogenicity;

— the epidemiology and spread of pathogens

and infectious disease transmission;

• Resources to enable the sequencing of the entire

genome of additional microbial pathogens

(including problem pathogens in developing

countries).

Antimicrobial resistance

• Research into the source of antibiotic resistance

genes; the mechanisms/frequency of ‘reassortment’ of these genes, the emergence and transfer of resistance genes among pathogens in vivo

(in the host), and the distribution and dissemination of specific antimicrobial resistance genes

over time, and factors affecting the loss of

resistance determinants;

• Research on the correlations between resistance

determinants in normal flora and the prevalence

of resistant pathogens;

• A better understanding of the ability of genetic

material to transfer in the bacterial ecosystem;

• Studies on the ability of bacteria to amplify genes

and exchange genes leading to multiple drug

resistance in bacteria;

• Mechanisms of antimicrobial resistance emergence, acquisition, spread, persistence, and decline of multidrug-resistant microorganisms;

• Research on factors that accelerate the development of drug resistance and methods to delay

or reverse drug resistance;

• The need for more research examining ways to

decrease resistance frequency.
55

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

New technologies

• Provide technologies to researchers to allow for

the identification of quality, novel targets;

• Develop tools such as microbial genome

sequence data, comparative genomics, DNA

chip technology, and bioinformatics;

• Research in molecular genetics to identify novel

targets.

New antimicrobials, vaccines, disease prevention and

diagnostics

• Provide opportunities to translate basic research

findings into applied, medically useful products/

devices/technologies (i.e., drugs, diagnostics,

vaccines, and other tools to inhibit antimicrobial resistance);

• Research the role of host factors and immunomodulation in clinical resistance and the human

immune response to infectious diseases;

• Basic research towards the development of

effective vaccines;

• Research of development of vector control

interventions;

• Basic research on other disease preventative

measures;

• Support of research and development and standardization of diagnostic tests;

• Research to discover/design/develop more reliable, rapid diagnostic techniques for identification of infections causing specific disease states;

• Increased research into methods to detect resistance to antimicrobial agents;

• Tools for the clinical/epidemiological researcher

that can be used to more accurately and efficiently identify optimal therapeutic options for

treatment of antibiotic resistant strains.

Research on antimicrobial use

• Links between prescribing and resistance at both

the individual and population levels;

• Concepts concerning antibiotic use and their

influence on delivery and compliance;

• Factors leading to inappropriate prescribing;

• An understanding of variation in antimicrobial

use patterns that affect emergence and spread of

resistance;

• Effect of preventative, therapeutic and growthpromoting agents used in the animal use field

on the community microbiota.

Surveillance and information management

• Research to improve of surveillance tools, including computer programmes for data management

and reporting;

• Research in methods for monitoring drug resistance;

• Development and assessment of computerized

decision-support systems in hospitals;

• Encourage sharing of antimicrobial resistance

data between industry, universities, and governmental authorities.

Additional research areas to consider

Understanding the costs of resistance

a) to the bacterium

One of the major research areas only minimally

touched on in the reports reviewed was that of the

cost of resistance to the bacterium (1,74). The

understanding of the cost to the bacterium that

receives or adapts to the resistant state is better

understood in terms of the change in pathogenicity as the ‘expense’ of increased resistance. Where

previously, resistance acquisition was viewed as a

crippling event, it is now understood that it may

actually confer a selective advantage to the pathogen (74).

b) costs to the health care system

A new field of marketing research and business

management has arisen over the past years dealing

with the pharmacoeconomics of health care (75),

in which factors indirectly related to outcomes may

be drawn into the value of one action over the other.

For example, the ‘cost’ of antimicrobial resistance

in the patient population may take into account

loss of work time, allowing a quantitative assessment of the ‘cost’ of infection beyond the drug costs

alone. If a treatment regimen gets the patient out

of the hospital on oral medication, rather than continuation of therapy by intravenous administration,

then the ‘cost’ of therapy overall, in terms of measuring the ‘cost’ of antimicrobial resistance, may

factor in the absence of 2–5 additional hospital days

(that may range from $1500–$2500 per day). Even

the selection of the ‘right’ first-line antibiotic the
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

56

first time by the practicing physician, versus requiring a follow-up visit because the ‘older’ or generic

antibiotic (with cost saving) did not work, has a

‘cost’ associated with the patient’s return to the

physician, as well as the cost to the physician. One

of the criticisms of the for-profit-managed health

care delivery systems may be that by providing an

allotment of dollars per patient per year to the physician by contact regardless of the true cost, pushes

the physician to cost-cutting methods (including

the choice of an inappropriate antibiotic).

Areas where there is lack of consensus

There is no consensus as to the cause, effect, or

solution to the worldwide antimicrobial resistance

problem, nor as to the origin of antimicrobial resistance genes. However, it is clear that antimicrobial resistance stems from the use of antibiotics.

While there is no high-level disagreement about

the unmet medical need posed by antimicrobial

resistance, there are differences in opinion vis-a-vis

the scientific priorities.

Not surprisingly, there is no consensus as to the

specific ‘cause-and-effect’ and assignment of ‘blame’

on the increase in antimicrobial resistance (1,5,6,7,

8,11,19,20,21,22,39,49,50,53,54,60–69); more

basic and applied research is needed to answer this

complex question definitively. However, it is clear

to virtually all opinion leaders that antimicrobial

resistance begins with the routine use of antibiotics for human health care, animal health, and agricultural purposes. There is most probably a link to

the resistance emergence to the most frequently

prescribed antibiotics and the alarming increase in

resistant bacteria (11). For example, greater than

90% of Staphylococcus aureus were resistant to penicillin and other β-lactams as of 1994, and there is

an notable increase in vancomycin resistance in

enterococci. Likewise, but of unknown clinical relevance, there is an increase in the resistance to

penicillins by Streptococcus pneumoniae.

Concerning resistance and selective pressure,

there is not consensus among scientists as to

whether removal of an antibiotic from the treatment regimen will: reduce the risk and/or expansion of resistance in the pathogen population;

reverse the resistance frequency or prevalence in the

bacterial population; or have no effect on the resistance frequency. In the House of Lords report

(21) Reeves is quoted as stating “There is plenty of

evidence, that if you remove the selection pressure,

the organisms will slowly revert [to susceptible]....”,

whereas Davey provided evidence directly linking

resistance to overall usage. In contrast to Reeves,

Levin was quoted (21) that resistance is a one-way

street, that if antibiotic use is cut back sharply, the

proportion of resistant strains wanes slowly (if at

all).

Effective efforts

The review of the expert reports seems to indicate

the effectiveness of basic research in increasing our

understanding of antibiotic resistance and the development of new drugs. Extensive research efforts

in academia continue, albeit dwarfed by support

to AIDS research, and have yielded excellent results from a better understanding of the molecular

mechanisms responsible for antibacterial resistance,

(72, and references cited therein) to new medicinal

chemistry approaches to combat resistance in bacteria (76, and references cited therein). Historically,

basic research has provided numerous advancements in understanding of microbes which has been

applied to the engineering of drugs by pharmaceutical companies.

Ineffective efforts

Many of the US reports indicate funding (that is

US-based) is woefully lacking for basic and applied

research concerning antimicrobial resistance. As

pathogens can vary greatly in industrialized versus

developing countries (77), the priorities of ‘medical need’ are often misaligned. Priorities for funding have shifted away from bacteria-associated

research to AIDS research over the past fifteen years.

The lone exception appears to be the increase in

TB research support (although this is still disproportionately small considering the worldwide morbidity and mortality due to TB).

Research and development efforts to provide

compelling support for the ‘prudent’ use of antibiotics have failed to translate into prudent use;

Reducing inappropriate use of antibiotics with supportive basic and applied research (1,50,39,78,79)

has proved ineffective.

A critical role for new technologies

There is consensus (1,5,6,7,8,11,19,20,21,22,

39,49,50,53,54) that the molecular detection of

genes that are associated with antimicrobial resistance is expected to be ascertained by the analyses

of microbial genomes (22). The principles and
57

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

implications of mapping the prokaryotic genome(s)

are to acquire the full sequence of microbial genes

and to manage great volumes of sequence data

through bioinformatics. It is hoped that once this

‘raw’ data is collected in analysable form (hence the

‘informatics’ in bioinformatics), this ‘knowledge’

(as opposed to raw data) will provide a foundation

for the discovery and development of new antimicrobial agents, new vaccines, and new diagnostic

tools for infectious diseases.

Consensus throughout the documents (1,5,6,7,

8,11,19,20,21,22,39,49,50,53,54) holds that comparative genomics (i.e., the ability to compare full

length sequences of different bacterial, or even

eukaryotic, genomes) may present the opportunity

for the informatic-assignment of ‘putative’ essential function in microbes based on consistency of

sequence similarity, but wet-biology proof is needed

to confirm this informatics assignment. The best

example of successful gene sequencing/bioinformatics may be The Institute for Genomic

Research (TIGR), with the intention to sequence

50–100 microbial genomes within just a few years.

But beyond the cataloging of raw sequences, TIGR

and other groups are developing gene array technology that will allow for the simultaneous assessment of expression of all genes in a microbe under

different environmental conditions (growth condition changes, stress, antibiotic insult, etc.).

Among the data expected to be ascertained are: 1)

the identification of genes involved in susceptibility or resistance to antimicrobial agents; 2) specific

knowledge of gene function, including regulatory

functions of different genes; 3) the identification

of polymorphism shifts signaling the evolution of

infectivity (virulence) and/or susceptibility/resistance to antimicrobials; and 4) the identification of

potential antigens/proteins against which vaccines

may be devised (22).

The genetic basis of resistance in bacteria may

supersede the phenotypic (macro-) detection of

resistances, frequently based on microbiological

susceptibilities (minimal inhibitory concentrations,

etc.). Undertaking the identification of the genotypic cause for changes in susceptibility may

provide insight into the development of novel

approaches to combat resistance. A shortcoming

of genotypic characterization of resistance factors

is that it provides but a ‘snapshot’ of genotypic character; it gives a single time point of ‘data’, but not

necessarily a proven link to the resistance pattern,

or an understanding of antimicrobial resistance. A

match of both genotypic and phenotypic data is

most probably the best approach and will most

likely provide the greatest opportunities for advancements in the short-term. The expanded and

coordinated use of resistance surveillance systems

such as SENTRY or the Alexander Project (80,81)

would provide ‘live’ tracking of antimicrobial resistance, allowing action to be taken as appropriate

to contain antimicrobial resistance, as well as predict emerging deleterious trends or appearance of

emerging pathogen susceptibility problems.

There is agreement (1,5 ,6,7,8,11,19,20,21,22,

39,49,50,53,54) that practical applications arising

from genomic analyses and bioinformatic tallying/

annotation of sequence function of microbial

genomes may be limited only by the imagination

of the researcher. From these analyses a selection of

high quality novel targets is expected to emerge,

allowing the applied research groups to select any

of the following subsets of data: 1) essential genes;

2) virulence/pathogenicity genes (non-essential

genes); 3) broad spectrum genes (gram-positive and

gram-negative); 4) narrow spectrum genes (grampositive or gram-negative); and 5) targeted spectrum genes (i.e., Mycobacterium tuberculosis,

Chlamydia pneumoniae). In addition, selectivity

and specificity may be ascertained by comparative

genomic analyses, such as comparison to eukaryotic

sequences, to determine minimal sequence overlap

as a surrogate “in silico” indication of selectivity

for the microbial target (i.e. decrease in toxicity)

(22).

Additionally, molecular technologies can and

have been employed downstream to identify “in

silico” essentiality of genes, and subsequently proven

by so-called “knock-out” approaches in which the

selective inhibition of expression of individual genes

and monitoring of survival and/or growth of the

knock-outs, is a surrogate of ‘essential function’ in

vitro (albeit negative selection data-based). Alternatively, genomic footprinting methodologies and

temperature-sensitive mutants also provide surrogate assays for ‘essentiality’ determination in bacteria.

Consensus throughout the documents (1,5,6,7,

8,11,19,20,21,22,39,49,50,53,54,55) holds that

taking genomic sequence information to practical

application of screen design has provided a variety

of high-throughput screening assay formats including cell-free biochemical or genetic assays, assays

based on phenotypic changes, binding assays,

enzymatic assays, etc. Genetic technologies may

ultimately allow multiplexing of prokaryotic targets, which in turn may increase the chances of
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

58

success and decrease overall research and development costs (22). Thus these new technologies are

seen to play a critical role in future discovery

efforts for new antimicrobials.

Funding for research

The estimate for infectious disease deaths throughout the world in 1998 was over 13 million (54) or

almost a quarter of all deaths worldwide. Of these

deaths, 3.5 million were due to pneumonia, 2.2

million to diarrhoeal disease, 1.5 million to M.

tuberculosis, 2.3 million to AIDS, 1.1 million to

malaria, and 1 million to measles (54). The first

three of these diseases, totaling 7.2 million deaths,

were the top infectious disease killers as well as the

overall top three causes of deaths worldwide in 1900

(54), indicating little impact of research and development on reducing this infectious disease

burden.The current estimate is that less than 2%

of the total health research expenditures throughout the world is devoted to antimicrobial usage,

delivery, and resistance (49). To quote from the

WHO report (49): “Incentives are needed to encourage pharmaceutical companies to discover and

develop new compounds, as well as intensify research into dosage regimens calculated to minimize

the likelihood of selecting for resistance.”

US funding of infectious disease, AIDS, and

tuberculosis research

The priorities for research in the United States can

be clearly identified in a review of funding amounts

from 1993 through 2001 (estimated), in which over

an 8-year period the total research budget doubled

from $9.765 billion (1993) to $18,812 billion

(2001, estimated). The AIDS research portion of

this budget increased by 1.97-fold increase in funding support. Infectious disease research (other than

AIDS and TB) received a 1.97-fold increase and

TB research increased from $35 million (1993) to

$86.8 million (2001, estimated), or a 2.48-fold

increase in the research funding. Although the TB

research budget represents a disproportionate increase in funding, it is in turn disproportionately

less than that for AIDS research (82,83). From the

1995 CISET report (7), funding of work related

to infectious diseases other than AIDS or TB was

c.5% of total research funding; the Centers for

Disease Control and Prevention (CDC) dedicated

c.95% of its budget for prevention and control of

infectious diseases to AIDS, TB, sexually transmitted diseases and vaccine-preventable diseases (7).

Product development—antibiotics,

vaccines and diagnostics

Antibiotics

The UK Standing Medical Advisory Committee

was commissioned to examine the issue of antimicrobial resistance in relation to clinical prescribing

practices (19). Their mission was to examine all

factors that may contribute to antimicrobial resistance, including the role of research. From this report, one very relevant observation is made: “The

thrust of this report is focused on the conservation

of present antimicrobial agents. However, it must

be recognized that the way in which past resistance

problems have been overcome (if only temporarily) has been by the development of new agents.”

The “Report of the ASM Task Force on Antibiotic Resistance” (8), based on the workshop on

“Antibiotic Resistance: Current Status and Future

directions” held in 1994, drew consensus from a

group of almost three dozen scientists from

academia, government and industry. It states: “The

relative utility of antibiotics is eroding, tipping the

balance in favor of multidrug-resistant pathogens,

and there appears to be few new drugs in the pipelines of the USA pharmaceutical companies. These

developments amount to an incipient public health

emergency, albeit one that is poorly appreciated or

recognized” (8).

Also from the Task Force report (8), “...it should

be realized that the research-intensive pharmaceutical industry is the source for most new drugs and

that industries need to profit from their investments

in order to pay for the research.” As marketing projections are primarily based on historical usage, they

may be misleading. Marketing and business

specialists in industry should be involved in discussions on the problems of emerging antibiotic

resistance (8). In addition, as cost can drive prescription use, the national and regional health care

providers/payers should be involved in the consideration of use of antibiotics, balancing the use of

antibiotics and risk of emergence of resistance

against cost in the selection of appropriate type and

use of antibiotics. In exchange for the rational market-support approach for selling products, industry should help support national efforts for the

prudent use of antibiotics (8). In addition, the potential association of infectious diseases (including

bacterial infection) with chronic diseases needs to

be better understood (82), and this will require an
59

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

immense, long-term, research investment. Overall,

research has been found to be ‘cost effective’ (11).

This section contains a synthesis of the many

suggestions and recommendations for product development that came from the reports cited in the

references. A summary is given at the end of the

section.

Industry engagement

Industrial infectious disease research remains a puzzle. Clearly in the 1970s and 1980s major companies decreased support for their infectious disease

efforts (84,85), especially antibacterials, with the

understanding that the antibacterial needs were

diminished, but the reality is that pharmaceutical

companies have continued to support to some degree infectious disease, moving towards antiviral and

in some cases antifungal research efforts, but not

to the same extent as the increases in non-infectious disease research areas such as cardiovascular,

CNS, lipid disorders, oncology, dermatology, etc.

The success rate for antibacterial discovery and

development, much diminished since the ‘hey days’

of the 1960s–1970s, continues to pose a “value risk”

for industry (21). There is, however, no shortage

of good ideas (84,86,87).

The UK Standing Medical Advisory Committee (SMAC) report (19) notes that: “It is also recognized that over recent years the pharmaceutical

industry has developed vastly more efficient systems for seeking new antimicrobial agents. These

strategies will, hopefully, yield new generations of

antimicrobial agents by the end of the next decade.” According to the report (19), development

of a new antimicrobial agent costs about $500 million (£350 million), over an estimated 7–10 year

period (within a 17–20 year window of patent life,

depending on country of filing). The costs, together

with an understanding that these agents will be used

for a relatively short period of time in a therapeutic

area subject to the development of resistance and

high competition, it is easy to see why pharmaceutical companies may elect to invest in research in

other therapeutic areas (84,85).

A survey of the public domain reports (see

Table 1), databases and literature by this author

indicates major efforts by large pharmaceutical companies, start-up biotechnology-based pharmaceutical companies, and many smaller start-up

initiatives, directed towards antibacterial resistance

problems. But with success being harder to come

by and with very few new antimicrobial agents

reaching the market, the perception of lack-ofeffort is apparent.

TABLE 1

Company Research area(s)

Abbott Labs Antibacterials/genomics

Astra-Zeneca Antibacterials/antifungals/genomics

Bristol-Myers Squibb Antibacterials/antifungals/genomics

Cubist Pharmaceuticals Antibacterials/genomics

Eli Lilly Antibacterials/antifungals

Glaxo-Wellcome1 Antibacterials/antifungals/genomics

Johnson & Johnson Antibacterials/antifungals

Merck Antibacterials/antifungals

Microcide Pharmaceuticals Antibacterials/antifungals/genomics

Pfizer Pharmaceuticals2 Antibacterials/antifungals/genomics

Schering-Plough Antibacterials/antifungals/genomics

SmithKline-Beecham Antibacterials/genomics

1

 Now one research unit.

2

 Through strategic external aliances

The decrease in industrial support may be revealed by the number of commercial Investigational

New Drug (IND) submissions in infectious diseases from 1991 to 1999, dropping from 327

(1991) to 265 (1995) to 52 (1999) (82,83). At the

equivalent interval of 9 years (but shifted backwards

in real time due to unavailability of more current

data), overall funding for research (all therapeutic

areas) by industry increased at a rate more than 50%

higher than that of government funding for research, with industry support rising from $6.19

billion (1986) to $18.65 billion (1995) (82,83).

However, this increase does not reflect a commitment to infectious disease, but rather an increase

in funding in the chronic disease areas, with an

emphasis on non-infectious disease research.

As most INDs submitted for infectious diseases

are not for individual, novel chemical entities, an

examination of the serious downtrend in industrial

support for infectious diseases can be seen in the

comparison of New Molecular Entity (NME) submissions in the FDA Division of Anti-Infective

Drug Products, indicating a decreasing trend in the

deliverability of novel agents (82,83). The NME

approvals in the years from 1991 to 1999 are summarized in Table 2. NMEs dropped from 4–6 per

year in the early 1990s to just 1 per year in the late
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

60

1990s (although there was a single-year spurt of

agents in 1996 with 8 NMEs). This may represent

an under-reporting of agents in the late 1990s with

the shifting of some approvals to the FDA Division of Special Pathogens and Investigational Drug

Products, but even with these numbers factored in,

the NMEs have dropped more than 2-fold in the

10-year period ending with the turn of the millennium (82,83).

Virtually all antibacterial agents over the past

18–20 years, up to the approval/launch of the first

oxazolidinone in 1999 (LinezolidTM, PharmaciaUpjohn), have been against ‘old’ targets, i.e.,

targets subject to the emergence of resistance. Even

SynercidTM (Rhone-Poulenc Rorer) is a new analogue of the virginiamycins used for many years in

animal husbandry in the UK, with pre-existing

resistance in the gene pool. Numerous problems

have delayed or denied support, development, or

approval of novel antibacterial agents, among them:

toxicological problems with novel chemotypes;

development of resistance, even among the quinolones; concern for restricted use of new antibacterial agents; and loss of gram-negative activity in the

newer agents in development.

Development of new antimicrobials

Wise and colleagues (71,72) provide an overview

of the development of new antimicrobial agents,

categorizing research strategies into three groups:

1. improvement of existing agents;

2. vaccine developments; and

3. genomic approaches.

Existing classes (β-lactams, cephalosporins, and

carbapenems) have been a rich source of agents in

the past, but limited novelty opportunities and

emerging resistance have diminished these agents’

value. Older agents used solely in animal health,

such as orthosomycins and avilamycins, may

provide novel chemotypes for human drug development. Everninomycins, virginiamycins (streptogramins), oxazolidinones, t-RNA synthase

inhibitors (MupirocinTM), magainin-like peptides,

antisense agents, quorum-sensing agent inhibitors,

and efflux pump inhibitors may provide novel

approaches to combat resistance. These and others

are summarized in Table 3.

TABLE 3. SPECIFIC AREAS IDENTIFIED (6) WHICH MIGHT

YIELD PROMISING PRODUCTS WITH ACTIVITY

AGAINST ANTIBIOTIC RESISTANT BACTERIA

INCLUDED:

Streptogramins

Tetracycline analogues

Dual-action cephalosporins

Newer vancomycin analogues or vancomycin-like glycopeptides

Macrolides

Catalytic antibodies

Oligosaccharide-derived antibacterials

Antibiotic peptides

Bacterial/permeability increasing peptides

Magainins, cecropins, defensin-like molecules

Steroid antibiotics

Lactoferrin-based antibiotics

Anti-sense nucleotides

New strategies in antimicrobial development

may afford unprecedented opportunities for new,

novel antibacterial agents (88). The development

of three major technologies have provided hope:

• the use of genomics to identify novel targets;

• the use of combinatorial chemistry, including

parallel synthesis, providing a new level of highthroughput medicinal chemistry synthesis of

compounds; and

• advancements in screening technologies have

increased daily throughput by over 100-fold,

which use much smaller amounts of compounds,

and screen up to 20,000 compounds per day

(19).

TABLE 2

1991 1992 1993 1994 1995 1996 1997 1998 1999

# NMEs 5 6 4 NR 2 8 1 NR 1

Average NME 27.4 21.1 24.9 — 25.6 14.3 15.0 — 7.8

Approval Time mo. mo. mo. mo. mo. mo. mo.

NR = none reported
61

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Partnerships and incentives for development of new

antimicrobials

The Office of Technology Assessment (OTA) report (6), concerning research and development and

its impact on antimicrobial resistance, suggested

several options for encouraging the development

of new antibiotics; among them was a commontheme found in many of the other reports i.e., the

need for cooperative research among the government regulatory bodies, academia, and industry (6).

In the SMAC report (19), the following incentive recommendation is made to increase the pharmaceutical company support in a competitive and

profit-limited ‘competitive’ market: “One possible

way forward, balancing the need for continued innovation with that of drug conservation, lies in the

trade-off between extended patent life and increased

restriction.”

Vaccines

“Vaccination is one of the safest and most costeffective ways of preventing disease” (19).

Vaccines may represent the best chance for targeted coverage of a pathogen, although “resistance”

to a vaccine may also be unavoidable if variants of

the pathogen emerge which are not covered by the

vaccine. McKeller et al. (89) suggest that the use of

vaccines rather than prophylactic use of antibiotics

should be the norm in infection management in

animal health.

Vaccines may pose the most straightforward

option for long-term solutions to the resistance

problem e.g., for meningitis (pneumococcal,

Haemophilus influenzae or Neisseria) (6,21,90).

However, scientific feasibility, production capacity,

delivery infrastructure, social compliance, political

pressures, and cost constraints are not always easily

managed in industrial countries, let alone developing countries (6,21,90).There are a number of

important issues to deal with in developing a vaccine i.e.:

• Selection of disease states, microorganisms to

target (geographical, patient population differences such as age, gender, culture);

• Risk versus benefit;

• Efficacy (different efficacies and length of protection);

• Antigenic variation of pathogens (that reduce the

efficacy of the vaccine);

• Use of therapeutic vaccines;

• Choice in industrialized versus developing world

vaccine targets;

• Delivery of a vaccination programme to developing world needs.

Also vaccination against a pathogen that is also

a member of the normal commensal flora (e.g.,

Escherichia coli, enterococci, etc.) may be problematic or deleterious for the host.

Worldwide medical needs for bacterial vaccines

are summarised in Table 4 (6,21).

TABLE 4

Bacteria Infection

Neisseria meningitidis Meningococcal infection

(serotype B)

Mycobacterium tuberculosis Tuberculosis

Streptoccoccus pneumoniae Pneumonia for children under

12 years of age

MRSA Systemic infections; endocarditis

Vancomycin-resistant Systemic infections; endocarditis

enterococci

Neisseria gonorrhoeae STDs

Staphylococcus species Skin and soft tissue infections; Upper

respiratory, including sinusitus

Helicobacter pylori GI diseases (ulcer)

Group A streptococci Pharyngitis

Clostridium difficile Colitis

Shigella flexneri Gastrointestinal dysentery

Pseudomonas aeruginosa Respiratory (cystis fibrosis);

burn wounds

Chlamydia STDs; coronary artery disease

The National Institute for Biological Standards

and Controls cited in (21) suggested that much

more needs to be done about vaccine research and

development, especially aspects of research in immunology, microbial genetics, epidemiology, and

pathogenesis. In addition, issues surrounding the

formulation and delivery of vaccines are in need of

major initiatives worldwide.

Diagnostics

The delay in the diagnosis of a specific pathogen in

an infectious state may be the major reason for socalled “empirical use” of antibiotics and increases

the risk of inappropriate use. As the typical anti-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

62

microbial susceptibility testing takes ≥48 hours, the

overall process from first contact with medical care

to delivery of a specific diagnostic report (21) may

be longer.

Among the new technology detection systems

for rapid diagnosis of bacterial pathogens and resistance are (6):

• DNA probe assays.

• Target amplification methods.

• Enzymatic tests for specifically detecting resistance (i.e., β-lactamases).

• Tests based on indicator dyes or light-producing enzymes.

• DNA-based methods for testing antibiotic resistance.

Whereas rapid and reproducible bacterial identification in the clinic may become reality in the

future, the estimates are minimally 5–10 years out,

and most probably much longer when one considers the standardization issues, technology limitations, scale-up issues, cost constraints, politics, and

legal issues (risk of putative action for making the

wrong call). Genotypic testing, in which polymerase

chain reaction (PCR) technology is used to amplify

as little as a single bacterium’s DNA (in vitro), may be

technically feasible but the scale-up and application

in the clinic will be a major undertaking. Most importantly, the identification of a microorganism by

this technique in the patient may not always signal

a causal relationship to the infection.

Novel interventions

Levy (91) encourages the prudent use of antibiotics and for us to stop trying “...to sterilize our environment.” Levy argues that we need to review

how antibiotics are used and where resistant strains

reside, since resistance is mobile from country to

country. We need to examine the “ecology” of the

resistance, as this may tell us where the future resistance may occur from selective pressures. Lastly,

the indiscriminate use of disinfectants designed to

“...indiscriminately destroy bacteria...” rather than

reserving the arsenal for a defensive approach,

diminishes our capacity and capability to act when

human health is threatened by multidrug-resistant

pathogens (91).

A new approach to combating antimicrobial

resistance has emerged in which relevant human

host factors are identified and stimulated, especially

at the first site of pathogen attack, the epithelial

surface. Study of the intrinsic resistance of oralnasal-pulmonary sites, gastrointestinal sites, and

genitourinary sites may provide opportunities for

host-facilitated resistance to microbial invaders. The

link of pathogenesis and immunological response

to microbial insult is a new field of study (beyond

the many years of vaccine development), and may

provide an “immunoprotective” approach to combating antimicrobial resistance (22).

Summary of recommendations for

research and development

The generalized strategies from the USAID Report

(39) with five key recommendations, the Epilogue

from the Task Force on “Antimicrobial Use and

Resistance Worldwide” (1) with eleven recommendations, and the 1999 WHO report (50) with

eleven key recommendations, and the recommendations of other expert groups can be summarized

and focused towards industrialized and developing

countries as follows:

Industrialized countries

• Fund basic and applied research in academia,

government and industry to better understand

all relevant aspects of antimicrobial resistance

(genetic, epidemiological, mechanisms, transfer

of genetic material, etc.) and to ascertain shortterm gains to combat the ongoing threat of antimicrobial resistance. Support surveillance of

antimicrobial resistance as a research tool, and

link the data from surveillance to action in

response to the data (i.e., update old product

labelling for pathogen/indication coverage for

older antimicrobial agents that may be contributing to antimicrobial resistance by inappropriate use).

• Provide incentives to industry to address unmet

medical needs and provide new antibacterials to

combat antimicrobial resistance worldwide in

the short term, while encouraging partnerships

between industry, academia and government to

better exploit existing and new technologies to

combat antimicrobial resistance (drugs, vaccines,

diagnostics). Remove ‘anti-trust’ risk of having

industry collaborate on antimicrobial resistance.

Provide intellectual property protection rights

and enforcement to encourage industry to invest in antibiotic research and development in

developing countries.
63

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• Where industrial concerns elect to “pass” on infectious disease opportunities, provide a mechanism for a government or not-for-profit

leadership/risk in development of an essential

infectious disease therapy product (such as

vaccine or drug or diagnostic test); in a reverse

strategy of industry licensing-in from academia,

rather establish the option for the reverse process (license from the industrial concerns) to

occur.

• Ramp-up applied research, pairing pre-clinical

and clinical research to better assess the correlation between in vitro antimicrobial resistance and

clinical efficacy of drugs, and the links between

the bacterial infectious state and chronic diseases.

• Provide sound experimental support for the

rational and prudent use of antibiotics, in particular:

— Engage in clinical data-proven epidemiological outcomes research to determine methodology to decrease antimicrobial resistance

by improvement in best practices for antibiotic use.

— Demonstrate proof of concept of using the

most active (and safe) appropriate antibacterial regardless of cost, rather than the

historical or least expensive agent;

— Explore clinical usage of ‘resistance suppressive’ agents (agents with decreased resistance

development) such as the new quinolone

antibacterial agents with the C8-methoxy

substituent, and other chemotype antibacterials or anti-resistance agents if clinical

data supports in-vitro data;

— Explore the use of adjunct therapy with

“non-antibiotics”, similar to β-lactamase inhibitors, to control or reverse antimicrobial

resistance (e.g., efflux inhibitors);

— Stop using ‘old’ antibacterials with poor

activity and efficacy and adopt more appropriate therapeutic agents (regardless of cost).

This can be accomplished by the use of surveillance of antimicrobial resistance to guide

appropriate therapeutic decisions;

— Examine pharmacokinetics, pharmacodynamics, and dosage regimens of antibiotics

in relationship to resistance emergence probability;

— Recognize that the “prudent use of antibiotics” is not synonymous with “restriction of

antibiotic use” in man.

— Address the use of antibiotics in agricultural

and animal husbandry/feed (growth promoters) and act appropriately on the basis of

definitive data/conclusions.

• Ramp-up basic research to provide for the exploitation of new technologies to capitalize on

the genomic revolution. Exploit genomic information in its basic form to turn ‘data’ into

‘knowledge’ and extract information for new

targets, new opportunities for vaccines, new

opportunities for diagnostics, new insights into

molecular mechanisms of antimicrobial resistance, and to identify up-and-coming antimicrobial resistance problems

Developing countries

• Identify and implement plans to identify solutions to major impact diseases in developing

countries providing new therapeutic intervention options.

• Fund basic and applied research in academia,

government and industry to better understand

all relevant aspects of antimicrobial resistance in

the developing world and provide research and

development support for successful delivery of

treatment regimens to developing countries that

do not have the infrastructure to do so themselves by innovative approaches to treatment

options.

• Invest in improving the quality of life and health

overall, thus decreasing the risk of spreading infectious disease. Invest in local research and development to specifically address antimicrobial

resistance problems and solutions.

• Invest in education about the appropriate treatment regimen (preventative measures, drug

therapy, vaccines); provide support to invest in

developing world diseases (even developments

without industrial country ‘value’); assist in implementation of preventive strategies through

improving social infrastructure, sanitation, and

water supply systems. Provide education about

the relevance of surveillance that may be employed to implement appropriate antibiotic

treatment regimens. Invest in education to provide a framework for future research and development in developing countries themselves.

• Help provide developing countries the same

opportunity to build a quality infrastructure to

address health needs in the long term, includ-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

64

ing self-investment in research and development,

through sharing of resources with developing

countries.

• Invest in a vaccine strategy to combat antimicrobial resistance by preventing infectious diseases in man from vaccine-preventable diseases

worldwide. Consider combining genetically-engineered vaccines and food stuffs as a delivery

system for both food and vaccines (i.e., engineer specific antigens into the potato or rice

plant).

• Remove governmental control/blockage from

efforts to address antimicrobial resistance worldwide.

Conclusion

The need for basic and applied research and for

new product development is recognized throughout the literature reviewed. The introduction of new

technologies in drug discovery provide hope for the

future but the lack of research support for nonAIDS infectious disease research, especially TB research and other unmet medical needs in the

developing world, remains a serious limitation to

global solutions of antimicrobial research. The refusal to recognize antimicrobial resistance in the

clinic as a serious, relevant, real problem compromises world health.
65

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

CHAPTER V

Improve antibiotic use in animals

Scott A. McEwen

Introduction

The human health impact of non-human uses of

antimicrobials is an exceedingly controversial part

of the overall resistance problem, and a part that is

not very well understood. Antimicrobials have for

years been used in food animals, pets, and farmed

fish for treatment of disease and in some cases for

growth promotion and disease prophylaxis; they

have even been used to prevent bacterial infections

in fruit. Humans do not live in a bubble; we share

the environment with animals and plants. Bacteria

that are around us and within us can move relatively freely throughout the ecosystem in food,

water, air, and the soil. Most of the attention on

non-human use has focused on animal agriculture

because of the large volumes used there: as much

as 50% of total antimicrobial production by weight.

Important findings from the

literature review

Most of the documents reviewed made at least some

reference to the public health problems of antimicrobial resistance from antimicrobial use in animals,

plants, and aquaculture. A few documents

(9,18,24,25,92–95) were wholly devoted to the

subject. Some mentioned concerns about using resistance genes as markers in genetically-engineered

plants. While there is uncertainty about the environmental impact of resistance marker genes, it is

believed that the probability of their transfer to

microorganisms leading to health problems is extremely low (95).

Antimicrobials are used therapeutically to treat

food animals (cattle, sheep, poultry, fish, etc.) and

pets for bacterial infections (9,20,25,93). Some

animals are treated individually, although food animals may be treated in groups through medicated

feed or water if individual animal administration is

not feasible (e.g., poultry, fish) or is less efficient.

Therapeutic doses are administered for varying

periods of time, ranging from one to several days,

depending upon the drug and approved application as indicated on product labels. In some cases,

Abstract

Expert scientific panels from all over the world have

reviewed the evidence for resistance selection in

food animals and resultant human disease. Reports

of several of the most recent expert deliberations

are reviewed here, some of them devoted wholly to

the subject of non-human antimicrobial use. While

many uncertainties remain, recent studies have

shown that agricultural uses of antimicrobials do

have an impact. There is consensus among the

documents reviewed that antimicrobial use in animals selects for resistance in zoonotic pathogens and

commensal bacteria, and these resistant bacteria can

be transmitted to humans through contact with

animals or food, and that they can infect humans

and cause disease which can be more severe or

longer lasting than non-resistant infections. Furthermore, there is increasing concern about the reservoir of resistance that is building in enteric

commensals of animals (e.g., Escherichia coli, Enterococcus faecium) which may be transferred to

related, or even completely unrelated human

commensals and pathogens through exchange of

genetic material.

A number of strategies have been recommended

to reduce human health impacts from non-human

uses of antimicrobials, the most important being

to increase surveillance of resistance and antimicrobial use, to implement good regulation to control antimicrobial use in animals in light of

resistance concerns, and to take steps to ensure the

prudent use of antimicrobials in animals, especially

by reducing exposure of animals to low doses of

antimicrobials for long periods of time (i.e., growth

promoters and prophylactics) if such uses select for

resistance to drugs used in human medicine. Other

strategies include educational programmes for

veterinarians, food animal producers, and dispensers of antimicrobials for non-human uses, reducing the need for antimicrobials through alternative

treatments and infection control, and research.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

66

veterinarians prescribe antimicrobials in an extralabel manner (e.g., increased dose or duration of

treatment), either because labeled drugs are unavailable for the condition, or they are considered

no longer effective.

Food animals, especially those raised intensively,

may also be administered antimicrobials (usually,

but not always under veterinary prescription) for

prophylactic purposes during especially high-risk

periods for infectious disease (e.g., after weaning

or transport) or when one or more animals in the

group are observed with clinical disease and more

cases can be expected. Fruit may also be treated

with antimicrobials (e.g., tetracycline and streptomycin) in some countries to prevent certain bacterial infections, for example, Erwinia amylovora

(19,21).

Most controversially, food animals may also be

administered antimicrobials for growth promotion

or performance enhancement purposes (e.g., feed

efficiency). In some cases, the distinction between

prophylaxis and growth promotion is unclear because certain drugs may be approved for both purposes, and growth promoters may have disease

prophylaxis benefits. Growth promoters are usually administered in relatively low concentrations,

ranging from 2.5–5 mg/kg (ppm) depending on

the drug and to some extent the species treated (93).

Despite the fact that these drugs have been used

extensively in agriculture for over three decades

(21), scientists are not sure exactly how they improve growth efficiencies. It is believed, however,

that in addition to dampening the effects of subclinical disease on growth, the drugs may suppress

certain susceptible bacteria that compete for nutrients with the host animal. It has been pointed out

that the benefits are greater under poor hygiene

conditions, and their current efficacy is questioned

because other means of controlling disease (e.g.,

biosecurity, vaccination) have been introduced more

widely into intensive animal husbandry. It is believed that efficiencies of 1–11% can be realized

(21,93). Another purported benefit of growth promoters is a reduction of total nitrogen and fecal

output per animal marketed, which has environmental impact implications. One expert panel (25)

went so far as to state that antimicrobials, in particular at sub-therapeutic doses (as in growth promotion and disease prophylaxis), had an important

positive role in facilitating the intensification of

food animal agriculture that is characteristic of

many industrialized and some developing countries,

thereby enabling the production of abundant quantities of food. Other reports contend that this intensification of food animal production is at least

partially responsible for antimicrobial resistance

problems in agriculture, by increasing the need for

antimicrobial use. Aside from growth promoter use,

which is more common under intensive animal rearing conditions than in extensive, or pasture-based

husbandry, intensive rearing can increase the need

for treatment by fostering the spread and clinical

expression of infectious diseases of animals, and by

enhancing the spread of resistant foodborne pathogens and other bacteria among animals.

Antimicrobial use data are sparse and most documents cite the difficulty in obtaining accurate, upto-date consumption figures by species and

intended use. It has, however, been estimated that

as much as 50% of total antibiotic production (by

weight) is used in animals and plants, with 50–80%

used in some countries for growth promotion or

disease prophylaxis and the rest used for therapeutic purposes (9,20,21). Usage patterns vary tremendously, but in some countries, a majority of food

animals receive antibiotics at some point in their

lives, and many for extended periods of time at

subtherapeutic doses.

Many antimicrobials are administered to animals

under veterinary prescription, but in some countries, they may also be available for veterinary use

without a prescription. These drugs are frequently

available over the counter in feed stores and pet

shops and may be included in purchased feeds without veterinary prescription. Financial incentives

exist for the production and distribution of veterinary drugs, just as they do for human antimicrobials. Pharmaceutical companies, importers,

pharmacies and other retailers may all profit from

the sale of antimicrobials to animal owners.

Veterinarians may also profit from the sale of

antimicrobials to food animal producers, and it has

been reported that as much as 40% of their income

can come from this source (50).

Most of the classes of drugs used in human medicine are also used in veterinary medicine, although

there is considerable variability within and between

countries in the range of drugs approved for use in

various animal species. Some examples of antimicrobials approved (as of 1999) in the United

States are presented in the Table.

Very little attention was given to antimicrobial

use in pets in the documents reviewed, although

this area will probably receive more attention in

the future. Pets are frequently in close contact with

their owners and when ill they are often treated
67

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

with the same drugs used in human medicine.

Regulatory approval for use of antimicrobials in

animals and plants, when it is accompanied by

human health risk assessment by competent

national regulatory authorities, may not include

considerations of microbial safety (especially resistance). In fact, until recently only a small number

of countries considered resistance at all in the veterinary drug approval process (93). Traditionally,

human health safety determinations of veterinary

antimicrobials focused on the effects of antimicrobial residues in foods of animal origin. The United

States (18) required pharmaceutical companies to

compile and report microbial safety data in their

pre-approval submissions to regulatory authorities

for drugs intended for long-term prophylactic or

growth promotion use in feeds. Even in recent years

when antimicrobial resistance issues have been in

the forefront, some countries approved important

drugs (e.g., fluoroquinolones) in light of epidemiological evidence from other countries of resistance

emergence in foodborne pathogens (19). This suggests that antimicrobial resistance concerns were not

addressed in the approvals, or any human health

risks that were identified were insufficient to override other considerations.

There is consensus among the documents reviewed that treatment of animals and plants with

antimicrobials leads to resistance in bacteria. The

selection pressure of antimicrobial usage is thought

to be greatest during low-dose, long-term exposure,

which is characteristic of growth promoters and

some disease prophylaxis. However, therapeutic

TABLE. EXAMPLES OF ANTIMICROBIALS APPROVED FOR USE IN THE UNITED STATES (ADAPTED FROM 25)

Antibiotics approved in the United States for various species

Purpose Cattle Swine Poultry Fish

Treatment of various Amoxicillin Amoxicillin Erythromycin Ormetoprim

infections Cephapirin Ampicillin Fluoroquinolone Sulfadimethoxine

Erythromycin Chlortetracycline Gentamycin Oxytetracycline

Gentamycin Erythromycin Neomycin

Novobiocin Gentamycin Penicillin

Penicillin Lincomycin Spectinomycin

Sulfonamides Sulfamethazine Tetracyclines

Tilmicosin Tiamulin Tylosin

Tylosin Tylosin Virginiamycin

Growth and feed efficiency Ampicillin Arsenilic acid Bambermycin

Bacitracin Bacitracin Bacitracin

Chlortetracylcine Bambermycin Chlortetracycline

Lasalocid Chlortetracycline Penicillin

Monensin Penicillin Tylosin

Oxytetracylcine Tiamulin Virginiamycin

Tylosin

Virginiamycin

treatments, administered at higher doses for shorter

periods of time to individuals or groups of animals,

can also select for resistance. Enteric bacteria of food

animals are especially exposed to selection pressure

because many drugs are administered in food or

water but bacteria in other anatomic locations may

also be exposed because many drugs are absorbed

from the gut and others are administered parenterally. In addition, many drugs are excreted in active

form in urine or faeces and peresist in the environment for prolonged periods of time, where they

may exert selection pressure on environmental bacteria. In fish farming, for example, it has been estimated that as much as 70–80% of antimicrobials

administered may end up in the sediment of the

body of water (96). In general, the implications of

this environmental exposure are poorly understood.

Antimicrobial resistance occurs in the target

species of organisms (animal pathogens in the case

of veterinary drugs) and in a variety of non-target

species in the gut or in other sites. Resistance in

the animal pathogens of most importance to animal health is often of little direct human health

significance. While there are many bacterial infections of animals that can cause disease in humans

(zoonoses), few of these (Salmonella is a notable

exception) are important causes of clinical disease

in food animals or pets. There are a variety of ways,

however, that antimicrobial resistance arising in agriculture can have a negative impact on public

health. The first two were most frequently mentioned in the reviewed documents:
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

68

1. Treatment of animals with antimicrobials important in human medicine, or drugs of the same

family or class, can select for resistance to these

drugs in zoonotic pathogens (e.g., Salmonella,

Campylobacter). Resistant zoonotic pathogens

can be transmitted from animals to humans

through direct contact or indirectly through food

or water, and cause illness which does not respond to treatment. Exposure of animals to

drugs not used in humans (or no longer used in

humans) can also select for resistance to drugs

important in human medicine if the resistance

determinants are genetically linked. For this reason, the linkage of two or more resistance genes

on transmissible elements such as plasmids is of

increasing concern. This phenomenon also

makes the separation of antibiotics into “animal”

and “human” use categories less tenable from a

resistance point of view.

2. Genetic determinants of resistance in commensals of animals (e.g., Escherichia coli, enterococci)

may be shared by exchanging plasmids, transposons or other transferable elements with

related or even unrelated human pathogens during transient colonization of the gut of humans

after ingestion of contaminated food or water.

Some of the documents drew attention to other

potential human health impacts:

3. Extending the principle in (2) above, resistant

bacteria from animals or plants are part of a larger

antimicrobial resistance ecosystem, and their

resistance genes could find their way through a

variety of poorly understood, indirect pathways

to human pathogens. These pathways could

involve transfer of resistance genes through intermediary environmental organisms. Concern

in some quarters has been expressed about

inclusion of resistance markers in geneticallymodified plants, however the documents reviewed do not consider this as an important issue

(93,21).

4. As a consequence of taking an antimicrobial for

some other reason (e.g., ear infection or pneumonia), people become more susceptible to disease when exposed through food or other source

to a pathogen from animals that happens to be

resistant to that drug (e.g., multi-resistant

Salmonella spp.).

5. Resistance may be linked with other genetic

determinants which render pathogens more

capable of causing disease, and thereby increase

their virulence. In this instance, resistant pathogens may cause more severe or longer-lasting

disease in people than comparable susceptible

pathogens.

6. Antimicrobial use in food animals may, in some

cases, lead to an increase in the shedding of

zoonotic pathogens (e.g., Salmonella) in animal

faeces and thereby available for human exposure,

whether or not the pathogen is resistant. This is

a phenomenon called “pathogen load”, and it

could occur through a number of complex and

poorly understood mechanisms whereby antimicrobial use in animals results, for example, in

an increase in the duration of faecal shedding of

foodborne pathogens, or an increase in the concentration of pathogens in faeces which may then

contaminate food or water.

7. There is some concern that antibiotic residues

eliminated in animal faeces and urine may exert

resistance selective pressure on bacteria in soil

and water. Treated animals and humans may excrete considerable quantities of active drug or

metabolite and many of these residues are slow

to degrade in the environment.

Most of the documents acknowledge that the

public health impacts of antimicrobial use in animals and plants are complex and poorly understood.

These issues have been the subject of considerable

controversy and scientific debate for decades. There

is consensus, however, that resistance does occur in

zoonotic pathogens and commensals when animals

are treated, that humans are occasionally exposed

to these bacteria through contaminated food and

water, and that illness, and sometimes treatment

failure, does occur due to these resistant zoonotic

infections. There is also consensus, however, that

much uncertainty remains about the frequency with

which these events occur, and the overall magnitude (numbers of people affected, severity of outcome, economic impact, etc.) of the public health

impact of resistance arising in agriculture.

Some of the uncertainties were reconciled in

recent years through a number of well-conducted

epidemiological studies, carried out principally in

Europe and the United States. The results of these

studies are summarized later in the chapter. However, the reviewed documents were virtually unanimous in recommending more research and

enhanced surveillance to better understand resistance in both medical and veterinary medicine. Surveillance of antimicrobial resistance among zoonotic

pathogens and commensals in food animals, food
69

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

products, and foodborne infections of humans, as

well as monitoring non-human uses of antimicrobials is thought to be the best way to identify

and quantify the effects of non-human antimicrobial use on resistance throughout the food chain.

“Only quantitative data, obtained through application of standardized laboratory methods, will

allow for meaningful epidemiological analysis and

evaluation” (9).

Antimicrobial resistance from agriculture is in

many ways a food and water safety issue (8). Over

the past couple of decades, food and waterborne

diseases appear to have increased in incidence in a

number of countries. A number of factors are probably responsible for this, including a greater burden of pathogens (resistant and susceptible) that is

transmitted through the food chain from animal

populations and plant products to humans. No

doubt myriad factors are responsible for the emergence and dissemination of the wide range of these

food and waterborne infections that are major public health problems for both industrialized and

developing countries. These same factors may be

important in promoting the spread of resistant

zoonotic pathogens and commensals, as well as

environmental bacteria, to humans. By the same

token, steps that are being taken throughout the

food chain to reduce the impact of food and

waterborne infections in which resistance is not yet

recognized to be a problem (e.g., E. coli O157:H7,

Salmonella enteritidis) may also reduce the public

health burden of resistance. Some of these steps

include Hazard Analysis, Critical Control Point

(HACCP) programmes, quality assurance programmes, irradiation and pasteurization (19,92).

The most important strategies that were recommended specifically to reduce the public health

impact of antimicrobial use in agriculture fell into

the following major categories (9,25,50,53,92–95):

government regulation; education and prudent or

judicious antimicrobial use guidelines; monitoring

of antimicrobial use; surveillance of resistance; reducing the need for antimicrobials through alternative treatments and infection control; and

research.

Effective and non-effective strategies

The human health impact of antimicrobial use in

agriculture has been the subject of debate, discussion, analysis, expert panel deliberation, and qualitative risk assessment for decades. National and

international expert panels and committees have

produced a large number of documents; many of

those are reviewed here. One of the most cited of

these was the UK Swann Report of 1969 (97). This

report is remembered as one of the first recommending that antimicrobial growth promoters and

other drugs used without prescription in animal

feeds should be restricted to antimicrobials that have

little or no application as therapeutic agents in humans or animals, and will not impair the efficacy

of a prescribed therapeutic drug through development of resistance. Secondly, the Swann Report

recommended that therapeutic antimicrobials for

animals should only be available under a veterinary

prescription. These principles have been endorsed

by most subsequent expert panels and task forces

and lay a foundation for modern recommendations.

The British government later implemented the

Swann recommendations, and some credit was

given to a reduction in antimicrobial-resistant

Salmonella infections. Some have claimed, however,

that the measures recommended by Swann were

not effective because total antimicrobial consumption in UK agriculture did not decline, and further

outbreaks of antimicrobial resistant salmonellosis

eventually occurred. In reality, it is difficult to determine the effects on resistance and total use because there was no comprehensive surveillance

system in place at the time. The US Food and Drug

Administration (FDA) proposed in the 1970s to

stop the sub-therapeutic (growth promotion and

prophylactic) use of penicillin and tetracycline in

animal feeds but was criticized because there was

inadequate evidence of adverse human health

effects and the proposal was unsuccessful (6,24).

In 1986, Sweden banned the use of growth promoters in animal production (21). Unfortunately,

at the time the Swedish government did not have a

resistance surveillance system in place with which

to measure the effects of the ban on resistance in

animals, foods, and humans. However, the quantities of antimicrobials sold for use in animals were

monitored. Animal health statistics show that in

the early stages after the rather abruptly introduced

ban, increases in morbidity and mortality were

observed (e.g., post-weaning diarrhoea in piglets

and necrotic enteritis in chickens). To counteract

this, antimicrobials used earlier for growth promotion were prescribed for prophylaxis during highrisk periods. Efforts were made to improve

management, feed, and hygiene in order to adapt

to non-routine use of antimicrobials. In the early

1990s, zinc oxide replaced antibiotics as prophylaxis for piglets. Since 1998, zinc oxide is only avail-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

70

able in Sweden on prescription and use has declined

to less than 10% of its maximum. Total sales of all

antimicrobials for animals decreased fairly substantially (by approximately 60%) (98).

In the 1990s, public health surveillance in the

UK and elsewhere in Europe identified some new

resistance issues that once again heightened concerns about agricultural use of antimicrobials.

Among these issues were the increase in Salmonella

typhimurium DT104 infection in humans and animals, the appearance of fluoroquinolone-resistant

Campylobacter jejuni infections in humans and

poultry, and the occurrence of vancomycin-resistant enterococci (VRE) in pigs and poultry.

Salmonella typhimurium DT 104 was first identified in the UK but has since been found in many

countries throughout the world where it is an important cause of disease in humans, cattle, pigs,

poultry, and other animals. Salmonella strains

appear to come and go in “waves” every few years

(epidemics of DT29, DT204, DT193 and DT104

strains were observed in the UK (21) but DT104

was particularly concerning to public and animal

health officials because of its pathogenicity and the

fact that most isolates were resistant to at least five

antimicrobials (pentaresistance). While the role of

agricultural antimicrobial use in the genesis and

spread of Salmonella typhimurium DT104 is unknown, there is good evidence that antimicrobial

use in animals was associated with development of

reduced susceptibility to fluoroquinolones among

some isolates of this organism. This evidence rests

mainly on the temporal relationship between approval of fluoroquinolones for use in food animals

and identification of resistant (reduced susceptibility) strains. Shortly after fluoroquinolones were

licensed as therapeutic agents for food animals in

the UK, public health laboratories began to identify isolates with decreased susceptibility to

quinolone drugs. This was particularly alarming

because fluoroquinolones are very valuable drugs

for treating humans for a variety of infections, including invasive salmonellosis.

Similarly, investigators in other European countries, (e.g., the Netherlands, Spain) where

fluoroquinolones were approved for therapeutic

treatment of poultry, identified substantial increases

in the prevalence of fluoroquinolone resistance

among poultry and human isolates of Campylobacter jejuni. This type of resistance was remarkable in the rapidity with which it appeared and

increased in prevalence (21,92). Other countries

have reported similar findings.

Avoparcin is a glycopeptide antimicrobial in the

same family as vancomycin. It was approved for

use in many European countries as a growth promoter. At the time since vancomycin was not widely

used, there was little reason to be concerned about

resistance problems in humans. Things changed,

however, when vancomycin became critical in

human medicine for treatment of methicillinresistant Staphylococcus aureus (MRSA) and other

serious infections. Resistance to vancomycin, especially among enterococci (VRE) became an important public health problem in many countries.

Researchers identified VRE in food animals exposed

to avoparcin, where they were not found in animals in countries where avoparcin was not used as

a growth promoter. Furthermore, the prevalence

of VRE among non-hospitalized people in the community was much higher in countries that used

avoparcin. There is evidence that VRE in food

animals may have been a reservoir for resistance in

humans, perhaps through exchange of genetic

material between animal and human strains, or

through transient colonization of the human gut

by animal strains.

It is worth reiterating that prior to identification of the link between avoparcin use and VRE in

food animals, the drug was thought to be an

appropriate choice for a growth promoter. This is a

good example of a major problem confronting the

animal and pharmaceutical industries and those

charged with drug regulation. Growth promoter

drugs that are seemingly safe today because they

are not used in people and do not select for resistance in people may not be in the same position

tomorrow, if the same or related drugs become

important in human medicine. Some older families of pharmaceuticals, previously not considered

necessary or desirable for human medicine, are “retrieved” in order to combat new resistance problems (e.g., vancomycin for MRSA). More recently,

the same sort of thing has happened with

virginiamycin, which is a streptogramin antimicrobial that has been used for many years in agriculture, principally as a growth promoter in poultry

and pigs but also in some cases for disease prophylaxis. There is now evidence that virginiamycin use

selected for streptogramin resistance in enterococci

and there is considerable concern that this could

compromise the usefulness of related streptogramin

drugs (e.g., pristinamycin and quinupristindalfopristin), which have been recently introduced

for treatment of vancomycin-resistant enterococci

and other bacterial infections in humans.
71

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Growth promoters do not necessarily cause resistance problems in humans. For example,

ionophores are a group of antimicrobials used

widely in veterinary medicine for growth promotion in a variety of species, and for treatment and

prevention of coccidiosis in poultry. Resistance has

so far not been identified as a problem in animals

and there are no indications that the family of drugs

will become useful in humans, perhaps because of

toxicity concerns.

It is important to point out that these examples

of recent resistance concerns involve both growth

promoters (avoparcin, virginiamycin) and therapeutic drugs (fluoroquinolones). Strategies to address

these concerns are likely to be somewhat different;

with the former, regulatory measures (i.e., decision

to permit their use or not) are most important; with

the latter, assurance of prudent use is very important in minimizing concerns.

Collectively, public health concerns arising from

Salmonella typhimurium DT104, quinolone resistance in Campylobacter jejuni and Salmonella, and

glycopeptide and streptogramin resistance in enterococci substantially raised the profile of antimicrobial resistance as a public health issue in the

veterinary, agricultural and food industries. Some

strategies have been implemented to reduce the

public health impact, or to improve understanding of the type and magnitude of the impacts and

these are discussed below.

Government regulation

Mention has already been made about the measures taken in UK after the Swann Report of 1969

(97) to restrict the use of growth promoters to drugs

not used in human medicine, and about the suggestions in the literature that these measures were

not effective in reducing total antimicrobial use in

animals. There may, however, have been benefits

in reducing incidence of resistant Salmonella.

Although not discussed in the reports reviewed, it

has been pointed out in the literature that any reduction in usage achieved through restrictions on

growth promoters was compensated by increases

in prescription drug use. This underscores the need

in any overall strategy to carefully monitor all uses

of antimicrobials and take appropriate control

action if excesses are detected, and to reduce the

need for antimicrobials by making improvements

in animal management, hygiene, and health.

Many countries, most notably in Europe, have

banned the use of avoparcin in animal feeds, and

in some countries (e.g., Australia) the drug has been

withdrawn voluntarily. Fortunately, some countries

have monitored VRE prevalence in animals, food

and humans and there are reports that the prevalence in food animals (initially in poultry) has

decreased in Denmark and Germany since the withdrawal (4). Although immediate decreases were not

seen in pigs in Denmark, recent data suggest that

the prevalence of VRE in pigs is decreasing, and

that levels may have been maintained, at least in

part, by cross-resistance with macrolides (e.g.,

tylosin). Reduction in tylosin use has been accompanied by a decrease in VRE prevalence (99).

In 1999, four drugs (tylosin, virginiamycin,

spiramicin, and bacitracin) were banned as growth

promoters on the basis of the precautionary principle that they or related drugs are used in human

medicine, or select for resistance to drugs used in

human medicine. This action was also consistent

with recommendations from the Swann Report and

WHO. While this action was mentioned in the

reviewed documents, the ban is so recent that there

were no data available on its effects in terms of

resistance trends among zoonotic or commensal

bacteria, trends in antimicrobial usage in animals,

or in terms of effects on the health of animals or

indices of production (e.g., feed conversion, days

to market, etc.). It is too early to tell what these

effects will be; nevertheless, there are some recently

published data from Denmark where reductions

began a little sooner than in the rest of Europe (99).

Danish farmers had actually decided voluntarily in

1998 to stop feeding growth promoters to food

animals and phase out their use by 2000. The

DANMAP 99 report (Danish Integrated Antimicrobial Resistance and Research Program) describes

drug use patterns in the country in 1998, after the

reductions were in place (99). The early stages of

reduction in growth promoters were not accompanied by an increase in consumption of therapeutic

drugs, but between 1998 and 1999 there was an

increase in tetracycline use for treatment of enteric

disease in swine.Time will tell whether additional

positive or negative effects on therapeutic drug use

will be seen in Denmark.

The effects of the European ban of 4 growth

promoters on resistance in zoonotic bacteria and

commensals are also largely unknown because the

ban is so recent. DANMAP reported that samplingrelated problems made the Danish Salmonella

results from 1998 difficult to interpret, because

many isolates from both animals and humans were

linked epidemiologically. Resistance in Campylo-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

72

bacter coli to erythromycin dropped by almost 50%

in 1998, and this was attributed to withdrawal of

tylosin (another macrolide) as a growth promoter.

Among enterococci of pigs and poultry, reduction

in resistance to vancomycin, virginiamycin, and

erythromycin were observed after the ban. Among

E. coli, the proportion of isolates resistant to one

or more antimicrobials decreased over the same period, but changes in prevalence of resistance to specific banned growth promoters were not observed

(99).

Another important regulatory development that

has taken place in some, but not all countries, is

the inclusion of antimicrobial resistance considerations in the drug approval process. In the United

States, a great deal of attention has been given to

the so-called “Framework Document” (Proposed

Framework For Evaluating And Assuring The

Human Safety Of The Microbial Effects Of Antimicrobial New Animal Drugs Intended For Use In

Food-Producing Animals), developed within the

Food and Drug Administration and published in

1998 (24). The Framework is “intended to provide a mechanism for evaluating and ensuring the

human safety of antibiotics and other antimicrobials

used in food animals, including those used for

growth promotion” (24). The Framework is a conceptual risk-based process with the stated goal of

preserving the effectiveness of drugs which are important in human medicine while enabling the safe

use of antimicrobials in food animals. It provides

for categorization of antimicrobials on the basis of

an assessment of their importance to human medicine. Category I drugs (or members of a class of

drugs) are essential for treatment of life-threatening diseases of humans, or are important for treatment of foodborne diseases of humans, or are

members of a unique class of drugs used in

humans. Examples include quinolones, vancomycin, and quinupristin-dalfopristin. Category II

drugs are important for treatment of potentially

serious human diseases, but for which suitable alternatives exist (e.g., ampicillin, erythromycin).

Category III drugs have little or no use in human

medicine or are not the drug of first choice for

human infections.

Importantly, the Framework strategy would also

categorize, into high, medium and low, the likelihood of human exposure of resistant human pathogens arising from the use of drugs in food animals.

This is an attempt to use in the characterization of

risk information on the ability of the drug to select

for resistance in bacteria, the likelihood that resistant bacteria will be transmitted to humans through

foods or other sources, and the likelihood that this

transfer will result in the loss of treatment options.

Categorization would include consideration of drug

attributes (e.g., mechanism and rate of resistance

or cross-resistance induction), the expected product use patterns (e.g., duration of treatment, species, number, and type of animals treated), and

potential human contact (e.g., bacteria of concern,

environmental and food contamination, food

processing effects). Examples that were given include: a growth promoter used in multiple species

and inducing resistance to an antimicrobial used

in human medicine would be placed in the high

potential human exposure category; a drug used

for entire herd therapy during outbreaks of disease

which occur in a small fraction of herds would be

placed in the medium category; and a drug used

for individual animal treatment of only occasional

animals in herds, for a short duration, would be

placed in the low category.

Another very important feature of the Framework in a regulatory sense is the notion of establishing safe resistance threshold levels for

antimicrobials. Conceptually, the threshold level

could be set at the level of resistance that carries

with it insignificant likelihood of transfer to

humans, if it were possible to accurately determine

such a level. There is also provision for establishing

levels for Category I drugs to be used in postapproval monitoring of resistance and which could

serve as an early warning system indicating that

resistance was reaching a level of concern. The document acknowledges that the usefulness of such

thresholds depends upon the ability to demonstrate

that they are sufficiently protective of public health,

and that there is a capability of detecting when such

levels are reached.

The Framework document also makes provision

for requiring pharmaceutical companies to conduct

pre-approval studies of drugs in order to characterize the type and rate of resistance development.

Post-approval monitoring studies may also be

required of certain drugs in order to identify emergence of resistance of sufficient concern to public

health to trigger intervention and mitigation strategies. Finally, there is provision for requiring submission by pharmaceutical companies of detailed

drug sales information by species, state, dosage

form, year, and estimate of active units sold.

Another important initiative undertaken by

FDA in 1999 was preparation and public presentation of a “Draft Risk Assessment on the Human
73

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Health Impact of Fluoroquinolone Resistant

Campylobacter Associated with the Consumption

of Chicken”. This effort could be a milestone in

evidence-based regulatory decision-making in the

area of antimicrobial resistance in agriculture. The

risk assessment is a highly focused, structured assembly of scientific and public health information

from a variety of relevant sources, including the

scientific literature, public health surveillance

databases, and expert opinion. The assessment is

an attempt to estimate in quantitative terms the

public health risk in one year from resistant foodborne pathogens due to the use of antimicrobials

in food producing animals. Within the assessment,

a mathematical model was developed which related

the prevalence of fluoroquinolone-resistant

Campylobacter infections in humans to the prevalence of fluoroquinolone-resistant Campylobacter in

chickens (a major source of Campylobacter jejuni

infection in the United States). Fluoroquinolone

resistance in Campylobacter was selected because

campylobacteriosis is the most commonly reported

bacterial foodborne disease in the United States,

fluoroquinolones are important drugs in human

medicine which are sometimes used to treat people

sick with this disease, and fluoroquinolones are

approved for use as therapeutic agents in poultry.

As previously mentioned, fluoroquinolone resistance has been identified as a problem in Campylobacter jejuni in a variety of other countries where

these drugs are used to treat poultry.

Using data from epidemiological studies and the

FOODNET surveillance system in the United

States, the model estimated the most likely and estimated range of cases of fluoroquinolone-resistant

Campylobacter jejuni infections that occur in one

year in the United States, and which are treated

with fluoroquinolones by physicians. The risk assessment clearly describes the assumptions that are

made in construction of the model and identifies

the various uncertainties that arise from lack of

knowledge or variability in data inputs. As an

example of one outcome from this model, the estimated mean number of people with fluoroquinolone-resistant Campylobacter infection from

chicken who received fluoroquinolone in 1998 was

5065 (with a 90% confidence interval of 2585,

8595).

This risk assessment is important for a number

of reasons. Many stakeholders in the veterinary,

animal production, and pharmaceutical sectors have

for years been asking for a risk-based regulatory

decision-making process on antimicrobials. Quantitative risk assessment is used in a number of fields

to assist risk management decision-making when

the magnitude of health impacts is clouded by complexity and uncertainty. This is certainly the case

with estimating the human health impacts of antimicrobial use in agriculture. The FDA assessment

is also a good example of the use of available surveillance data to estimate quantitatively the human

health impact. Quantitative risk assessment is being used increasingly in other microbial food safety

issues, and experience and confidence in the process are growing. An important next step for regulators is to identify the public health risks from

resistance that are “acceptable” to society. A generally acceptable level of cancer risk from environmental chemicals is one per million in the

population over a lifetime of exposure. It remains

to be seen whether acceptable levels for microbial

risks can be agreed upon internationally. If such

levels (or “risk standards”) can be agreed upon,

quantitative risk assessment could be used to identify resistance thresholds, beyond which public

health impacts become unacceptable. This will no

doubt prove to be a difficult, but important task.

Education and prudent use of antimicrobials

None of the documents reviewed educational or

prudent antimicrobial use strategies which have

been shown to be effective in reducing resistance

risks, nor was evidence presented that any have

actually been implemented. There are anecdotal

reports in the scientific literature that a number of

national and international organizations (e.g., professional veterinary associations) have begun to

develop prudent or judicious use guidelines for

antimicrobials in animals, and in some cases, codes

of antimicrobial prescription in veterinary practice.

There are also some reports of attempts to draw

attention to the issue in the minds of veterinarians

and food animal producers, many of whom still

believe that the only public health concerns that

arise from antimicrobial use in food animals are

residues of drugs in edible tissues.

Although not mentioned in the documents,

Denmark has recently put significant limits on the

ability of veterinarians to profit from the sale of

antimicrobials in food animal production. The

effects of this measure on antimicrobial sales and

consumption are not yet known.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

74

Monitoring of antimicrobial use

Some of the documents mentioned that some countries (notably in Scandinavia) have been assembling

national antimicrobial consumption data, or have

recently instituted the assembly of these data.

Sweden was able to document the effects of their

growth promoter ban on consumption of

antimicrobials for prophylactic and therapeutic

purposes because they had an antimicrobial use

monitoring system in place. As described above,

the United States has declared plans to require the

submission of antimicrobial sales data to the FDA,

which can be used to monitor trends in consumption, and in epidemiological and risk assessment

studies addressing the associations between antimicrobial use and resistance in animals and humans.

Although not specifically mentioned in the documents reviewed, Denmark has instituted an antimicrobial use monitoring system (DANMAP) to

accompany its resistance monitoring.

Surveillance of resistance

Calls for resistance surveillance systems figure

prominently in nearly all reviewed documents. It

is generally hoped that these systems will provide

descriptive data on resistance, which will enable the

identification of temporal trends, emerging issues,

and the extent of resistance in human and animal

populations and food products.

Many countries have for some time had elements

of national resistance surveillance in place. It was

surveillance of resistance data assembled by the

Public Health Laboratory Service in the UK which

identified the emergence of decreased susceptibility to fluoroquinolones among Salmonella

typhimurium DT104 isolates (21). Public health

scientists in other countries have made similar contributions to our understanding of resistance issues.

Two comparatively new antimicrobial resistance

surveillance programmes are the previously mentioned DANMAP in Denmark, and NARMS in

the United States. DANMAP is run by the Danish

Veterinary Laboratory (22,99). DANMAP reports

are issued annually and describe antimicrobial consumption data in animals and humans, resistance

in zoonotic bacteria (e.g., Salmonella, Campylobacter), resistance in indicator bacteria (e.g., E. coli,

enterococci), and resistance in bacteria from diagnostic submissions from humans and animals. Summaries are included which include interpretation

of observed trends, relationships between antimicrobial use patterns and resistance, and sources of

potential bias. This programme is able to document

the effectiveness of some of the strategies that have

been used in Denmark to curtail resistance from

food animals, most notably the ban on growth promoters.

In the United States, NARMS (National Antimicrobial Resistance Monitoring System) Enteric

Bacteria Program tests antimicrobial resistance related to agriculture (22,24). It began in 1996 as a

joint effort by the Centers for Disease Control and

Prevention (CDC), FDA and US Department of

Agriculture. Isolates (initially Salmonella, with addition of Campylobacter in 1997) are obtained from

human clinical specimens, animal clinical specimens, normal animals, and carcasses at slaughter

from across the United States. Data from NARMS

were used in the FDA’s quantitative risk assessment

of fluoroquinolone-resistant Campylobacter from

chicken (described above) and have been presented

in a variety of scientific venues.

Alternative treatments and infection control

As mentioned above, Sweden reported that farmers eventually adapted to the ban on growth promoters by a number of means, including the

implementing improved husbandry practices and

increased use of zinc oxide (which has been criticized on environmental grounds (21), but now

appears to be under control (98). While this is evidence that antimicrobial needs were reduced, there

was no resistance monitoring in place that could

measure the effect of management changes on

resistance.

Barriers to action

There are many disincentives and barriers to the

further implementation of resistance risk reduction

strategies. These include a general lack of acceptance among veterinarians and food animal producers that a resistance problem exists in agriculture; a

lack of scientific information on the extent and

magnitude of public health risks; conflicting economic interests; the costs of implementing alternatives; lack of regulatory will and capability; lack

of efficacious and economical alternatives to

antimicrobials; and lack of resources to develop and

implement strategies.

A major barrier is the lack of acceptance that

agriculture and veterinary medicine are significant

contributors to the human health impacts of resistance. Large numbers of veterinarians, other sci-
75

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

entists involved in agriculture, and food animal

producers simply do not believe that antimicrobial

use in food animals has substantial negative health

effect on humans. This is not simply a lack of awareness due to inadequate or insufficient education or

training, but has to do with the relative lack (until

recently) of concrete examples clearly documenting the impacts. Unlike physicians, who see patients

with disease caused by resistant bacteria, and who

can see that resistance in hospital and communityderived pathogens is related to use of antimicrobials

in those settings, veterinarians and producers do

not see these cases. Until recently, few welldocumented examples of human illness from

resistant pathogens originating on the farm have

been described, (e.g., the recently-described case

of ceftriaxone resistant salmonellosis in a child

apparently infected on a farm) (100). The tremendous complexity of the food production, processing, distribution and food service system in

industrialized countries makes it extremely difficult to trace infections and resistance genes. If

people do not believe that their practices and behaviours create public health risks, it is more difficult to get them to change these behaviours.

The lack of scientific information presents a

further barrier to obtaining general agreement, even

among people without a financial stake in the

issue, when intervention strategies are warranted.

Almost intuitively, many stakeholders in food

animal industry and veterinary medicine call for a

“science-based” or “risk-based” regulatory decisionmaking process on resistance issues. Many government agencies themselves call for more evidence

before implementing interventions (24). There is a

conflict between those who believe that enough

evidence exists to warrant risk-reduction actions,

and those who believe there is a need for more evidence of the nature and extent of the problem before attempting to fix it.

Balancing the risks of resistance against the benefits of antimicrobial use in agriculture is also a

barrier to action. One of the reasons for this is that

the risks and benefits are borne by different groups.

The food animal producer might save the life of an

animal (and therefore his investment) by treating

it; he realizes directly the benefit of treatment. Any

resistance risks arising from that treatment would

most likely be realized by someone exposed to the

resistant bacteria, far down the food chain. Conversely, if the producer reduces antibiotic use on

his farm, he may not realize any direct benefit.

Just as there are some financial incentives for

antibiotic use in humans, strong financial reasons

exist for continued use of antibiotics in foodproducing animals for food animal producers,

veterinarians, and pharmaceutical companies.

If society as a whole is not prepared to accept

some risk from the non-human use of antimicrobials then all uses would be banned from

agriculture. Few people subscribe to this extreme

view. This implies that some level of risk, however

small, is acceptable in exchange for the perceived

benefits of treating sick animals (alleviation of animal suffering) or reducing losses due to disease in

animals. The difficulty comes in identifying the line

of demarcation between acceptable and unacceptable risk. The general feeling among the veterinary

and animal production communities is that the

benefits of antimicrobial use in treating and preventing infectious disease in animals far outweigh

the risks associated with their use in animals. As

long as this feeling prevails, it will be a major

barrier to implementing the strategies intended to

reduce any risks that are indeed present.

There is a strong perception in some quarters

that more drugs are needed in veterinary medicine

so that food animal production can continue to be

efficient and sick animals can be treated. The majority of bacterial infections of animals are not

zoonotic and most veterinarians and producers feel

that resistance among these pathogens is purely an

animal health concern. Historically, the response

to problems of resistance in veterinary medicine

has been to reach into the cabinet for another new

drug. Notably, an antimicrobial resistance crisis has

not been perceived in veterinary medicine, as is the

case in human medicine. Hence, some groups call

for more regulatory approvals of new drug applications without acknowledging in any substantial way

the need for stewardship of available antimicrobials

in agriculture (25). There does not appear to be an

appreciation of the animal health costs of antimicrobial resistance and that there are good animal

health reasons to preserve the currently available

drugs. Perhaps in the past, new drugs were so readily available that this was unnecessary, or pharmaceutical companies were sufficiently successful in

marketing their new products that veterinarians and

producers looked to new drugs rather than preserving the existing ones. In many ways, the effectiveness of drugs that have been available for therapy

in veterinary medicine (e.g., penicillin, tetracycline)

has in some countries been squandered by their

excessive use as prophylactic agents or growth promoters.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

76

Another barrier is the financial interest of various participants in food animal and plant production. These are not simply the interest in

minimizing losses due to bacterial disease, or the

financial interests of the pharmaceutical industries,

which are essentially the same as those encountered

in human medicine. Unlike physicians in most industrialized countries, antimicrobial sales are often

an important source of income for veterinarians.

Many include charges for other services (health

management advice, for example) within the markup for drugs, and this source of income helps sustain rural veterinary practice, which can be difficult

in many areas. Most professional organizations and

individual veterinarians would recoil at the suggestion that profit was a motive for prescribing

antimicrobials, and few if any data are available to

support the contention. It would nevertheless be

desirable to remove such financial incentives.

Many food animal producers operate on very

narrow profit margins, and to stay in business they

need to be as efficient and economical as possible.

The costs of implementing animal husbandry or

other management changes that could decrease

resistance risks are a barrier. Many food animal industries have made major investments in control

of infectious diseases for the simple reason that it

was in their interest (and in their animals’ interests) to eliminate or substantially reduce the impact of infectious diseases on their operations.

Measures that reduce clinical disease in animals will

decrease the need for antimicrobial treatment,

which could reduce human health resistance risk.

Some, perhaps many, of these changes (e.g.,

biosecurity measures) may also reduce transfer and

dissemination of resistant zoonotic agents and

commensals. However, few of the commonly used

biosecurity measures or vaccination programmes are

aimed specifically at foodborne zoonotic pathogens

or commensals (with the exception of Salmonella

programmes in some species), because they are

normally not important causes of clinical disease

in animals.

The lack of suitable, economically attractive,

alternatives to antimicrobials is also a barrier to

change. The experience of major changes instituted

in some countries (e.g., Sweden, Denmark) is having an impact in other countries, but it would help

greatly to have local examples of alternatives in place

on typical farms in many or most countries, relevant to the agricultural systems of those countries.

From a regulatory standpoint (which is arguably more important to resistance containment for

non-human than human uses of drugs) there are a

number of barriers to implementation. There may

be a lack of regulatory will in some countries because the subject is so controversial and rife with

uncertainty, and effective political lobbying may

be conducted by those in opposition to resistance

control measures. Many countries lack the resources

to conduct risk assessments to support regulatory

change, and resources to implement surveillance

programmes. There may also be reluctance or

inability to regulate prescribing practices of

veterinarians at the national level.

Recommended strategies

A recent WHO document (94) relevant to use of

antimicrobials in animals has been produced which

contains specific recommendations on a number

of these strategies. This document is the most complete and recent set of recommendations pertaining to animal use and the interested reader should

refer to the original in its entirety.

The document entitled “A Public Health Action

Plan To Combat Antimicrobial Resistance” contains many action items for the implementation of

strategies to address antimicrobial resistance within

the United States (53). These are presented at a level

of detail not found in most of the other documents

making mention of non-human uses of antimicrobials and the interested reader should also to

the original document for details.

Many of the documents reviewed mentioned

that antimicrobial resistance is a global issue and

steps are needed to control the international spread

of resistance through movement of humans, animals and food products (7). One major document

relating to the animal area was much more conservative than the others in its recommendations

pertaining to resistance from agriculture (25). This

document was prepared by a committee that was

much more heavily representative of veterinary and

pharmaceutical company interests than was the case

with the other reviewed documents. It did not include in any of its major recommendations a call

for the abolition or withdrawal of growth promoters of a similar class to drugs used in human medicine, or which select for resistance to these drugs.

Nor did it recommend greater efforts to ensure the

prudent use of antimicrobials. The other documents

called for these actions.

The general strategies are presented below in

abbreviated form from the original documents

(7,9,25,50, 53,92–95), and in descending order of
77

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

priority. The main headings are given in order of

priority (e.g., “surveillance of resistance” first), then

specific strategies under each heading are prioritized

by this author. In general, the most important strategies are to increase surveillance of resistance and

antimicrobial use, to implement good regulation

to control antimicrobial use in animals in light of

resistance concerns, and to take steps to ensure the

prudent use of antimicrobials in animals, especially

by reducing exposure of animals to low doses of

antimicrobials for long periods of time (i.e., growth

promoters and prophylactics) if such uses select for

resistance to drugs used in human medicine.

The top priority strategy is to improve surveillance of resistance arising in agriculture. Increased

surveillance of resistance in foodborne pathogens,

commensals of animals and humans, and monitoring of drug use is essential for the assembly of

data that can be used to identify the important

human (and animal) health impacts of resistance,

and how these impacts relate to actual drug use in

animals. This information is vital to good policymaking, and to convince people where the problems exist. To date, only a few countries have been

able to construct reasonably comprehensive surveillance systems and none has a perfect programme

in place. Other industrialized countries should be

able to implement surveillance systems within 2–3

years. Developing countries in particular will have

difficulties with this strategy, given the financial,

human and other resource demands required for

implementation. International cooperation is

needed to disseminate the results of surveillance

among all countries, so that even those without the

infrastructure can use the results to conduct risk

assessment, make policy, and manage risk.

Secondly, good regulation at the national level

is urgently needed in all countries to control antimicrobial use. Since many countries have not even

considered resistance issues when developing

current policies, these need to be revised appropriately. Most countries will not have the resources to

undertake elaborate risk assessments of all drugs

used, however, examples of regulation and policy with

supporting data should be made available through

WHO to countries that can make use of it.

Third, encouraging prudent use of antimicrobials in all aspects of animal and plant

production is essential. Veterinarians and animal

owners in particular must be made aware of the

facts of the impact of resistance on humans, and of

the costs of resistance to themselves, their families

and animals, and to the public. People need to have

good reasons to modify their behaviour and these

should be provided to them.

Surveillance of resistance

• Identify the components of a national postapproval resistance surveillance plan including

organisms (zoonotic pathogens, enteric

commensals from animals, food, humans),

standards and methodologies, and core capacity

(laboratory, etc);

• Undertake regular monitoring for resistant bacterial pathogens and commensals in foodproducing animal populations and animal-based

food products;

• Resistance monitoring in food animals should

allow for correlation with similar data from

humans;

• Data generated from surveillance of resistance

and antimicrobial use should play a key role in

the development of national policies;

• Closely monitor the use of antimicrobials in

animal surveillance programmes. Post-approval

surveillance is essential and should be able to

detect resistance in time to take corrective measures;

• The threshold levels of resistance that are of

public health concern must be defined; these

levels should be low enough that any interventions they may trigger can still be efficacious;

• If resistance increases above levels of concern,

then incremental interventions up to withdrawal

of the drug from the market should be considered;

• Evaluate the usefulness of monitoring sentinel

human populations (e.g., farm and abattoir

workers) and people in the community for infection with resistant bacteria;

• Incorporate antimicrobial resistance explicitly in

food safety monitoring of imported foods.

Monitoring of antimicrobial use

• Monitor closely the use of antimicrobials in

animal surveillance programmes;

• Post-approval surveillance is essential and should

be able to detect resistance in time to take

corrective measures.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

78

Government regulation

• Enforcement policies should be designed to

ensure compliance with laws and regulations

pertaining to the authorization, distribution,

sale, and the use of antimicrobials in foodproducing animals;

• Licensing of veterinary antimicrobial products

should include consideration of safety issues related to the human health impact of resistance

developing in food animals;

• Abolish the use of antimicrobials that are of a

similar class to those used for treating humans

as growth promoters in animals;

• A single, multidisciplinary government committee should oversee the regulation of antimicrobials in both human and non-human fields;

• Threshold levels of resistance for post-approval

surveillance should be defined and provision

should be made to modify or suspend the marketing of antimicrobials if thresholds are

surpassed;

• Governments should assess the risks and benefits of antimicrobial use in agriculture; a riskbased evaluation of human health effects of all

antimicrobials should be conducted, including

currently registered products;

• Registration decisions should include consideration of the potential rate of resistance in the

pre-approval evaluation.

Prudent or judicious use

• Encourage the prudent use of antimicrobials in

animals, in accordance with similar strategies for

humans; recommended dosages should be optimal for therapy and minimize the development

of resistance;

• Develop and implement standards of practice

to ensure that antimicrobials are not used as substitute for good farm hygiene;

• Ensure that animal producers employ production systems that promote animal health/

welfare such that the use of antimicrobial agents

is part of, not a replacement for, an integrated

animal health programme;

• Prophylactic use of antimicrobials can only be

justified when it can be shown that a particular

disease is present or likely to occur, and such

use should be regularly assessed for effectiveness

and need;

• Establish codes of practice for veterinarians that

reflect antimicrobial resistance concerns;

• Locally derived treatment guidelines should include a list of antimicrobials for conditions commonly presented in various species and offer a

rational treatment choice based on scientific

data;

• Treatment records should be kept and veterinarians should continuously evaluate their

prescribing practices;

• Evaluate the impact of making all systemic

veterinary antimicrobials available by prescription only;

• Support demonstration projects to evaluate programmes which use multiple interventions to

promote judicious drug use and reduce infection rates;

• If sufficient evidence exists that profit from sales

negatively impacts on prescribing, appropriate

countermeasures should be taken;

• Advertising and promotion of animal health

products should comply with national guidelines

and codes of practice.

Education

• Conduct education programmes for veterinarians and farmers on the prudent use of

antimicrobials (including the potential risks to

human health of emerging resistance);

• Veterinary undergraduate, postgraduate and continuing education should be evaluated to ensure

that prudent antimicrobial use and resistance are

given high priority;

• Convey information to involved parties (e.g.,

veterinarians, farmers and dispensers) that

facilitates understanding of the human health

impacts of resistance;

• Expand the understanding of the ecology of

antimicrobial resistance among involved parties;

• Support public health education campaigns on

food safety and the merits of irradiation for

reducing foodborne infections.
79

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Research

• Evaluate the nature and magnitude of impacts

of antimicrobial growth promoters and use the

information to assist in risk-benefit assessments

of each use;

• Seek alternatives (including vaccines) to antimicrobials for food animals;

• Conduct research to define the effects of antimicrobials in veterinary use and used in plants

on the emergence of resistant bacteria;

• Evaluate the effect of current food processing

and distribution methods on the emergence and

spread of resistant organisms;

• Conduct research to better understand the

molecular epidemiology and mechanisms of

gene transfer, and the population biology and

epidemiology of resistance;

• Assess the impact on household contacts of

antimicrobial use in pets;

• Conduct pilot studies to assess the extent of

environmental contamination by antimicrobial

residues and resistant organisms that enter the

soil or water from human and animal waste;

• Gather information on the relationship between

antimicrobial pesticides and emergence of resistance.

Alternatives to antimicrobials

• Streamline the regulatory process for drugs and

products that are not likely to cause antimicrobial resistance;

• Seek alternatives to antimicrobial growth promoters (vaccines, nutrition, etc).

Conclusion

Stuart B. Levy

mark’s success. By eliciting support from research

scientists, health care providers, educators, and

policy-makers, the resistance problem can be controlled in each country.

Because infectious disease seriously threatens the

health and economy of each country, preserving

the power of antibiotics should become a national

priority. The WHO global strategy (26) provides

an excellent framework for action by all country.

Industrialized countries can take the lead in committing resources for more basic, clinical and

applied research, and related interventions to curb

antibiotic resistance. In all countries, government,

non-governmental organizations, professional societies and clinical leaders at appropriate levels of

jurisdiction must develop feasible approaches that

are tailored to local conditions and available resources. In some instances, a simple hand washing

or “antibiotic use improvement programme” will

make an enormous difference (20). It is the combined efforts of these individual interventions that

will become the global solution.

The year 2000 was a banner year for the recognition of antibiotic resistance as a priority public

health problem around the world. The World

Health Organization provided leadership in developing a global strategy for addressing antibiotic

resistance (26). United States governmental organizations developed a detailed interagency plan with

specific agency assignments (53). In addition, the

United Kingdom, Sweden, Canada, and others

began strong public awareness campaigns to improve antibiotic use. Even more remarkable is the

commitment of countries with limited resources

which have instituted national regulations to protect the potency of existing antimicrobial agents in

their region. Of note, Chile, Panama and Costa

Rica have recently established national regulations

for the sale and prescription of antibiotics. To build

on this momentum, a commitment from each

country and institution is needed to roll back antibiotic resistance on a global basis.

Optimism for the future

Nations and local institutions must work together

to preserve the power of antibiotics. Each country

needs to act as a steward of antibiotics to pass them

on to the next generation. Individual countries

should maximize accessibility to appropriate antibiotics and minimize

their misuse in order to extend their

life in the country. The literature now

documents that national and institutional initiatives can dramatically reduce the prevalence of antibiotic

resistance (14,20). The strict enforcement of antibiotic use policies in hospitals has helped Denmark achieve a

drastic reduction in the incidence of

methicillin-resistant Staphylococcus

aureus (see graph, 101). Compliance

with infection control procedures

and the inclusion of clinical

microbiologists in the prescribing

process have also contributed to Den- Source: V.T. Rosdahl, and A.M. Knudson (101). Reprinted with permission from SLACK, Inc.

20

15

10

5

0

1960 1965 1970 1975 1980 1985

Percent resistant strains

FREQUENCY OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA) IN DENMARK

81

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

References

immediate threat to the nation’s health. The role of

research. 1997.

12. Royal Society of Medicine. Resistant Organisms:

Global impact on continuum of care. Proceedings

of a conference sponsored by 3M Health Care and

Regent Medical, London, September 27, 1996.

13. Shlaes DM, Gerding DN, John JF, Craig WA,

Bornstein DL, Duncan RA, et al. Society for

Healthcare Epidemiology of America and Infectious

Diseases Society of America Joint Committee on the

prevention of microbial resistance: guidelines for the

prevention of antimicrobial resistance in hospitals.

Infect Control Hosp Epidemiol 1997;18:275–291.

14. Chadwick D, Goode J, editors. Antibiotic resistance:

origins, evolution, selection and spread. Proceedings

from a Ciba Foundation Syposium, London July 16–

18, 1996.John Wiley & Sons, Inc. 1997.

15. World Health Organization. The current status of

antimicrobial resistance surveillance in Europe. Report of a World Health Organization workshop in

collaboration with the Italian Associazone Culturale

Microbiologia Medica; 1997 Dec 12; Verona, Italy.

Geneva, World Health Organization, Geneva 1998.

WHO/EMC/BAC/98.1.

16. Proceedings of the international conference on

emerging infectious diseases, Atlanta, March 1998.

Emerging Infectious Diseases, special issue.

17. Centers for Disease Control and Prevention. Preventing emerging infectious diseases: a strategy for

the 21st century, 1998.

18. Food and Drug Administration. Antibacterial drugs

in animal feeds. Human health safety criteria guideline 18, 1998.

19. Department of Health, UK. The path of least resistance. Main report of the Standing Medical Advisory Committee, Sub-Group on Antimicrobial

Resistance. London, UK: Department of Health;

1998.

20. Antimicrobial resistance. Br Med J 1998 Sep;

317:609–690.

21. House of Lords, UK. Resistance to antibiotics and

other antimicrobial agents. Seventh Report of the

House of Lords’ Select Committee on Science and

Technology; 1997–98. London, UK: The Stationary Office; 1998.

1. Levy SB, Burke JP, Wallace CK, editors. Antibiotic

use and antibiotic resistance worldwide: report of a

study sponsored by the Fogarty International Center

of the National Institutes of Health, 1983–1986.

Rev Infect Dis 1987; 9(suppl3):231–316.

2. Public Health Service USA. Healthy People 2000:

National Health Promotion and Disease Prevention.

Full report with Commentary, 1990.

3. Lederberg J, Shope RE, Oats SC, editors. Emerging

infections: microbial threats to health in the United

States. Report from the Institute of Medicine Committee on Emerging Microbial Threats to Health.

Washington, DC: National Academy Press; 1992.

4. Centers for Disease Control and Prevention.

Addressing emerging infectious disease threats: a

prevention strategy for the United States. 1994.

5. World Health Organization. Proceedings of the

WHO Scientific Working Group on Monitoring and

Management of Bacterial Resistance to Antimicrobial Agents; 1994 Nov 29–Dec 2; Geneva, Switzerland. Geneva Switzerland: World Health

Organization; 1995.

6. Office of Technology Assessment, US Congress.

Impacts of antibiotic-resistant bacteria. Washington,

DC: US Government Printing Office; 1995.

7. National Science and Technology Council, US. Infectious disease—a global health threat. Report of

the National Science and Technology Council Committee on International Science, Engineering, and

Technology Working Group on Emerging and Reemerging Infectious Diseases. Washington DC: US

Government Printing Office; 1995.

8. American Society for Microbiology. Report of the

ASM taskforce on antibiotic resistance. Proceedings

of the American Society for Microbiology; 1994 Jul

6; Washington, DC. Washington DC: Office of

Public Affairs, American Society for Microbiology;

1995.

9. World Health Organization. The medical impact of

the use of antimicrobials in food animals. Report

and proceedings of a WHO meeting, Berlin, Germany, 13–17 October 1997. WHO/EMC/ZOO/

97.4.

10. Institute of Medicine. America’s vital interest in

global health, report of a workshop, November 1995.

11. American Society for Microbiology. New and

reemerging infectious doseases: a global crisis and

83

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

84

22. Harrison PF, Lederberg J, editors. Antimicrobial resistance: issues and options, workshop report. Proceedings of the Forum on Emerging Infections of

the Division of Health Sciences Policy, Institute of

Medicine; 1997 Jul. Washington DC: National

Academy Press; 1998.

23. Centers for Science in the Public Interest. Protecting the crown jewels of medicine: a strategic plan to

preserve the effectiveness of antibiotics. 1998.

24. General Accounting Office. The agricultural use of

antibiotics and its implications for human health.

1999.

25. National Research Council. The use of drugs in food

animals: benefits and risks.1999.

26. WHO Global Strategy for the Containment of Antimicrobial Resistance. World Health Organization

2001. WHO/CDS/CSR/DRS/2001.2.

27. World Health Organization. WHO international

collaborative study of antibiotic sensitivity testing,

1968–1970. In: ACTA et Microbiologia Scandinavia. Suppl 217; Sec B; 1971.

28. World Health Organization. WHO scientific working group on microbial resistance. Proceeds from a

working group; 1981 Nov 23–27; Geneva, Switzerland. Geneva, Switzerland: World Health Organization; 1982.

29. World Health Organization. WHO consultation

group for surveillance of antimicrobial resistance.

Proceedings from a conference of the World Health

Organization; 1982 Nov 22–26; Geneva, Switzerland. Geneva, Switzerland: World Health Organization; 1982.

30. American Academy of Microbiology. Report from

the American Academy of Microbiology: antimicrobial resistance, an ecological perspective. Washington DC: American Society of Microbiology; 1999.

31. US Interagency Task Force on Antimicrobial Resistance. Draft public health action plan to combat antimicrobial resistance. Proceeds from a task force

co-chaired by the Centers for Disease Control and

Prevention, the Food and Drug Administration, and

the National Institutes of Health; 1999. Draft for

comment; 2000.

32. Avorn JL, Solomon DH. Cultural and economic

factors that (mis)shape antibiotic use: the nonpharmacologic basis of therapeutics. Ann Intern Med

2000;133:128–135.

33. Metlay JP, Stafford RS, Singer DE. National trends

in the use of antibiotics by primary care physicians

for adult patients with cough. Arch Intern Med

1998;158:1813–1818.

34. Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract

infections, and bronchitis by ambulatory care physicians. JAMA 1997;278:901–904.

35. Avorn, J, et al. Information and education as determinants of antibiotic use: report of task force 5. Rev

Infect Dis 1987;9:S286–S296.

36. Wilson AA, Crane LA, Barrett PH, Gonzales R.

Public beliefs and use of antibiotics for acute respiratory illness. J Gen Intern Med 1999;14:658–662.

37. Watson RL et al. Antimicrobial use for pediatric

upper respiratory infections: reported practice,

actual practice, and parent beliefs. Pediatrics 1999;

104:1251–1257.

38. Bell RA, Kravitz RL, Wilkes MS. Direct-toconsumer prescription drug advertising and the public. J Gen Intern Med 1999;14:651–657.

39. US Agency for International Development. Reducing the threat of infectious diseases of major public

health importance: USAID’s initiative to prevent and

control infectious diseases. Manuscript; 1998.

40. Davis DA, Thomson MA, Oxman AD, Haynes RB.

Changing physician performance. A systematic review of the effects of continuing medical education

strategies. JAMA 1995;274:700–705.

41. Soumerai SB, Avorn J. Economic and policy analysis of university-based drug “detailing.” Med Care

1986;24:313–331.

42. Green LW and Kreuter MW. Health Promotion

Planning: an Educational and Environmental

Approach. Mountain View, Calif.: Mayfield Publishing Co., 1991.

43. Prochaska JO, DiClemente CC, Norcross JC. In

search of how people change. American Psychologist

1992;47:1102–1114.

44. Ross-Degnan D, Laing R, Santoso B, Ofori-Adjei

D, Diwan V, Lamoureux C, Hogerzeil H. Improving pharmaceutical use in primary care in developing countries: a critical review of experience and lack

of experience. Prepared for the International Conference on Improving Use of Medications; 1997;

Chaing Mai, Thailand.

45. Pestonik SL, Classen DC, Evans RS, Burke JP.

Implementing antibiotic practice guidelines through

computer-assisted decision support: clinical and

financial outcomes. Ann Intern Med 1996;124:884–

890.

46. Pestonik SL et al. Therapeutic antibiotic monitoring: surveillance using a computerized expert

system. Am J Med 1990;88:43–48.

47. Shojania KG et al. Reducing vancomycin use utilizing a computer guideline: results of a randomized

controlled trial. J Amer Med Inform Assoc 1998;

5:554–562.

48. Gonzales R et al. Decreasing antibiotic use in

ambulatory practice: impact of a multidimensional

intervention on the treatment of uncomplicated

acute bronchitis in adults. JAMA 1999;281:1512–

1519.
85

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

49. Overcoming antimicrobial resistance. World Health

Organization, Geneva, Switzerland 2000.

50. World Health Organization. Containing antimicrobial resistance: review of the literature and report of

a WHO workshop on the development of a global

strategy for the containment of antimicrobial resistance. Proceedings of a WHO workshop; 1999 Feb

4–5; Geneva, Switzerland. Geneva, Switzerland:

World Health Organization; 1999. WHO/CDS/

CSR/DRS/99.2.

51. Fidler DP. Legal issues associated with antimicrobial drug resistance. Emerg Infect Dis 1998;4:169–

177.

52. Codex Alimentarius. FAD/WHO Standards. Codex

Committee on residues of veterinary drugs in foods.

Discussion paper on antimicrobial resistance. Drafting group meeting, May 15–16, 2001.

53. Centers for Disease Control and Prevention. Public

health action plan to combat antimicrobial resistance. Atlanta, GA: Centers for Disease Control and

Prevention; draft manuscript; 2000.

54. Cohen ML. Changing patterns of infectious diseases.

Nature 2000;406:762–767.

55. Dougherty TJ et al. Antimicrobial resistance-why do

we have it and what can we do about it? Exp Opin

Invest Drugs 2000;9:1707–9.

56. Bjorkman J, Anderson DJ. The cost of antibiotic

resistance from a bacterial perspective. Drug Resistance Update 2000;3:327–345.

57. Mazel D, Davies J. Antibiotic resistance: the big picture. Adv Exp Med Biol 1998;456:1–6.

58. Liu HH. Antibiotic resistance in bacteria: a current

and future problem. Adv Exp Med Biol. 1999;

455:387–396.

59. Guillemot D. Antibiotic use in humans and bacterial resistance. Curr Opin Microbiol 1999;2:494–498.

60. Barker KF. Antibiotic resistance: a current perspective. Br J Clin Pharmacol 1999;48:109–124.

61. Phillips I. The subtleties of antibiotic resistance.

J Antimicrob Chemother 1998;42:5–12.

62. Levy SB. Antimicrobial resistance: bacteria on the

defense. Resistance stems from misguided efforts to

sterilize our environment. BMJ 1998;217:612–613.

63. Rao GG. Risk factors for the spread of antibioticresistant bacteria. Drugs 1998;55:323–330.

64. Bergogne-Berezin E. Who or what is the source of

antibiotic resistance? J Med Microbiol 1997;46:461–

464.

65. Kumar A. Microbial resistance to drugs—a universal problem in urgent need of a comprehensive

approach. Natl Med J India 1997;10:221–224.

66. Baquero F, Nergi MC. Strategies to minimize the

development of antibiotic resistance. J Chemother

1997;9(suppl3):29–37.

67. Levy SB. Antibiotic resistance: an ecological imbalance. Ciba Found Symp 1997;207:1–9.

68. Postier RG. Antibiotic-resistant organism infection.

Am Surg 2000;66:112–116.

69. Lipsitch M, Bergstrom CT, Levin BR. The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. PNAS 2000;97:1938–1943.

70. Institute of Medicine. Emerging infections: microbial threats to health in the United States. Washington, DC: National Academy Press; 1992.

71. Wise R et al. Antimicrobial resistance is a major

threat to public health. BMJ 1998;317:609–610.

72. Wise R. The development of new antimicrobial

agents. BMJ 1998;317:643–644.

73. Huovinen P, Cars O. Control of antimicrobial resistance: time for action. The essentials of control

are already known. BMJ 1998;317:613–614.

74. Eandi M, Zara GP. Economic impact of resistance

in the community. J Clin Pract 1998;95(Jun

Suppl):27–38.

75. Nathwani D, Malek M. Cost considerations in the

evaluation of new therapies for Gram-positive

bacteria. Int J Antimicrob Agents 1999;13:71–78.

76. Wright GD. Resisting resistance: new chemical strategies for battling superbugs. Chem Biol 2000;

7:R127–132.

77. Urassa W, Lyamuya E, Mhalu F. Recent trends on

bacterial resistance to antibiotics. East Afr Med J

1997;74:129–133.

78. Fauci AS. New and reemerging diseases: the importance of biomedical research. Emerg Infect Dis

1998;4:374–378.

79. Relman DA. Detection and identification of previously unrecognized microbial pathogens. Emerg

Infect Dis 1998;4:382–389.

80. Sentry: http://www.ewi.med.uu.nl/enare/sentry_

antimicrobial_surveillance.html

81. Alexander project : http://www.nearchus.com

82. NIH funding data; public domain through web

searching.

83. Parexels Pharmaceutical R&D Statistical Sourcebook. 2000.

84. Bax R. Antibiotic resistance: a view from the pharmaceutical industry. Clin Inf Dis 1997;24:S151–

S153.

85. Culotta E. Funding crunch hobbles antibiotic

resistance research. Science 1994;264:362–363.

86. Walsh C. Molecular mechanisms that confer antibacterial drug resistance. Nature 2000;406:775–781.

87. Kessler RE. Perspective on chemotherapeutic

approaches to antibiotic-resistant bacteria. Clin Inf

Dis 1997;24(Suppl 1):S146–S147.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

86

88. Kotra LP, Vakuleno S, Mobashery S. From genes to

sequences to antibiotics: prospects for future development of microbial genomics. Microbes Infect

2000;2:651–658.

89. McKeller QA. Antimicrobial resistance: a veterinary

perspective. Antimicrobials are important for animal welfare but need to be used prudently. BMJ

1998;317:610–611.

90. Mawle AC. Vaccine-preventable diseases. Emerg

Infect Dis 1998;4:404.

91. Levy SB. The challenge of antibiotic resistance. Sci

Amer 1998;278(3):46–53.

92. Advisory Committee on the Microbiological Safety

of Food, UK. Report on Microbial Antibiotic

Resistance in Relation to Food Safety. London, UK:

The Stationery Office; 1999.

93. Joint Expert Advisory Committee on Antibiotic

Resistance (JETACAR). The use of antibiotics in

food-producing animals: antibiotic resistant bacteria in animals and humans. Australia: Commonwealth Department of Health and Aged Care,

Commonwealth Department of Agriculture, Fisheries and Forestry; 1999.

94. World Health Organization. WHO global principles for the containment of antimicrobial resistance

in animals intended for food. report of a WHO consultation 5–9 June 2000.Geneva, Switzerland.

WHO/CDS/CSR/APH/2000.4.

95. European Commission, Scientific Steering Committee. Opinion of the Scientific Steering Committee

on antimicrobial resistance. Brussels: European

Commission, Directorate-General DGXXIV; 1999.

96. Health, Education, and Human Services Division,

USA General Accounting Office. Antimicrobial

resistance: data to assess public health threat from

resistant bacteria are limited. Washington, DC:

USA General Accounting Office; 1999.

97. Report of the Jt. Committee on the use of Antibiotics in Animal Husbandry and Veterinary Medicine. Chairman Professor M. Swann, Cmnd 4190.

The Stationary Office, London UK, 1969.

98. Greko C. Sweden and the European Union: what

is happening in relation to antibiotics in feed. In:

Annual conference proceedings of Australian

veterinarians in industry and Australian veterinatrians in public health. Proceedings of Australian Veterinarian Association Annual Conference;

2000 June 26–30; Perth, Australia. 2000. p. 18–

22.

99. Bager F, editor. DANMAP99. Danish Zoonosis

Centre, Danish Veterinary Laboratory, bulowsvej

27 DK-1790 Copenhagen V, Denmark. (http://

www.svs.dk).

100. Fey PD et al. Ceftriaxone-resistant Salmonella infection acquired by a child from cattle. N Engl J

Med 2000; Apr 27;342:1242–1249.

101. Rosdahl VT, Knudson AM. The decline of methicillin resistance among Danish Staphylococcus

aureus strains. Infect Control Hosp Epidemiol 1991;

12:83–88.

102. Thomas M, editor. Guidelines to antibiotic policy.

Proceedings from a workshop of the World Health

Organization in collaboration with the Christian

Medical College; 1998 Jan 22–23; Vellore, India.

Emppee Graphics;1998.
87

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Some useful web sites

■ Alliance for the Prudent Use of Antibiotics

www.apua.org

■ BUBL Catalog of Internet Resources—Infectious Diseases

http://bubl.ac.uk/link/i/infectiousdiseases.htm

■ Canadian Committee on Antibiotic Resistance

http://www.ccar-ccra.org

■ Center for Adaptation Genetics and Drug Resistance

http://www.healthsci.tufts.edu/labs/Sblevy/home.html

■ Center for Complex Infectious Diseases

http://www.ccid.org/

■ Centers for Disease Control and Prevention

www.cdc.gov

■ Eurosurveillance

http://www.eurosurv.org/

■ Global Polio Eradication Initiative

http://www.polioeradication.org

■ National Institute of Allergy and Infectious Diseases

www.niaid.nih.gov/factsheets/antimicro.htm

■ Infectious Disease News

http://www.slackinc.com/general/idn/idnhome.htm

■ Infectious Diseases Society of America

www.journals.uchicago.edu/IDSA/guide/SE39_584.pdf

■ International Society for Infectious Diseases

http://www.isid.org

■ Johns Hopkins University—Infectious Diseases

http://www.hopkins-id.edu/index_id_links. html

■ Karolinska Institut, Sweden

http://micf.mic.ki.se/Diseases/

■ National Foundation for Infectious Diseases, USA

http://www.nfid.org/

■ Project Icare: Intensive Care Antimicrobial Resistance Epidemiology

http://www.sph.emory.edu/ICARE/

■ Roll Back Malaria

http://www.rbm.who.int/

■ TDR (Special Programme for Tropical Disease and Research)

http://www.who.int/tdr
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

88

■ The Copenhagen Recommendations. http://www.sum.dk/publika/micro98

These recommendations are a report from a conference on “The Microbial Threat,” which promotes

collection of data concerning the supply and sales of antimicrobials from individual nations to be shared

internationally.

■ The Epic Project: Developing National Evidence-Based Guidelines for Preventing Health-care-Associated Infection.

http://www.epic.tvu.ac.uk/

■ The Hot Zone: Emerging Infectious Diseases Reports and Web Sites

http://www.qis.net/~edwardmc/eid.htm

■ The HELICS project: (Hospitals in Europe Link for Infection Control Through Surveillance).

http://helics.univ-lyon1.fr

■ The MIKSTRA Programme

http://www.stakes.fi/mikstra/e/

■ The Scottish Intercollegiate Guideline Network (SIGN) Guideline on Antibiotic Prophylaxis in Surgery.

http://www.show.scot.nhs.uk/sign/home.htm.

This has national guidelines on antibiotic prophylaxis in surgery which addresses the benefits and risks

involved in using antibiotics to prevent surgical site infections.

■ The Swedish Strategic Program for the Rational Use of Antimicrobial Agents and Surveillance of Resistance

http://www.strama.org

■ UK Public Health Laboratory

http://www.phls.co.uk/

■ UK Public Health Laboratory Service’s Management of Infection Guidance for Primary Care.

http://www.phls.co.uk/advice/antibiotic/old/phls%20antibiotic%20guides%20refs% 2009.01.01.rtf

The guidance template found on the website is designed so that the antibiotics and advice given may be

changed to suit local circumstances, for example to reflect laboratory resistance data and cost.

■ USA National Center for Infectious Diseases

http://www.cdc.gov/ncidod

■ Washington University Infectious Disease Division

http://www.id.wustl.edu/

■ World Health Organization

http://www.who.int/

■ WHO Antimicrobial Resistance InfoBank

http://oms2.b3e.jussieu.fr/arinfobank/

■ WHO Communicable Diseases home page

http://www.who.int/health-topics/idindex.htm
89

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

APPENDIX A

Summaries of reports by expert policy groups

(1987–2000)

• Support for and expansion of WHO’s surveillance program for the global prevalence of antibacterial resistance.

• Studies on the mechanics of antibiotic resistance

on the level of genetic elements, in order to

devise plans on how to contain and reduce resistance.

• Research studies on antibacterial regulation that

include the following:

— Long-term, multicountry studies to determine whether or not regulation of antibiotic use and the enforcement of such rules

have any effect on the development of antibiotic resistance.

— Studies of the consequences of implementing restrictive regulations and enforcement,

including the need to train health care personnel and possible economic impacts.

— Studies that specifically examine the effects

that regulations and enforcement have on

children.

— Investigation of the potential consequences

to human health that would arise from

restrictions on antibacterial use in food

production and animal husbandry.

— Studies that examine how national, regional,

and institutional antibiotic use policies influence the training and education of physicians and other health care workers.

• Improved communications between the regulatory agencies that govern antibacterial use, and

the people responsible for prescribing and using

such agents.

• Research studies on antibacterial use in developing countries that include the following:

— Studies that determine the efficacy of

national formulary schemes, including drug

costs, availability, as well as research and development of new agents.

— Studies on the effects that having access to

microbiology laboratory tests has on antibiotic prescription and use.

• Redesign of the curricula of medical schools in

developing countries to provide more thorough

(1) *Task Force Reports on Antibiotic Use

and Resistance Worldwide (Fogarty

Report)

Organization: National Institutes of Health, Fogarty

Center

Year published: 1987

Selected key findings

• Antibiotic use varies greatly from country to

country; surveillance data on antibiotic use,

emergence of resistant strains, and availability

to consumers were difficult or impossible to

obtain.

• Practitioner knowledge, drug availability, and

drug price are the three key factors that influence a prescriber’s choice of antibiotics. Where

antibiotics are available without a prescription,

the same factors influence the choice of the

consumer.

• The task force did not find enough evidence to

prove that the implementation of firmer

regulations regarding antibiotic use, or stricter

enforcement of or better compliance with such

regulations, slows the development or spread of

resistance.

• Medical students in developing countries often

receive inadequate training in basic bacteriology,

infectious diseases diagnosis, and antimicrobial

use. Theories of antimicrobial therapy are not

always integrated with practical experience.

• There are almost no regulated requirements for

health care providers to continue their education in pharmacological developments beyond

their formal training. This lack is evident in both

developing and industrialized countries.

Key recommendations

• Uniform data-collection systems at the national

level.

* The number in parenthesis refers to the citation listed in

References.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

90

education on diagnosing and managing infectious diseases.

• Creation of systems which will disseminate

information on patterns of antibiotic use and

development of antibiotic resistance to hospital

staff.

• Research studies on the effects of education and

information on determining antibiotic use,

including: cultural and social reasons behind

patient demand; the quality of physician education on the use of antibiotics, both during the

course of study and after graduation; and the

effects of pharmaceutical marketing campaigns

on physicians’ prescriptions of antibiotics.

• Evaluation of current policies on the use of

antibiotics to determine what effects they have

on the pharmaceutical industry’s incentives to

research, develop, and market new antibiotics.

Implementation suggestions

• To achieve standardized data on antibiotic use,

institute “a standard index for measuring drug

use in each country by using the same system of

drug classification, the same unit of measurement (e.g., DDDs/1,000 population per day or

grams/1,000 population per day), and the same

point in the distribution channel in each country [and] by obtaining access to data of this type

that are currently collected by private companies (i.e., International Medical Statistics) but

are not made publicly available.”

• WHO, USA Public Health Service, and ministries of health in other countries “should support research studies proposed by the task force,

assist countries in establishing or improving their

systems of drug regulation, facilitate collaborative research among investigators in different

countries, and improve cooperation among regulatory agencies, physicians and other health

workers, and drug companies.”

• Regional and international centers for the study

of antibiotic resistance should be established in

Asia, Africa and Latin America by WHO, NIH,

and CDC/USA Public Health Service/USA

Department of Health and Human Services, in

collaboration with ministries of health and other

relevant agencies.

• “Establishment of field surveillance teams

located in representative regions in developing

nations. Such teams would gather information

on actual antibiotic use, develop affordable strategies for preventing or curing infectious diseases,

and determine the social, behavioral, and economic determinants of antibiotic usage for

particular geographic areas and demographic

groups.”

Conclusions

“The importance of social and behavioral characteristics of individuals receiving antimicrobial

therapy (as well as the supply and variety of antibiotics available) was noted in plenary discussions as

influencing courses of antibiotic therapy. Studies

of such variables are needed in order to answer

questions related to under- or overutilization of

antibiotics.”

“There was the consensus that there is considerable suboptimal antibiotic use in the developing

countries, where there is a tendency...for higher levels of microbial resistance... The developing nations

have environmental conditions, infectious disease

burdens, and associated needs and factors affecting

antibiotic use and resistance patterns that differ

from those in the developed nations. The participants in this project stressed the importance of recognizing and addressing these distinctions.”

“Better data on utilization of antimicrobial

agents in the developing world are needed. This

would include information from studies on the

magnitude of inadequate doses resulting in the

failure to achieve bactericidal concentrations, on

improper duration of therapy...and on the use of a

single capsule or a limited number of capsules...for

cultural, financial, or idiosyncratic reasons (associated with a transient sense of well-being).”

“Projects focusing on improving our understanding of the observed correlation between antibiotic

use and subsequent resistance should be carried

out... Multiple parameters should be assessed:

microbiologic susceptibility patterns of the organisms principally involved; the kinds of diagnostic

tests being performed; demographic patterns and

associated social and behavioral characteristics;

policies affecting antibiotic utilization; and the

quantity and cost of antibiotics used. Such data

assembled in one system have heretofore not been

available.”

“What is lacking, and of fundamental importance, is detailed information on the distribution

over time of specific antimicrobial resistance genes

and plasmids in the global bacterial ecosystem.

Geographic information on individual components... is needed to trace and understand better

the emerging patterns of such resistance.”

“Some unified way to follow the incidence and

prevalence of microbial resistance on a global scale
91

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

is required; however, it is not yet clear how best to

proceed... It is, therefore, recommended that a

workshop be convened to help elucidate the direction in which future surveillance studies should

proceed, as well as to work out the details of a uniform methodology for collection and comparison

of data.”

“Fundamental studies at the cellular level concerning the cell’s impressive capacity over time to

defend itself against foreign agents should be supported and extended, particularly studies involving genetics and mechanisms for gene amplification

and gene exchange leading to multidrug resistance.”

“New diagnostic tools, simplified, appropriate,

and more accurate and sensitive than tests currently

available, are coming into use. The utilization of

these newer techniques at the central surveillance

level needs to be encouraged. These central surveillance systems, particularly those focusing on

selected and important infectious disease in the

developing nations...and on specific etiology agents

...should be expanded.”

“Vaccine development and newer, more rapid

diagnostic tests should provide additional means

to combat the problem. Economic conditions and

a climate favorable for the continued progress and

expansion of medical therapeutics, as well as the

widespread utilization of new antimicrobial agents,

remain important factors in considering antibiotic

use and antibiotic resistance worldwide.”

Authors: Task Force participants: Stuart B. Levy (General Chairperson and Guest Editor), Jacques F. Acar,

Gianni Acocella, Jerry Avorn, Ingebjorg Baksaas,

Fernando Baquero, Gilles Bardelay, F. Ralph Batchelor,

Karen Bell, Ulf Bergman, Enriquetta Bond, Kenneth

Bridbord, James J. Burchall, John P. Burke (Guest

Editor), Felipe C. Cabello, Charles C.J. Carpenter III,

Georges Y. Causse, Leighton E. Cluff, Mitchell Cohen,

Nananda F. Col, John V. Copeland, George Curlin,

Joseph T. Curti, I. Damansjah, F. Daschner, Irving P.

Delappe, M.N.G. Dukes, John M. Eisenberg, Tamara

Erickson, Enrique Feffer, Susan E. Feinman, Peter I.

Folb, Ernst Freese, Ryochi Fujii, Aleksander Goic, Julio

Gonzales-Molina, Joseph E. Grady, Richard L.

Guerrant, Richard Gustafson, Ken Harvey, Andrew

Herxheimer, Scott D. Holmberg, M. Imdadul Huq,

Hu Zhen, N. Islam, John E. Jefferis, Amir Jivani, Bengt

Jönsson, William S. Jordan, Jr., Edward H. Kass,

Dianne Kennedy, Thomas Kereselidze, H.H.

Kleeberg, Dieter Koch-Weser, Goran Kronvall, Calvin

M. Kunin, Yankel M. Kupersztoch, Louis Lasagna,

Norman W. Lavy, Donald Le Blanc, David Lee, Philip

R. Lee, Alan H. Linton, Helen Levens Lipton, Robert

H. Liss, Hubert Loncin, Per Knut Lunde, Edgar J.

Martin, R. Russel Martin, Ramiro Martines-Silva,

Charles Medawar, Dianna Melrose, Arnold S. Monto,

Stuart L. Nightingale, Richard Norton, Thomas F.

O’Brien, Ronald W. O’Connor, Makoto Ohashi, Jorge

Olarte, Nancy Olins, Peng Wen Wei, Maria Eugenia

Pinto, Philip A. Pizzo, Richard J. Plumridge, Wayne

Ray, J.P Revill, Ahmed Rhazaoui, Frederick C.

Robbins, O.P.W. Robinson, Heonir Rocha, Vidal

Rodriguez-Lemoine, Bernard Rowe, T. Donald

Rucker, Theodore Sacks, Jay P. Sanford, William

Schaffner, William E. Scheckler, Roy Shaffer, K.B.

Sharma, Richard P. Silver, Harold J. Simon, Ewe Hui

Sng, Stephen B. Soumerai, Visanu Thamlikitkul, John

F. Timoney, A. Tognoni, Luiz R. Trabulsi, Themlma

Tupasi, John R. Virts, V. Vymola, Craig K. Wallace

(Guest Editor), Wang Fu, Bernd Wiedemann, Sidney

Wolfe

Type of publication: Supplement to Reviews of Infectious Diseases; Volume 9, Supplement 3, May–June

1987

Pages: 89

Intended audience: International; policy-makers, government, health care providers

Study timeframe: The Task Forces met between fall

of 1983 and spring of 1986.

Study process: Six task forces were assembled, comprised of representatives from different disciplines

and countries. Each Task Force focused on a different aspect of antibiotic resistance; they developed

their sections of the report over a year and a half of

meetings and revisions.

Type of organization: Professional society

Languages (published in): English

Key contact

Ordering information: International Studies

Branch, Fogarty International Center, Bethesda,

MD 20892

Content: Stuart Levy, General Chairperson for the

Task Force
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

92

(2) Healthy People 2000: National Health

Promotion and Disease Prevention. Full

report, with commentary

Organization: Public Health Service; USA Department of Health and Human Services

Year published: 1990

Selected key findings

• Patients in hospital Intensive Care Units account

for about 15% of hospital admissions, but at

least 50% of nosocomial infections (data from

1990).

• Approximately 40,000 people die each year from

complications arising from pneumococcal

disease.

Key recommendations

By the year 2000:

• “Reduce by at least 10 % the incidence of surgical wound infections and nosocomial infections

in intensive care patients;

• Reduce acute middle ear infections among children aged 4 and younger, as measured by days

of restricted activity or school absenteeism, to

no more than 105 days per 100 children;

• Increase to at least 90 % the proportion of public health departments that provide adult

immunization for influenza, pneumococcal

disease, hepatitis B, tetanus, and diphtheria;

• Develop a set of health status indicators appropriate for Federal, State, and local health agencies

and establish use of the set in at least 40 states.”

Implementation suggestions

Reduction of nosocomial infections to be achieved

through collaboration of hospital epidemiologists,

infection control practitioners, the Association of

Practitioners in Infection Control, Society of Hospital Epidemiologists of America, Surgical Infection Society, American Hospital Association, Joint

Commission on the Accreditation of Health Care

Organizations, and the Health Care Financing

Administration.

Conclusions/Executive Summary

“In addition to application of specific measures,

such as immunization and regulation of food,

water, and sewage disposal, there is a need for continued public education about basic hygienic

practices, in home, school, and occupational settings; for continued education of health care

students and workers about the epidemiology and

prevention of these diseases; and for research to

improve immunizations, diagnostic methods, and

therapeutic modalities.”

Authors: Principal staff/editors: James A. Herrell, Lynn

M. Artz, Ashley Files, David Baker. Project Coordination

and Development: Barbara Anderson, John Bailar, Amber Barnato, Sandra Buesking, Mary Jo Deering,

Christopher DeGraw, Olga Emgushov, Martha G.

Grazier, Toni M. Goodwin, Linda M. Harris, Douglas B. Kamero, Thomas Kim, Loretta M. Logan,

Patricia Lynch, Caroline McNeil, Linda D. Meyers,

Diane Rittenhouse, Marilyn K. Schulenberg, Sara L.

White, Jennifer Woods, Christina Wypijewski,

Michael Yao, Daniel Yarano

Type of publication: Report

Pages: 692

Intended audience: United States; citizens, policymakers

Study timeframe: N/A

Study process: The report is the result of a collaboration of 22 expert working groups, a consortium

including almost 300 national organizations and

all state health departments, and the Institute of

Medicine of the National Academy of Sciences. The

IOM and the USA Public Health Service held

regional and national hearings and gathered testimony from over 750 individuals and organizations.

More than 10,000 people participated in the public review, after which the objectives were revised

and refined.

Type of organization: United States Federal Government

Languages (published in): English

Key contact

Ordering Information: Superintendent of Documents, Government Printing Office, Washington,

DC 20402-9325; tel.: (202) 783-3238; fax:

(202)275-0019.

(3) Emerging Infections: Microbial Threats

to Health in the United States

Organization: Institute of Medicine

Year published: 1992

Selected key findings

The Committee focused on factors that contribute

to the emergence and re-emergence of infectious

diseases, including:
93

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• Human demographics and behavior. Contributing factors are movement of the ever-growing

global population into urban areas, with corresponding crowded conditions, poor hygiene and

sanitation, and lack of clean water supplies; increasing numbers of people with suppressed

immune systems, including the elderly and

people infected with HIV; and the transmission

of disease through sexual activity and substance

abuse.

• Technology and industry. Hospitals are increasingly implicated as sources of infection; many

nosocomial infections have developed resistance

to antibiotics thanks to the combination of a

population very susceptible to infection, and the

widespread therapeutic and prophylactic use of

antibiotics.

• Microbial adaptation and change. The evolutionary mechanisms of microbial pathogens allow

them to adapt to new host cells or host species,

produce “new” toxins, bypass or suppress inflammatory and immune responses, and develop

resistance to drugs and antibodies.

• Breakdown of public health measures. Inadequate

sanitation, complacency on the part of medical

officials, physicians, researchers and other public health workers, war, economic hardship, and

natural disasters may all undermine any progress

made by advances in science and technology.

Key recommendations

• “The committee recommends the development

and implementation of strategies that would

strengthen state and federal efforts in USA surveillance. Strategy development could be a function of the Centers for Disease Control (CDC).

Alternatively, the strategy development and coordination functions could be assigned to a federal coordinating body (e.g., a subcommittee of

the Federal Coordinating Council for Science,

Engineering, and Technology’s Committee on

Life Sciences and Health), specifically constituted to address this issue.”

• “The committee recommends that additional

resources be allocated to the to the Centers for

Disease Control to enhance the National Nosocomial Infections Surveillance System in the

following ways:

— Include data on antiviral drug resistance.

— Include information on morbidity and mortality from nosocomial infections.

— Increase the number of NNISS member

hospitals.

— Strive to make NNISS member hospitals

more representative of all USA hospitals.

— Evaluate the sensitivity and specificity of

nosocomial infection surveillance activities

performed in NNISS member hospitals.

— Determine the reliability of antimicrobial

susceptibility testing performed in NNISS

member hospitals.”

• “The committee recommends that the USA

Public Health Service develop a comprehensive,

computerized infectious disease database.”

• “The committee recommends that international

infectious disease surveillance activities of USA

government agencies be coordinated by the

Centers for Disease Control (CDC). Alternatively, a federal coordinating body could be

assigned the coordinating function. Implementation of surveillance activities, however, should

remain with the appropriate federal agencies

(e.g., the CDC, Department of Defense,

National Institutions of Health, USA Department of Agriculture).”

• “The committee recommends that the United

States take the lead in promoting the development and implementation of a comprehensive

global infectious disease surveillance system.

Such an effort could be undertaken through the

USA representatives to the World Health

Assembly.”

• “The committee recommends the expansion and

coordination of National Institutes of Healthsupported research on the agent, host, vector,

and environmental factors that lead to emergence of infectious diseases. Such research should

include studies on the agents and their biology,

pathogenesis, and evolution; vectors and their

control; vaccines; and antimicrobial drugs. One

approach might be to issue a request for proposals (RFP) to address specific factors related

to infectious disease emergence.”

• “The committee recommends increased research

on surveillance methods and applied control

strategies; on the costs and benefits of prevention, control, and treatment of infectious disease; and on the development and evaluation of

diagnostic tests for infectious diseases. Reinstating and expanding (both in size and scope) the

extramural grant program at the Centers for

Disease Control, which ceased in 1973, would

be one important step in this direction. Similarly, the Food and Drug Administration’s (FDA)

extramural grant program should be expanded

to place greater emphasis on the development
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

94

of improved laboratory tests for detecting emerging pathogens in food.”

• “The committee recommends the domestic and

global expansion of the CDC’s Epidemic Intelligence Service program and continued support

for Centers for Disease Control’s (CDC) role in

the Field Epidemiology Training Program.”

• “The committee recommends continued

support, at a minimum at their current level of

funding, of Department of Defense overseas infectious disease laboratories.”

• “The committee recommends that Congress

consider legislation to fund a program, modeled

on the National Health Service Corps, for training in public health and related disciplines, such

as epidemiology, infectious diseases, and medical entomology.”

• “The committee recommends that clinicians, the

research and development community, and the

USA government introduce measures to ensure

the availability and usefulness of antimicrobials

and to prevent the emergence of resistance. These

measures should include the education of health

care personnel, veterinarians, and users in the

agricultural sector regarding the importance of

rational use of antimicrobials (to preclude their

unwarranted use), a peer review process to monitor the use of antimicrobials, and surveillance

of newly resistant organisms. Where required,

there should be a commitment to publicly

financed rapid development and expedited

approval of new antimicrobials.”

• “The committee recommends that the National

Institutes of Health give increased priority to

research on personal and community health

practices relevant to disease transmission. Attention should also be focused on developing more

effective ways to use education to enhance the

health-promoting behavior of diverse target

groups.”

Implementation suggestions

Responsibilities delegated to various government

agencies and departments of the United States,

primarily CDC and NIH.

Conclusions/Executive Summary

“The key to recognizing new or emerging infectious diseases, and to tracking the prevalence of

more established ones, is surveillance. A welldesigned, well-implemented surveillance program

can detect unusual clusters of disease, document

the geographic and demographic spread of an outbreak, and estimate the magnitude of the problem.

It can also help to describe the natural history of a

disease, identify factors responsible for emergence,

facilitate laboratory and epidemiological research,

and assess the success of specific intervention efforts. The importance of surveillance to the detection and control of emerging microbial threats

cannot be overemphasized. Effective intervention

against [emerging] diseases necessitates coordinated

efforts by a variety of individuals, government agencies, and private organizations. The committee

believes that the current USA capability for responding to microbial threats to health lacks

organization and resources. Vaccines and antimicrobial drugs have led to significant improvements

in public health in the United States and in many

other nations during the latter half of this century.

Despite this encouraging history, the committee is

concerned that many of the vaccines and drugs

available today are the same ones that have been

used for decades. It believes that there is a need to

review the present vaccine and drug armamentaria

with a view toward improving availability and

capacity, as well as safety and efficacy.”

Authors: Edited by: Joshua Lederberg, Robert E. Shope,

and Barry R. Bloom. Task Force Members: Robert L.

Buchanan, John R. David, Ciro A. De Quadros,

Patricia N. Fultz, John J. Holland, Dean T. Jamison,

Edwin D. Kilbourne, Adel A.F. Mahmoud, Gerald

L. Mandell, Stephen S. Morse, June E. Osborn,

William C. Reeves, Philip K. Russell, Alexis Shelokov,

P. Frederick Sparling, Andrew Spielman. Project Staff:

Ruth Ellen Bulger, Polly F. Harrison, Stanley C. Oaks,

Jr., Elizabeth E. Meyer, Nancy Diener, Greg W.

Pearson.

Type of publication: Report

Pages: 294

Intended audience: Primarily the United States; policymakers, lay public, government, scientists, physicians

Study timeframe: February 1991 to July 1992

Study process: 19-member multidisciplinary committee convened to identify significant emerging infectious diseases, develop plans on how to deal with

them, and make recommendations on how to

approach similar threats in the future. The full committee met four times during the 18-month study.

Four task forces and subcommittees also formed

according to specialties, and met to address more

specific topics.
95

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Type of organization: Non-profit public health and

advisory organization; advisor to Federal Government on issues of public health

Languages (published in): English

Key contact

Ordering information: National Academy Press,

www.nap.edu

Content: Joshua Lederberg and Robert E. Shope,

Committee Co-chairs

(4) Addressing Emerging Infectious

Disease Threats.A Prevention Strategy

for the United States

Organization: Centers for Disease Control and Prevention; National Center for Infectious Diseases

Year published: 1994

Selected key findings

Surveillance is the key to tracking the development

and spread of infectious diseases, reservoirs of disease, and antimicrobial drug resistance.

One weakness in the United States’ strategy to

control infectious diseases is the lack of multidisciplinary approaches. The USA needs stronger

connections between laboratory science and public health practices, as well as economic analyses of

the impacts of both infectious diseases and the interventions proposed to stop them.

Most federal government funds dedicated to

surveillance of infectious diseases at the state level

go towards only four categories of disease: tuberculosis, HIV/AIDS, sexually transmitted diseases,

and certain vaccine-preventable diseases. This leaves

a large number of other emerging infectious diseases under-funded and under-observed.

The current approach to public health in the

United States (i.e., the focus on treatment rather

than prevention; reactive rather than proactive policies; and general complacency) leads to the emergence and spread of infectious diseases that ought

to be preventable.

Key recommendations

• “Expand and coordinate surveillance systems for

the early detection, tracking, and evaluation of

emerging infections in the United States;

• Develop more effective international surveillance

networks for the anticipation, recognition,

control, and prevention of emerging infectious

diseases;

• Improve surveillance and rapid laboratory identification to ensure early detection of antimicrobial resistance;

• Strengthen and integrate programs to monitor

and prevent emerging infections associated with

food/water, new technology, and environmental forces;

• Strengthen and integrate programs to monitor,

control, and prevent emerging vector-borne and

zoonotic diseases;

• Expand epidemiologic and prevention effectiveness research;

• Improve laboratory and epidemiologic techniques for the rapid identification of new pathogens and syndromes;

• Ensure timely development, appropriate use, and

availability of diagnostic tests and reagents;

• Use diverse communication methods for wider

and more effective delivery of critical public

health messages;

• Establish the mechanisms and partnerships needed

to ensure the rapid and effective development and

implementation of prevention measures;

• Ensure the ready availability of the professional

expertise and support personnel needed to better understand, monitor, and control emerging

infections;

• Make available state-of-the-art physical resources

(laboratory space, training facilities, equipment)

needed to safely and effectively support the

preceding goals and objectives.”

Implementation suggestions

“Between 1994 and 1996, CDC intended to implement its recommendations by establishing

priority goals in the four areas of Surveillance,

Applied Research, Prevention and Control, and

Infrastructure. They include the following:

• Strengthen notifiable disease surveillance at the

state and local levels;

• Establish two physician-based Sentinel Surveillance Networks to detect and monitor emerging diseases;

• Establish four population-based Emerging Infections Epidemiology and Prevention Centers

to conduct focused epidemiology/prevention

projects emphasizing foodborne and waterborne

infectious diseases and potentially vaccine preventable diseases;

• Strengthen and link four existing sites for a

global consortium to promote the detection,

monitoring, and investigation of infections

emerging internationally that could affect the

health of Americans;
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

96

• Reestablish an extramural program to support

emerging infectious disease prevention and

control activities, such as evaluating the role of

prescribing practices in the development of

antimicrobial drug-resistant pathogens;

• Initiate prevention effectiveness studies to assess

the impact of food preparation guidelines on the

incidence of foodborne infections such as E. coli

O157:H7 and Salmonella enteritidis;

• Develop additional means to deliver laboratory

and public health information informing health

professionals about emerging infections and

antimicrobial drug resistance;

• Develop and implement guidelines for the

prevention of opportunistic infections in

immunosuppressed persons;

• Provide state-of-the-art training in diagnostic

evaluation and testing for medical laboratory

personnel to ensure the diagnosis and surveillance of emerging infection;

• Establish a public health laboratory fellowship

in infectious diseases that will train medical

microbiologists in public health approaches to

diagnosis and molecular epidemiology.”

Conclusions

“As the United States moves towards comprehensive health care reform, it is crucial that emerging

infectious disease threats be addressed and that the

basic tenets of prevention-oriented public health

policy form an internal component of plans for

health care reform.

Strengthened efforts in the prevention and control of emerging infectious diseases will complement and improve the effectiveness of current

efforts in HIV/AIDS, TB, STDs, and immunizations as well as other important infectious diseases.

To provide the vigilance and rapid response required

to effectively address emerging infectious diseases,

significant improvements in public health policy,

program design, and infrastructure are needed. A

far-reaching and comprehensive strategy, carefully

integrated with broader plans for health care reform is required.

Effective public health policy results from interaction, cooperation, and coordination among a

wide range of public and private organizations and

individuals. Particularly critical to this process are

CDC’s partnerships with state and territorial health

departments; other federal agencies; professional

organizations; academic institutions; private health

care providers; health maintenance organizations

and health alliances; local community organizations; private industry; and international partners,

including WHO and international service organizations and foundations. Each of these partners will

play an integral role in the cooperative efforts required to safeguard the public’s health from emerging infectious disease threats.”

Authors: Emerging Infections Working Group:

Ralph T. Bryan, M.D., Robert W. Pinner, M.D.,

Robert P. Gaynes, M.D., C.J. Peters, M.D.,

Meredith A. Hickson, M.P.H., Judith R. Aguilar

Type of publication: Report

Pages: 46

Study timeframe: The Advisory Committee considered scientific literature from 1976 to 1993.

Study process: The plan was developed by the CDC

in partnership with representatives from state and

local public health organizations, other federal agencies, health care professionals, members of medical

and public health professional associations, infectious disease experts, and public service organizations. Committee members met several times to

discuss the plan and gather additional input

between December 1992 and June 1993.

Type of organization: Federal Government

Intended audience: United States; physicians and other

health care providers, policy-makers

Languages (published in): English

Key contact

Ordering Information: Centers for Disease Control and Prevention, National Center for Infectious

Diseases, Office of Program Resources EP, Mailstop

C-14, 1600 Clifton Road, Atlanta, GA 30333

(5) WHO Scientific Working Group on

Monitoring and Management of

Bacterial Resistance to Antimicrobial

Agents

Organization: World Health Organization, Division

of Bacterial, Viral Diseases and Immunology.

Year published: 1994

Selected key findings

• There is a lack of data on the economic consequences of antibiotic resistance and of community-acquired infections.

• It may be useful to reconsider older alternatives

to antibiotics, including bacterial interference,

serum therapy, and bacteriophages.
97

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• The approach of the pharmaceutical industry to

the development and spread of antimicrobial

resistance includes: continued chemical modification of existing agent classes; interference with

resistance mechanisms to increase target access;

and searching for agents with novel mechanisms

of action.

Key recommendations

Recommendations for WHO:

• “Communicate the importance of the problem

of antimicrobial resistance to developed and

developing countries and other international

health agencies;

• Improve systems for surveillance of antimicrobial resistance;

• Develop recommendations to improve clinical

use of antimicrobial agents and decrease selection of resistant bacteria;

• Develop strategies to decrease the selection and

transmission of resistant microorganisms in

medical centers;

• Develop strategies to decrease transmission of

resistant microorganisms in the community and

plans for responding to outbreaks of bacterial

pathogens;

• Develop strategies to decrease the emergence and

dissemination of resistant organisms in veterinary medicine and the environment;

• Support the development and evaluation of new

preventive and curative modalities.”

Implementation suggestions

• Communication would be improved through

distribution of newsletters and bulletins (i.e.,

Weekly Epidemiological Record, WHO Drug

Information Bulletin); facilitation of interaction

among government agencies, academic institutions and the pharmaceutical industry; and data

sharing and surveillance system linkage.

• Improvement of surveillance systems would be

achieved by helping national laboratories to

determine their current status and needs to successfully identify bacterial pathogens and test

them for susceptibility; distribute and help to

install WHONET software in laboratories; help

laboratories to develop quality control and

assurance programs.

• Reduction of antibacterial resistance in medical

centers would be achieved by developing educational programs and hygienic standards in

daycare centers and long-term care facilities; infection control training programs for hospital

personnel; and linkage between hospital infection control programs to quality assurance

efforts at the national and local levels.

• Transmission of resistant organisms in the community would be decreased through promotion

of community hygiene standards for safe water

and food and support of programs for improved

access to treatment.

• The emergence and spread of resistant organisms in veterinary medicine and the environment

would be decreased by ensuring that only qualified veterinary personnel be permitted to prescribe antimicrobial agents for the treatment of

infections in animals; prohibiting the use of

antimicrobial agents for growth promotion that

are also used in human medicine; and by discouraging “the unnecessary use of therapeutic

antimicrobials for prophylaxis in food animals.”

Conclusions/Executive Summary

“Antimicrobial resistance represents a crisis at the

present time. It stems from a wide range of problems, but there are a number of key factors. A

primary one is the heavy usage of antimicrobial

agents. The intense selective pressure resulting from

antimicrobial overuse has been an important

factor in the rapid emergence of resistance. The dissemination of resistant strains in hospitals and other

institutional settings is largely attributable to

person-to-person transmission, due to the inconsistent application of basic infection control techniques and treatment of patients not guided by

susceptibility testing. Meanwhile, environmental

contamination with antimicrobial-resistant pathogens adds another dimension to the problem of

prevention and control. In addition, in some countries, availability of antimicrobial agents without

prescription is a major factor in their misuse. Elsewhere, the use of antimicrobial agents in animal

husbandry, particularly for growth promotion and

prophylaxis of infection, provides an additional

selective pressure which encourages the emergence

of drug-resistant organisms. Addressing the many

challenges posed by emerging antimicrobial resistance requires a strategy at institutional, community, regional, national, and international levels.

Partners in the development and implementation

of such a strategy should include representatives

from clinical and veterinary medicine, public

health, microbiology, animal husbandry, the pharmaceutical, agriculture and aquaculture industries,

as well as the behavioral sciences.”
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

98

Authors: Participants: Dr. Y.Z. Abou, Dr. J.F. Acar, Dr.

G.A.J. Ayliffe, Dr. N. Citri, Dr. B. Cookson, Dr. Wang

Fu, Dr. D.A. Goldmann, Dr. D. Grossklaus, Dr. M.

Guzman, Dr. R.E.W. Hancock, Dr. R. Helmuth, Dr.

P. Huovinen, Dr. J.M. Hughes, Dr. W. Johnson, Dr.

E.L. Kaplan, Dr. T.S. Kereselidze, Dr. P. Kriz, Dr. G.

Kronvall, Dr. A. Kucers, Dr. M.K. Lalitha, Dr. R.

Leclercq, Dr. B. Levin, Dr. I. Lind, Dr. A. Marton,

Dr. A. Medeiros, Dr. G.H. Miller, Dr. T.F. O’Brien,

Dr. G. Orefici, Dr. K. Rahal, Dr. B. Tasmussen, Dr.

B. Rowe, Dr. R. Bradley Sack, Dr. J. Schindler, Dr.

N.A. Semina, Dr. J. Stelling, Dr. F. Tenover, Dr. A.

Tomasz. Observers: Dr. R. Bax, Dr. D.H. Bouanchaud,

Dr. E. Bozkurg, Dr. I. Carugo, Dr. R. Charnas, Ms.

M. Cone, Dr. H. Dekoning-Gans, Dr. R. Kessler, Dr.

C. Krasemann, Dr. H. Locher, Dr. J.S. Mantell, Dr.

O. Morin, Dr. G. Mosely, Dr. D. Pontani, Dr. A.

Roos, Dr. C.D. Rothermel. WHO Secretariat: Dr. M.

Couper, Dr. D. Cohn, Dr. Svein-Erik Ekeid, Dr.

M.M. El-Nageh, Mrs. K. Esteves, Dr. E. Griffiths,

Dr. C.-C. Heuck, Dr. J.W. LeDuc, Dr. L.J. Martinex,

Dr. N. Pearce, Dr. A. Pio, Dr. J. Perriens, Dr. M.

Raviglione, Dr. K.B. Sharma, Dr. Hulian Sima, Dr.

A. Sow, Dr. K. Tankari, Dr. E. Tikhomirov, Dr. G.

Torrigiani, Dr. P.I. Trigg

Type of publication: Meeting report

Pages: 33

Intended audience: Global; policy-makers, pharmaceutical industry, health care providers

Study timeframe: The working group met from

November 29 to December 2, 1994.

Study process: The working group, comprised of

professionals from the fields of clinical medicine,

research and public health, met to review the current status of the nature and consequences of antimicrobial resistance, and to make recommendations

on alleviating the problem.

Type of organization: International, non-governmental, public health agency

Languages (published in): English

Key contact

Ordering Information: Communicable Disease

Surveillance and Response Documents, World

Health Organization, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4198, attention CSR

Documents; email: csr@who.ch, attention Documents.

(6) Impacts of Antibiotic-Resistant

Bacteria

Organization: Office of Technology Assessment; Congress of the United States

Year published: 1995

Selected key findings

• Inappropriate antibiotic use contributes to the

increase of selection pressure for the selection

and spread of antibiotic resistance. It is possible

that as much as 50% of antibiotic use is inappropriate.

• Although only one-third to one-half of the 24.5

million otitis media cases that occur each year

benefit from antibiotics, physicians often prescribe them. Parental pressure and time constraints that keep physicians from testing for viral

sources of the disease are common reasons for

resorting to potentially ineffective antibiotic

prescriptions.

• At any given time, 25% to 35% of all hospitalized patients are receiving antibiotic treatment,

whether therapeutic or prophylactic. The result

of such heavy use among a very vulnerable population often leads to the emergence and spread

of antibiotic-resistant bacteria.

Key recommendations

(The Advisory Board presents options, rather than

direct recommendations)

Surveillance

• “Congress could support the establishment of a

national surveillance system, including providing funding. The features of current, limited

systems can be incorporated and combined to

produce a system of desired size, complexity, and

cost. Any system must have a strong advisory

group that includes diagnostic laboratory and

computer experts, clinicians, hospital administrators, pharmaceutical company researchers,

academic scientists, and federal and state regulatory and health officials.”

Infection control

• “Congress could encourage all states to adopt

guidelines for the coordination of infection control measures between acute care and long-term

care facilities and to extend guidelines to include

all antibiotic-resistant bacteria.”

Research funding

• “Congress can make money available for studies

of the development, transfer, and persistence of
99

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

antibiotic resistance [and] for research into the

basic biology of bacteria;

• Congress can make resources available for the

study of appropriate use of devices that present

infection risks to hospitalized patients.”

Controlling antibiotic use

• “Review Medicare and Medicaid reimbursement

policies for their unanticipated effects on antibiotic prescription patterns.”

Antibiotics in animal husbandry

• “Collect information about associations between

animal husbandry uses of antibiotics and antibiotic-resistant bacteria in humans;

• Design a study to determine the sources of antibiotic-resistant bacteria in the human diet;

• Study the benefits of antibiotic use in animal

husbandry. An analysis of written information

could probably determine the costs of the antibiotics in feeds.”

Negotiated marketing agreements for antibiotics:

• “Congress can provide FDA with authority to

negotiate extended market exclusivity to manufacturers that agree to restrictions on marketing

of antibiotics.”

Development of off-patent compounds as antibiotics

• “Congress could authorize FDA to extend

market exclusivity for off-patent antibiotics that

are shown to be effective against antibioticresistant bacteria;

• Congress could establish a federal program to conduct clinical trials of antibiotics to determine if they

have uses against antibiotic-resistant bacteria.”

Implementation suggestions

The Advisory Panel suggested delegation of responsibilities to various government agencies and departments of the United States. Increased funding

for the creation of surveillance systems and infection control guidelines, and for research and development would come from Congress. FDA would

be responsible for facilitating the development of

new antibiotics, and for helping to determine the

future uses of antibiotics in food animals and plants.

Internal hospital surveillance systems should continue, and should be linked to other hospitals within

a geographical area, with the eventual goal of a nation-wide system overseen by CDC.

Conclusions/Executive Summary

“The problems caused by antibiotic-resistant bacteria can be ameliorated through two major routes:

1) prolonging the effectiveness of currently available antibiotics through infection control and optimal use of existing antibiotics and 2) developing

new antibiotics to treat resistant bacteria.”

“Although all persons are susceptible to illnesses

related to antibiotic-resistant bacteria, some are more

than others. The poor, people without adequate

health care, the incarcerated, the homeless, military personnel, children in daycare facilities, the

elderly, and the immuno-suppressed are more susceptible to these illnesses than the general population. However, because most of the general public

comes in contact with members of these vulnerable populations daily, the general public is at risk

because the diseases or illnesses can spread from

person to person... Therefore, it is crucial that the

scientific and medical communities, the pharmaceutical industry, and the general public cooperate

to find solutions that will slow the pace of antibiotic resistance and lessen the impact of illness on

public health.”

Authors: Advisory Panel: Gail Cassell, PhD; Anne

Bolmstrom; Robert J. Bywater, PhD; Barry Eisenstein,

MD; Prabhavathi B. Fernandes, PhD; Winston

Frederick, MD; Joshua Lederberg, PhD; Stephen

Lerner, MD; Stuart Levy, MD; Robert C. Moellering,

Jr., MD; Barbara Murray, MD; Tom O’Brien, MD;

Lone Simonsen, PhD; Harry Taber, PhD; Alexander

Tomasz, PhD; Richard Wenzel, MD, MSc; Craig

Townsend, PhD; Michael Zasloff, MD, PhD

Type of publication: Report

Pages: 183

Intended audience: United States; policy-makers,

health care providers

Study timeframe: The Advisory Panel reviewed the

scientific literature from 1961 to 1995, with a few

references from the late 1930s and 1940s.

Study process: The Advisory panel reviewed scientific literature, explored biological mechanisms

behind antibiotic resistance, and researched new

antibiotics.

Type of organization: Federal Government

Languages (published in): English

Key contact

Ordering information: USA Government Printing

Office, Superintendent of Documents, Mail Stop:

SSOP, Washington, DC 20402-9328
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

100

(7) Infectious Disease: A Global Health

Threat

Organization: National Science and Technology

Council; Committee on International Science,

Engineering, and Technology Policy (CISET)

Year published: 1995

Selected key findings

• The re-emergence of infectious diseases may be

linked to human behavior (increased travel and

trade across borders, shifts in population

demographics, the poor quality of public health

infrastructures) and ecological changes (climate

and weather changes, evolution of microorganisms, disruption of ecosystems due to human

use patterns).

• The cost of treating antibiotic-resistant bacterial infections in the United States was $4 billion in 1994, and projected to increase.

• The USA response to reports of outbreaks of

infectious disease is often informal, loosely coordinated among government agencies, and

hampered by a lack of funding to conduct a complete investigation.

Key recommendations

Work in partnership with other countries, with

WHO, and with other international organizations

to improve worldwide disease surveillance, reporting, and response by:

• Establishing regional disease surveillance and

response networks linking national health ministries, WHO regional offices, USA Government

laboratories and field stations abroad, foreign

laboratories and medical centers, and WHO collaborating centers;

• Ensuring that reliable lines of communication

exist between local and national medical centers

and between national and regional or international reference facilities, especially in parts of

the world where modern communications are

lacking;

• Developing a global alert system whereby national governments can inform appropriate

worldwide health authorities of outbreaks of infectious disease in a timely manner.

Strengthen the USA capacity to combat emerging infectious diseases by:

• Enhancing collaborations among USA agencies

to ensure maximum use of existing resources for

domestic and international surveillance and response activities;

• Rebuilding the USA infectious disease surveillance public health infrastructure at the local,

state, and federal levels;

• Working with the private and public sectors to

improve USA capacity for the emergency production of diagnostic tests, drugs, and vaccines;

• Strengthening technical training programs in

disciplines related to infectious disease surveillance and response;

• Establishing an Interagency Task Force to coordinate the implementation of these recommendations;

• Establishing a private sector subcommittee of the

Interagency Task Force that includes representatives of the USA pharmaceutical industry, medical practitioners and educators, and biomedical

scientists.

Implementation suggestions

The committee recommends giving greater authority to certain government agencies and departments

to monitor and respond to disease outbreaks. To

this end, it recommends the convening of an

Interagency Task Force, consisting of Centers for

Disease Control and Prevention, Food and Drug

Administration, National Institutes of Health, the

Department of State, Department of Defense, and

USA Agency for International Development, and

others as necessary.

Conclusions

The elements of a global network for disease surveillance already exist but need to be strengthened,

linked, and coordinated. For instance, many USA

Government department and agencies maintain or

support field stations and laboratories in Africa,

Asia, and the Americas that may be electronically

linked to provide an initial framework for a network for global infectious disease reporting. In partnership with other countries and with WHO, this

skeletal surveillance network could be expanded

over time to include many international resources,

including national health ministries, WHO

Collaborating Centers, hospitals, and laboratories

operated by other nations, and American and foreign private voluntary organizations.

Authors: Report generated by members of CISET

and its working group comprised of members from

28 government agencies and departments

Type of publication: Report

Pages: 56
101

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Intended audience: United States; policy-makers

Study timeframe: Working group convened December 14, 1994

Study process: Various government agencies and

departments contributed input on the role of the

United States in detecting, reporting, and responding to outbreaks of new and re-emerging infectious

diseases.

Type of organization: Government

Languages (published in): English

Key contact

Centers for Disease Control and Prevention,

Office of the Director, National Center for Infectious Diseases: (404) 639-2603

(8) Report of the ASM Task Force on

Antibiotic Resistance

Organization: American Society for Microbiology

Year published: 1995

Selected key findings

• Broad spectrum antibiotic use for otitis media

is selecting for resistance against other more

dangerous pathogens.

• Physicians contribute to the resistance problem

by inadequately diagnosing ailments before prescribing antibiotics, prescribing antibiotics to

treat viral illnesses, inappropriately prescribing

broad spectrum antibiotics, and acquiescing to

patient demand for antibiotic prescriptions when

their use would be ineffective.

• Nearly one half of antibiotics used in the USA

are used in farm animals (according to 1988

report by the National Academy of Sciences).

• The estimated yearly cost of treating infections

in humans that are related to antibiotic-resistant organisms in the United States is over $4

billion.

Key recommendations

• Establish a national surveillance system to do the

following:

— “Focus on the most prevalent bacterial and

fungal pathogens (not viral) that concern

human health. This will assess isolates from

clinical disease cases and routine isolates so

that no bias from one center testing only the

“problem” isolate or more resistant isolates

compromises the results. Attention will be

given to the trend in upward “creep” of MICs

[Minimal Inhibitory Concentration]. There

is also a need to monitor food sources such

as animal products at the supermarket level

as well as imported fruits, vegetables, and

other products that may carry colonizing,

drug-resistant bacteria and colonizing fecal

flora in some patient populations. Salmonella

and Shigella both should be monitored.

Salmonella gives the best window into the

impact of uses of antibiotics in the animal

world, and the fraction of Shigella that is

imported gives us an excellent view of the

impact of antibiotic uses in the developing

world. Monitoring of soil waste in farms

should also be considered;

— Establish a baseline of antimicrobial in vitro

efficacy to which the following can be compared: earlier data from similar surveillance

studies found in medical literature reviews,

especially if these studies utilized comparable methodologies and surveillance techniques;

subsequent surveillance data resulting from

the establishment of a national surveillance

system analyzed in a longitudinal manner;

non-USA data to assess the international

risks of resistance;

— Accumulate concurrent demographic profile

information to assess the relationships

between organisms emerging in hospitals of

various sizes or disease therapy focuses and

pathogens prevalent among ambulatory patients in the community and animals housed

in various environments. The role of drug

use in these environments shall be addressed;

— Establish a mechanism whereby organisms

possessing certain phenotypic and genotypic

resistance patterns will be referred to adequately funded laboratories for detailed study.

Various molecular typing and investigative

procedures can lead to earlier understanding of developing resistance mechanisms and

spread of epidemic clones;

— Allow for the future assessment of the

encountered resistant pathogens’ effect on

patient outcomes, general community

health, and the costs of health care delivery.

Surveillance will target areas for specific intensive interventions for prevention (like

vaccine campaigns and antimicrobial use reduction programs). Surveillance will also

identify areas where epidemiologic investigations are needed to improve understanding of spread of drug-resistant strains and to
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

102

identify ways to interfere with spread;

— Maximize the possibility that data will lead

to significant forms of professional health

care intervention to reduce the probability

that resistance to the drug will be spread

widely and have an adverse impact on the

national quality of health care outcomes.

Interventions ideally should be focused at the

local level but regional and national interventions could also provide great benefits;

— Provide expert federal agencies and societies

the information to modify recommendations

regarding therapy or prophylaxis of disease

or regarding testing procedures. These can

be implemented at various levels related to

patient or institutional demographics or by

geography (local, regional, national);

— Provide a compatible system in which subsets of participants could be grouped for

common benefits. Examples include federal

hospitals (Veterans Administration [VA],

military, etc.), animal care facilities (university-based, USA Department of Agriculture

[USDA], etc.), recognized HMO-like programs, and academic institutions such as

university teaching hospitals;

— Provide the accumulated data to pharmaceutical manufacturers, thus providing the

validations of contemporary drug spectrums.

This will be valuable in establishing meaningful organism coverage indications in

antimicrobial agent package inserts;

— Provide a system that can be modified to

address any discovered area of concern related

to the effective therapy of infectious organisms. This could allow expansion to cover

fungi, viruses, cell-associated organisms, and

some parasites.”

— Monitor bacterial pathogens considered

important in human and animal infections.

Testing schedules of various strains and species will vary according to the recommendations of the surveillance oversight panel. A

significant number of organisms should be

tested, with medical statisticians contributing input to the final list.

— Conduct a broad sampling of geographically

dispersed laboratory isolates, with a focus on

human pathogens. Criteria for selection of

laboratories will be based on state population density and diversity of demographic

populations.

— Monitor demographic profiles of participating hospitals and laboratories with yearly

updates.

— Establish testing methods that are of reference quality and closely follow the documents published by the NCCLS. Where

possible, conduct initial screening using the

disk diffusion method (MCCLS M2-A5) for

those pathogen-antimicrobial combinations

that can be accurately tested.”

• Strengthen professional and public education in

the area of infectious diseases and antibiotics to

reduce inappropriate usage of antibiotics.

— “An urgent need exists for more appropriate

selection and use of antimicrobial drugs. The

curriculum of health professional (medical,

dental, nursing, and veterinary) schools and

postgraduate educational programs should

be strengthened in the areas of sterilization,

disinfection, hazards of inappropriate antimicrobial drug use, appropriate diagnosis

and treatment of infectious diseases, and

antibiotic resistance. These efforts should

result in reduction of spread of infectious

agents and more prudent use of antibiotics;

— Better guidelines should be established and

enforced to reduce the spread of infectious

agents and antibiotic resistance in the hospital environment, nursing homes, daycare

facilities, and food production industries;

— Educational materials should be developed

and widely distributed to patients and food

producers. The need for partnerships in improving antimicrobial use of cost-effective

treatment of infections and to preserve the

effectiveness of antimicrobial drugs for the

future should be emphasized.”

• “There is an urgent need for more basic research

directed toward development of new antimicrobial compounds, effective vaccines, and other

prevention measures.

— In FY 1994 allocations to the National Institute of Allergy and Infectious Diseases of

the NIH for funding of non-AIDS infectious

disease research were reduced by $20 million. Increased appropriations are urgently

needed to fund areas of research directly related to new and re-emerging infections and

antibiotic resistance;

— More basic research is needed to delineate the

genetic and metabolic pathways, including

essential regulatory factors, that determine

virulence as well as antibiotic susceptibility
103

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

or resistance in pathogens of human and

veterinary importance...;

— More resources should be devoted to the

sequencing of the entire genome of microbial pathogens, particularly in closed populations (i.e., hospitals, child care facilities,

and food production facilities);

— More basic research is needed to better understand the genetics of microorganisms and

the development of antibiotic resistance,

particularly in fungi and newly described

pathogens;

— Research is needed for development of rapid,

reliable diagnostic techniques for identifying specific infectious causes of illness...;

— More basic research is needed to facilitate

development of effective vaccines and other

prevention measures.”

Implementation suggestions

Implementation of the task force’s recommendations would be conducted by the National Center

for Infectious Diseases of the CDC. Establishment

of priorities and implementation of policies would

be carried out by the National Institute of Allergy

and Infectious Diseases of the National Institutes

of Health (NIH), the USA Department of Agriculture, the Environmental Protection Agency, and

the Food and Drug Administration.

Conclusions/Executive Summary

“There is an urgent need for effective domestic and

global surveillance of antibiotic resistance in animals and humans. There is also an urgent need for

more prudent use of antibiotics in both human and

veterinary medicine, particularly as it relates to food

production. Of equal urgency is the need for better hospital infection control and implementation

of guidelines to reduce spread of infection and antibiotic-resistant pathogens in the hospital environment. There is a great need for strengthening the

curriculum of human and veterinary health care

professionals in the areas of sterilization and disinfection, mechanisms of antibiotic resistance, and

factors contributing to its spread, including inappropriate antibiotic usage. There is also a need for

patient education regarding appropriate uses of antibiotics. More basic research is needed to more clearly

delineate mechanisms of antibiotic resistance and

to identify new antimicrobial targets. Lastly, greater

emphasis must be placed upon research related to

rapid, reliable diagnostic tests and vaccines for prevention and control of infectious diseases.”

Authors: Task force: Gail H. Cassell, Ph.D., Gordon L.

Archer, M.D., Thomas R. Bear, M.D., Mary J.

Gilchrist, Ph.D., Donald Goldmann, M.D., David

C. Hooper, M.D., Ronald N. Jones, M.D., Stanley

H. Kleven, D.V.M., Ph.D., Joshua Lederberg, Ph.D.,

Stuart B. Levy, M.D., Donald H. Lein, D.V.M.,

Ph.D., Robert C. Moellering, M.D., Thomas F.

O’Brien, M.D., Bennie Osburn, D.V.M., Ph.D.,

Michael Osterholm, Ph.D., David M. Shlaes, M.D.,

Ph.D., Martin Terry, D.V.M., Sue A. Tolin, Ph.D.,

Alexander Tomasz, Ph.D. Government Liasions: Robert

F. Breiman, M.D., Jean Cooper, Ph.D., James M.

Hughes, M.D., John La Motagne, Ph.D., Edward

McSweegan, Ph.D., Albert T. Sheldon, Ph.D., Fred

Tenover, Ph.D. Industrial Liasions: Jerry Boscia, M.D.,

Carl J. Craft, M.D., Susan Froshauer, Ph.D., Michael

McCabe, D.V.M., Catherine Reese, Ph.D., Ray Testa,

Ph.D. Office of Technology Assessment: Sean Tunis,

M.D., Justin Latus, M.P.P.

Type of publication: Report

Pages: 23

Intended audience: United States; microbiologists

Study timeframe: N/A

Study process: Task Force members participated in a

workshop conducted July 6, 1994, and reviewed

relevant scientific literature.

Type of organization: Non-profit, life science society

Languages (published in): English

Key contact

ASM Headquarters, 202-737-3600.

Available on the web at: http://www.asmusa.org/

pasrc/pdfs/antibiot.pdf

(9) The Medical Impact of the Use of

Antimicrobials in Food Animals. Report

of a WHO Meeting.

Organization: World Health Organization, Division

of Emerging and Other Communicable Diseases

Surveillance and Control.

Year published: 1997

Selected key findings

• At the time of the report, Salmonella serotypes

showing reduced susceptibility to fluoroquinolones in humans had been observed in

France, Germany, Ireland, the Netherlands, Russia, Spain and the United Kingdom.

• There is a lack of quantifiable data on the preva-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

104

lence and spread of resistance in zoonotic bacteria or indicator agents, including Escherichia coli,

Entereococcus faecium and Enterococcus faecalis.

• Prior to the use of fluoroquinolones in poultry

production, there has been a dramatic rise in

the incidence of fluoroquinolone-resistant

Campylobacter jejuni in live poultry, poultry meat

and from infected humans.

Key recommendations

• Adherence to the recommendation made by the

WHO advisory group of 1994, specifically: “The

use of any antimicrobial agent for growth promotion in animals should be terminated if it is:

used in human therapeutics; or known to select

for cross-resistance to antimicrobials used in

human medicine.”

• “National authorities should define threshold

levels of resistance in bacteria and circumstances

where mitigation procedures should be instigated and, if such procedures are unsuccessful,

when approval should be withdrawn;

• No antimicrobial should be administered to a

food animal unless it has been evaluated and

authorized by competent national authorities.

This evaluation should include a thorough risk

assessment which includes the development of

resistance that may impact public health; and

post-market monitoring program to detect emergence of resistance of public health significance.

If such emergence is detected, appropriate

action should be taken, which may include the

withdrawal of the antimicrobial in question;

• Increased concerns regarding risks to public

health resulting from the use of antimicrobial

growth promoters indicated that it is essential

to have a systematic approach towards replacing

growth-promoting antimicrobials with safer

non-antimicrobial alternatives;

• Request the Codex Alimentarius Commission

to include issues of antimicrobial resistance

among the terms of reference of the Codex committee on Residues of Veterinary Drugs in Foods;

• National authorities should maintain records of

export/import figures of bulk chemicals with

potential antimicrobial use, as such information

is vital for quantitative assessments of the medical risks related to the use of antimicrobials in

livestock production;

• WHO should continue to support ongoing

efforts to harmonize residue standards internationally;

• Countries should ascertain and monitor the

prevalence of resistant bacteria in food-producing animal populations and animal-based food

products;

• Classes or organisms to be included in national

monitoring programs should be the important

zoonotic foodborne bacteria (with Salmonella as

the primary group of organisms) and key indicator bacteria... If feasible, programs should

include E. coli and Campylobacter. In addition,

other potential veterinary and human pathogens

(e.g., Enterococcus) should be considered, based

on an individual country’s requirements;

• National practices of antimicrobial use in animals would be reviewed, and antimicrobial use

policies be developed to reduce the risks of

selection and dissemination of antimicrobial

resistance.”

Implementation suggestions

• WHO’s Program on Antimicrobial Resistance

Monitoring would be responsible for coordinating international efforts to conduct surveillance

of resistant bacteria in food animals and food

from animal sources, and for training personnel

in the medical and veterinary sectors on antimicrobial resistance testing and national policy

framework development activities.

• An expanded version of the WHONET software

would be used to monitor data on bacteria collected from food animals and food of animal

origin.

• Collaborations among the medical, veterinary

and agricultural sectors would be responsible for

coordinating surveillance efforts at the local,

regional, or national level.

• WHO and the Food and Agricultural Association of the United Nations would convene

experts to develop international guidelines for

prudent use of antimicrobials in food animal

production.

Conclusions/Executive Summary

“Microbiological and clinical evidence is mounting that resistant bacteria or resistance determinants

might be passed from animals to humans, resulting in infections that are more difficult to treat.

With an increase in the prevalence and distribution of antimicrobial-resistant infections in hospitals and the community, the question has been

raised as to how this escalation of resistance could

have been influenced by the use of antimicrobials

in livestock production. Timely public health

action is needed to control or mitigate any medical
105

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

problem that might be related to the widespread

application of antimicrobials outside the medical

sphere. The most desirable action is the limitation,

or more prudent use, of antimicrobials, particularly where alternatives are available. In situations

where there is evidence of a link to medical problems, appropriate control action is needed. In light

of shrinking public resources and the increasing

need to conduct scientifically-substantiated risk

assessments for prioritizing public health action,

national policies on the use of antimicrobials in

animals must balance the possible benefits to livestock production against the medical risk and public

health consequences deriving from their use.”

Authors: Participants: Professor J. Acar, Dr. F. Angulo,

Dr. D. Bell, Professor T. Blaha, Dr. J. Boisseau, Dr. J.

Borvendég, Dr. Anne Brisabois, Dr. R. Buchanan, Dr.

Celia Carlos, Dr. Paula Fedorka-Cray, Professor A.

Franklin, Professor C. Friis, Professor H. Goossens,

Professor J. Gropp, Dr. R. Helmuth, Dr.A. Hoszowski,

Professor S. Jin, Dr. I.A. Kroetz, Dr. Hilde Kruse, Dr.

J.-P. Lafont, Professor R. LeClerq, Dr. S. Levy, Dr. J.

MacKinnon, Dr. J.L. Martel, Dr. G. Martin, Dr. S.

McEwen, Dr. S. McOrist, Dr. M.N. Mohd Nordin,

Professor A. Panin, Dr. Laura Piddock, Professor M.

Pugh, Dr. A. Rattan, Professor L. Songkram, Dr. S.

Sundlof, Dr. W. Thiel, Dr. Linda Tollefson, Dr. H.

Trolldenier, Dr. J. Turnidge, Dr. P. Wall, Dr. U. C.

Warsa, Dr. H. Wegener, Professor B. Wiedemann,

Professor M. Wierup, Professor W. Witte, Dr. C. Wray,

Dr. M. Zervos, Dr. Dorothée André, Dr. J. Blancou,

Dr. J. Paakkanen, Dr. J. Perez-Lanzac, Professor P.

Peters, Dr. Barbara Röstel, Dr. M. Rutter Observers:

Dr. P.P. Bosman, Dr. S. Brown, Dr. R. Bywater,

Dr. R. Carnevale, Dr. R. Froyman, Dr. T. Gomez,

Dr. S. Lens, Dr. M. Lütoz, Dr. Margaret Miller, Dr.

K. Morita, Dr. S. Pitlik, Dr. Andrea Sanwidi, Dr. T.

Shyrock, Dr. P. Sundberg, Dr. T. Tselentis, Dr. C.

Verschueren, Dr. L. Vogel WHO Secretariat: Dr. R.

Crom, Mr. G. Hartl, Dr. Sudarshan Kumari, Dr. N.

Moran, Dr. A. Reilly, Dr. K. Stöhr, Dr. Rosamund

Williams.

Type of publication: Meeting Report

Pages: 24

Intended audience: Global; policy-makers, agricultural

industry

Study timeframe: The meeting was held from the

13th to the 17th of October, 1997.

Study process: During the four weeks prior to the

meeting, 522 experts received 39 presentations

prepared by those who would be participating in

or observing the meeting. The experts discussed and

commented on the material. Presentations were

given and discussed during the first three days of

the meeting. On the last two days, working groups

drafted reports on medical impacts of antimicrobial use in livestock production, surveillance and

risk management. The reports were discussed and

adopted during the meeting’s final session.

Type of organization: International, non-governmental, public health agency

Languages (published in): English

Key contact

Ordering Information: Communicable Disease

Surveillance and Response Documents, World

Health Organization, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4198, attention CSR

Documents; email: csr@who.ch, attention Documents.

Available on the web at: http://www.who.int/emcdocuments/zoonoses/whoemczoo974c.html

(10) America’s Vital Interest in Global

Health: Protecting Our People,

Enhancing Our Economy, and

Advancing Our International

Interests

Organization: Institute of Medicine

Year published: 1997

Selected key findings

• The United States lacks a coordinated, national

plan for conducting basic health research and

development and applying it towards the improvement of global health.

• Prevention is the most cost-effective approach

to infectious disease, with millions of dollars

saved globally each year once a major disease is

eradicated.

Key recommendations

“The USA government should:

• act to facilitate the development of an effective

global network for surveillance of infectious

diseases, using the full potential of the information and communications revolution and

fostering the capacity of developing countries

in both biomedical surveillance and communications;

• further develop and extend the network to pro-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

106

vide an early warning system for possible biological or chemical attacks;

• take an active role in global efforts to share information between countries on the most effective means of financing and delivering health

care in order to maximize efficiency and equity;

• increase its investment in research and development in biomedical science related to major

global health problems through expanded partnerships and cost-sharing with other governments and international donors;

• continue federal support for the education and

training of health researchers and practitioners

from other countries as an international public

good toward health leadership that benefits both

our own nation and others;

• form an Interagency Task Force on Global

Health within the government to anticipate and

address global health needs and to take advantage of opportunities in a coordinated and strategic fashion.”

Implementation suggestions

The Task Force designates the USA Department of

Health and Human Services as the organization

most capable of carrying out the recommendations

in the report, including setting of priorities and

coordinating the efforts of other health agencies

around the world.

Greater financial support of the United Nations

by the United States would help to implement more

effective strategies for achieving better global health,

and give the USA more leverage to enact the kinds

of global policies that it considers to be necessary.

Conclusions/Executive Summary

“For the United States to engage successfully in global health, coordination among the multiple USA

agencies with statutory responsibilities in the area

will be needed, as well as the formation of partnerships with the USA industrial and academic sectors and nongovernmental organizations, other

nations, and international organizations. Without

active USA engagement and coordination, in concert with the complementary efforts of other

nations, the struggle to ensure health around the

globe threatens to fragment or falter, with the likely

outcome that our own national health, economic

viability, and security will suffer. This report outlines the compelling case for America’s active

engagement in global health and offers recommendations on how this may best be achieved.”

Authors: Barry R. Bloom, Harvey V. Fineberg,

Jacquelyn Campbell, Richard G. A. Feachem, Julio

Frenk, Dean Jamison, Eileen T. Kennedy, Arthur

Kleinman, William E. Paul, Allan Rosenfield,

Patricia L. Rosenfield, Thomas J. Ryan, Susan C.

M. Scrimshaw, June E. Osborn, John H. Bryant,

William H. Foege, David P. Rall

Type of publication: Report

Pages: 62

Intended audience: United States; policy-makers

Study timeframe: The report considers information

from 1985 to 1997.

Study process: Committee members conducted a

workshop in November of 1995, and solicited input from national and international public health

and government organizations.

Type of organization: Non-profit public health and

advisory organization; advisor to Federal Government on issues of public health

Languages (published in): English

Key contact

Ordering information: National Academy Press,

www.nap.edu

Content: Barry R. Bloom and Harvey V. Fineberg,

Co-Chairs of the IOM Board on International

Health

(11) New and Re-emerging Infectious

Diseases: A Global Crisis and

Immediate Threat to the Nation’s

Health; the Role of Research

Organization: American Society for Microbiology

Year published: 1997

Selected key findings

• Antibiotic-resistant bacterial infections in the

United States cost approximately $4 billion in

medical costs annually.

• Infectious diseases were the third leading cause

of death in the United States in 1996.

• From 1980 to 1996, the death rate from infectious diseases in the United States has increased

more than 50 percent.

Key recommendations

• Encourage investment in research in the fields

of microbiology, immunology and infectious

diseases.
107

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• Focus research on molecular genetics and the

biochemistry of bacteria, viruses, and fungi.

Implementation suggestions

Implementation of recommendations can be

achieved by increasing funding to USA government

agencies, including the National Institute of Allergy

and Infectious Diseases and the National Institutes

of Health.

Conclusions/Executive Summary

“Increased research funding is critical to address the

current threats from new and re-emerging infectious diseases through the development of better

diagnostic tests, new drugs, and vaccines. In addition, increased funding would provide new opportunities for making major advances to define the

potential role of infectious agents in chronic

diseases, such as cancer, that currently have no

known causes.”

Authors: Not specified

Type of publication: Booklet

Pages: 13

Intended audience: United States; scientists, policymakers

Study timeframe: Report considers scientific literature from 1992 to 1996

Study process: Analysis of documents on emerging

infectious diseases

Type of organization: Non-profit, Life Sciences Society

Languages (published in): English

Key contact

American Society for Microbiology, Public Affairs

Office, 202-942-9209

Available on the web at: http://www.asmusa.org/pasrc/

pdfs/newandre.pdf

(12) Resistant Organisms: Global Impact on

Continuum of Care

Organization: Royal Society of Medicine

Year published: 1997

Selected key findings

• Attitudes of patients and physicians are key

factors that contribute to the inappropriate prescribing and use of antibiotics (Levy; Plotnick).

• Resistance is a local problem, dependent on

patterns of use within a hospital and on each

hospital’s infection control programs (Levy).

• Resistance is an ecological problem; overuse of

antibiotics has removed susceptible organisms

and seen their replacement with resistant ones.

It is possible to reverse the problem through the

reduction of antibiotic use (Levy).

• Factors such as sterility and type of instruments,

wound preparation, wound closure, etc. contribute to the likelihood of infection during surgical procedures (Henderson).

Key recommendations

• More accurate diagnosis before prescribing any

medication (Levy; Plotnick).

• Resuscitate efforts to identify and monitor the

emergence and spread of infectious diseases

(Plotnick).

• Evaluate different methods of antibiotic use,

including shorter or cyclical courses.

• Improve staff to patient ratios in hospitals, to

allow for better diagnosis and prescribing (Lee).

• Modify prescribing practices to eliminate excessive antibiotic prophylaxis before surgery

(Henderson).

Implementation suggestions

Rear Admiral Plotnick and Laura Lee both recommended strategies developed by the CDC (in cooperation with a variety of regional, national, and

international public and private organizations)

which act on issues of surveillance, research, prevention, control, and institutional management.

Conclusions/Executive Summary

The abatement of the problem of antibiotic resistance can only be achieved through cooperation of

prescribers, patients, government, pharmaceutical

and agricultural industries. Surveillance, infection

control, and improved prescribing practices are all

important components of any collaborative effort.

Authors: Jean Davis, Professor S. Michael Emmerson,

David K. Henderson, MD (co-editor), Laura Lee,

Stuart B. Levy, MD (co-editor), Rear Admiral Julia

R. Plotnick

Type of publication: Conference proceedings

Pages: 70

Intended audience: United States, United Kingdom;

health care providers
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

108

Study timeframe: Conference held September 27,

1996

Study process: Varies with each presentation

Type of organization: Independent professional organization

Languages (published in): English

Key contact

Ordering information: Royal Society of Medicine

Press, Lmt., +44 (0) 20 7290 3945; email: kirsty.

orriss@roysocmed.ac.uk

(13) Guidelines for the Prevention of

Antimicrobial Resistance in Hospitals

(SHEA Position Paper)

Organization: Society for Healthcare Epidemiology

of America; Infectious Diseases Society of America

Year published: 1997

Selected key findings

• The authors contend that, contrary to many

studies, antibiotic-resistant bacteria are not necessarily less virulent than their susceptible

parents, and that even in cases where the second

generation bacteria are less virulent, they are no

less dangerous to vulnerable hospital

populations.

• Making a definite connection between antimicrobial use and antimicrobial resistance in hospitals is often confounded by lack of consistency

from hospital to hospital in defining resistance,

methodologies used in susceptibility testing, and

other variables.

Key recommendations

Recommendations for hospitals

• “Establish a system for monitoring bacterial

resistance and antibiotic usage;

• Establish practice guidelines and other institutional policies to control the use of antibiotics,

and respond to data from the monitoring

system;

• Adopt the recommendations of the Centers for

Disease Control and Prevention’s (CDC) Guidelines for Isolation Precautions in Hospitals, as

concerns the isolation of patients colonized or

infected with resistant microorganisms.”

Recommendations for prevention & reduction of

antimicrobial resistance in hospitals

• “It is recommended that hospitals have a system

for monitoring antimicrobial resistance of both

community and nosocomial isolate on a monthly

basis or at a frequency appropriate to the volume of isolates.

• It is recommended that hospitals monitor the

relationship between antimicrobial use and

resistance, and assign responsibility through

practice guidelines or other institutional policies.

• It is recommended that hospitals apply Contact

Precautions to specified patients known or

suspected to be colonized or infected with

epidemiologically important microorganisms

that can be transmitted by direct or indirect contact.”

Recommendations for future studies

• “It is recommended that research to define the

mechanism of transfer of bacteria and their

resistance determinants among patient populations and to determine methods to prevent

emergence and transfer of resistance, including

control of antibiotic usage, be supported with

increases in targeted research funding.

• The development and testing of protocols for

measuring the effect of a variety of antimicrobial usage controls is recommended for use in

multiple hospitals to determine the most effective ways to prevent and reduce antimicrobial

resistance in specific species to specific antimicrobials.

• It is recommended that educational methods,

including those that are interactive and computer-based, be developed to improve the appropriateness of antimicrobial prescribing.

• The efficacy of various levels of infection

control precautions should be documented by

controlled trials.

• Controlled studies of behavior modification,

including novel approaches, to permit the efficient application of recommended guidelines

within hospitals are recommended.

• The efficacy of quality improvement approaches

to control of resistance should be studied.”

Implementation suggestions

Guidelines developed by the CDC and the National

Committee for Clinical Laboratory Standards are

suggested as ways for microbiologists and physicians to monitor antibiotic prescribing and use.

Conclusions/Executive Summary

“There is convincing evidence that we share a
109

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

single ecosystem globally in terms of resistance. The

selection of resistance in one organism in one part

of the world, even within an animal population,

may have long-term, important implications for

human health globally. Therefore, management of

the problem of antimicrobial resistance within hospitals is a community responsibility, both within

and outside of the hospital...Good stewardship of

antibiotic usage combined with strong infection

control will be required. To achieve this, all levels

of personnel within the hospital must be involved,

from top administration down to individuals performing services and providing patient care.”

Authors: David M. Shlaes, MD, PhD; Dale N.

Gerding, MD; Joseph F. John, Jr., MD; William A.

Craig, MD; Donald L. Bornstein, MD; Robert A.

Duncan, MD; Mark R. Eckman, MD; William E.

Farrer, MD; William H. Greene, MD; Victor Lorian,

MD; Stuart Levy, MD; John E. McGowan, Jr., MD;

Sindy M. Paul, MD; Joel Ruskin, MD; Fred C.

Tenover, MD; Chatrchai Watanakunakorn, MD

Type of publication: Position paper

Pages: 17

Intended audience: United States; scientific community

Study timeframe: The authors reviewed scientific

literature dating from 1977 to 1996.

Study process: The authors analyzed existing scientific literature on antibiotic resistance mechanisms

and spread.

Type of organization: Non-profit public health organization

Languages (published in): English

Key contact

Reprint requests: David M. Shlaes, MD, WyethAyerst Research, 401 N. Middletown Rd., Pearl

River, NY 10965

(14) Symposium on Antibiotic Resistance:

Origins, Evolution, Selection and

Spread

Organization: Ciba Foundation

Year published: 1997

Selected key findings

• Antibiotic resistance is an ecological problem,

in that the balance between susceptible and resistant bacteria has been disrupted.

• In order to determine the extent of antibiotic

resistance in hospitals, it is necessary to take into

account each hospital’s pattern of antibiotic use.

• A report on the monitoring of antibiotic use in

a hospital in Greece proved the efficacy of a rigorous program of prescription control. The combination of prescription monitoring, improved

hygiene, educational programs and the limitation of certain antibiotics resulted in (for example) ceftazidime-resistant P. aeruginosa levels

decreasing from 45% to 8% after three years.

(Giamerellou & Antoniadou)

Key recommendations

• Increase development of novel antibiotic agents.

• Increase emphasis on infection control and hygienic practices.

• Enact multidisciplinary approaches to reducing

hospital resistance rates, including cooperation

between pharmacies and diagnostic laboratories,

and between infectious disease physicians and

clinicians.

Implementation suggestions

Not given

Conclusions/Executive Summary

“This meeting has put these issues [antibiotic use

and mechanisms of resistance] aside in order to

focus on a larger view of the problem, and to

define the potential for return to a healthier state

vis-à-vis susceptible flora. There is a need for new

guidelines on more rational utilization of future

novel antimicrobials within the context of ecology.

There is also a cost to discover and develop these.

Thus, we shall want to keep them from succumbing to a similar fate, i.e., encountering resistance.

In this effort, consumers can join physicians and

the pharmaceutical industry in maintaining this

efficacy. Whether antibiotics are available over-thecounter in developing countries or demanded and

stockpiled in the developed countries, they are too

often in the hands of consumers who use them incorrectly.”

Authors: S.B. Levy, J.E. Davies, P. Huovinen, H.

Sepplälä, J. Kataja, T. Klaukka, R. Gaynes, D. Monnet,

W. Witte, H. Giamarellou, A. Antoniadou, F. Baquero,

M.C. Negri, M.I. Morosini, J. Blazquez, M. Lipsitch,

B.R. Levin, R.E. Lenski, K. Bush, R.A. Skurray, N.

Firth, R.M. Hall, M.C. Roberts, M.L. Cohen

Type of publication: Report

Pages: 250
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

110

Intended audience: Global; scientists

Study timeframe: 3-day symposium in July of 1996.

Study process: Participating scientists discussed a variety of pre-submitted articles on antibiotic resistance.

Type of organization: International scientific and educational non-profit

Languages (published in): English

Key contact

Ordering: John Wiley & Sons, Ltd., cs-books@

wiley.co.uk; telephone: +44 1243 779777

Content: Stuart B. Levy, MD, Symposium Chairman 1996

(15) The Current Status of Antimicrobial

Resistance Surveillance in Europe:

Report of a WHO Workshop held in

Collaboration with the Italian

Associazione Culturale Microbiologia

Medica

Organization: World Health Organization, Division

of Emerging and Other Communicable Diseases

Surveillance and Control

Year published: 1998

Selected key findings

• There is not enough communication between

antimicrobial resistance surveillance networks

and the decision makers at the regional and national levels in Europe.

• Quality assurance standards that evaluate the

validity of surveillance data vary throughout

Europe, making it difficult to make accurate

comparisons.

• A coordinated effort by the various European

surveillance systems is necessary to effectively

address the emergence and spread of antimicrobial resistance.

Key recommendations

• “The communication chain between antimicrobial resistance surveillance networks and national

and regional decision makers must be strengthened and used.”

• “There is a need to harmonize quality assurance

standards throughout Europe.”

• “Adequate support for microbiology and epidemiology training programs, for laboratory

infrastructure, and for data analysis and communication, is required.”

• “Further discussions are necessary, to develop

collaboration between existing antimicrobial

resistance surveillance programmes.”

Implementation suggestions

According to participants’ responses to a questionnaire circulated before the workshop, implementation of any recommendations or improvements

depends on adequate funding, standardized methodologies of susceptibility testing, improved government support, a greater number of trained

professionals to carry out surveillance efforts, and

increased awareness of the resistance problem by

health care providers.

Conclusions/Executive Summary

“The emergence and spread of antimicrobial resistance is a significant problem to all people in all

countries, both developed and developing. It impacts both patients with infections and clinicians

facing growing limitations on their efficacious use

of antimicrobials. It influences a health care system’s ability to implement rational drug use policies and efficiently allocate resources. Because the

emergence of antimicrobial resistance is a global

problem that affects us all, national and international efforts are needed to address the problem.

Information and experience, must be shared so that

all can learn and benefit.”

“At present, many groups are attempting to harmonize local, national and international antimicrobial resistance surveillance methodologies. These

attempts are not necessarily coordinated with one

another, however, and there is a growing perception, reinforced by discussions held during this

workshop, that a positive role could be played by a

pan-European coordinating group. Such a group

could reflect the various national and Europeanwide interests in antimicrobial resistance surveillance. It could be initiated as a study group of the

European Society of Clinical Microbiology and

Infectious Diseases and focus on actively promoting the performance of good-quality local studies

which generate internationally comparable data.

Such data could, in turn, be used to facilitate the

accurate interpretation of results between studies

and generate information on the extent of antimicrobial resistance in Europe. An essential component of any group’s success, of course, will be

adequate funding.” (I. Phillips)

Authors: Participants: Professor Jacques F. Acar, Professor Fernando Baquero, Dr. Andre Bryskier, Dr. Otto
111

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Cars, Dr. Giuseppe Cornaglia, Dr. Patrice Courvalin,

Dr. Roberta Fontana, Dr. Herman Goossens, Dr.

Marija Gubina, Dr. Waleria Hryniewicz, Dr. Pentti

Huovinen, Dr. Vincent Jarlier, Dr. Mark E. Jones,

Professor Smilja Kalenic, Professor Conor T. Keane,

Dr. Marianne Konkoly, Dr. Karl G. Kristinsson, Professor Herminia de Lencastre, Dr. David Livermore,

Professor Enrico Magliano, Dr. Boyka Markova, Dr.

Anna Marton, Dr. Jolanta Miciuleviciene, Dr. Helmut

Mittermayer, Dr. Kathrin Muelemann, Professor Carl

Erik Nord, Professor Alvaro Pascual, Professor Ian

Phillips, Professor Arne C. Rodloff, Professor Jirí

Schindler, Dr. Ivonna Selga, Dr. Anatoly Shapiro, Dr.

Thomas Lund Sørensen, Dr. Marc Sprenger, Dr. Martin Steinbakk, Professor Leonid Stratchounsky, Professor Marc Struelens, Dr. Alkiviadis C. Vatapoulos,

Professor Jan Verhoef, Professor Richard Wise. WHO

Secretariat: Dr. Ana Estrela, Dr. Colette Roure, Dr.

John Stelling, Dr. Rosamund Williams, Dr. Clara

Witt.

Type of publication: Meeting report

Pages: 80

Intended audience: Europe; policy-makers, microbiologists, those who are responsible for surveillance

networks

Study timeframe: The workshop was held on December 12, 1997.

Study process: The participants met to present and

discuss the variety of antimicrobial resistance systems in operation throughout Europe, to highlight

the features of successful programs, and to discuss

how those features may be incorporated into other

systems.

Type of organization: International, non-governmental, public health agency

Languages (published in): English

Key contact

Ordering Information: Communicable Disease

Surveillance and Response Documents, World

Health Organization, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4198, attention CSR

Documents; email: csr@who.ch, attention Documents.

Available on the web at: http://www.who.int/emcdocuments/antimicrobial_resistance/whoemcbac

981c.html

(16) Papers presented at the International

Conference on Emerging Infectious

Diseases in Atlanta, GA, March 1998.

Compiled in Emerging Infectious

Diseases 4(3): 353–515

Organization: Centers for Disease Control and Prevention, National Center for Infectious Diseases

Year published: 1998

Selected key findings

• The National Institute of Allergy and Infectious

Disease (NIAID) dedicates about 21% of its

non-AIDS infectious disease budget to emerging infectious diseases. NIAID’s total emerging

diseases budget increased from $39.3 million in

1993 to a projected $85 million in 1999. (Fauci)

• Nosocomial infections were estimated to be responsible for 88,000 deaths and $4.5 billion in

treatment costs in 1995. Approximately onethird of such diseases are preventable.

(Weinstein)

Key recommendations

Surveillance

One author recommends “...dramatically strengthened local surveillance, including both laboratory

and epidemiologic capacity; commitment on the

part of local governments; and a strong collaborative international research and response system.”

(Broome)

Research

The NIH recommends expanding research on the

ecologic and environmental aspects of disease emergence and transmission; expanding research on the

microbial mechanics of disease emergence; supporting the development of vaccines and other preventive therapies, especially for diseases that are

threatening to emerge or reemerge; and “strengthening the current USA research and training infrastructure for detection and responding to outbreaks

of infectious diseases.” (Fauci)

Nosocomial infections

Improve national surveillance of nosocomial infections that occur in the hospital and in home healthcare settings; improve the design of devices that are

associated with nosocomial infections; institute

aggressive antibiotic control programs, perhaps

making them mandatory for hospitals that receive

federal reimbursements; and develop new and

microbiologic methods for detecting and investigating outbreaks of multidrug-resistant pathogens.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

112

Implementation suggestions

• Continuation and strengthening of Field Epidemiology Training Programs that respond to

reports of emerging infections. Use of the Internet and other communication technologies to

gather and share surveillance information.

(Broome)

• Continued collaboration between the public and

private sectors. (Fauci)

• Hospital personnel would be responsible for

implementing infection control policies,

especially those concerning basic hygiene.

(Weinstein)

Conclusions

• “We are better able in 1998 to address the threats

of emerging infections, but we are by no means

fully prepared. We must have the capacity to

identify new or reemerging threats and to respond successfully. We need to be creative and

efficient in identifying necessary resources...

Eradication activities also contribute to health

capacity development, and the laboratory and

surveillance capacities created for polio eradication should also be useful in detection of and

response to emerging infectious diseases. Many

other creative approaches and collaborations are

needed for an effective global response to whatever our microbial adversaries may produce.”

(Broome)

• “The importance of basic research to the control of emerging and reemerging diseases cannot be overemphasized. Emerging diseases

research encompasses many disciplines, and research advances that fall under the rubric of

emerging diseases will be relevant not only to

specific diseases being studied but to a broad

range of disciplines such as vaccinology, immunology, and drug development.” (Fauci)

• “Several enduring truths characterize the field

of infection control. Hospitals will become more

like ICUs, and more routine care will be delivered on an outpatient basis. Given the choice of

improving technology or improving human

behavior, technology is the better choice. The

major advances in overall control of infectious

diseases have resulted from immunization and

improved hygiene, particularly hand washing.

We must work with hospital personnel on better implementation of existing infection control

technologies so that we will not need to rely

solely on technologic advances.” (Weinstein)

Authors: Stephen A. Morse, Donna E. Shalala, Claire

Broome, James Hughes, David Heymann, Guenael

Rodier, Joshua Lederberg, D. Peter Drotman,

Anthony Fauci, Karen Hein, David Relman, Sir John

Pattison, Bradley Perkins, Thomas Nchinda, Alison

Mawle, Martin Cetron, Jay Keystone, David Shilm,

Robert Steffen, Kenneth Castro, Mary E. Chamberland, Jay Epstein, Roger Y.Dodd, David Persing,

Robert G.Will, Alfred DeMaria, Jr., Jean C.

Emmanuel, Beatrice Pierce, Rima Khabbaz, William

Foege, Donald Hopkins, Robert Weinstein, Jonathan

Kaplan, Gary Roselle, Kent Sepkowitz, Janet

McNicholl, Susan Cookson, Ronald Waldman, Brian

Gushulak, Douglas MacPherson, Frederick Burkle,

Jr., Christophe Paquet, Erich Kliewer, Patricia Walker,

Frederick Murphy, Robert G. Webster, Duane Gubler,

R Colwell, P. Epstein, M. Hall, P. Reiter, J. Shukla,

W. Sprigg, E. Takafuji, J. Trtanj, James Childs, Robert

E. Shope, Durland Fish, Francois X. Meslin, Clarence

J. Peters, Karl Johnson, Emilio Debess, David Dennis,

Suzanne Jenkins, Robert Tauxe, Samantha Yang,

Deborah Deppe, James LeDuc, Robert Pinner, Bradford Kay, Ralph J. Timperi, Stephen S. Morse, David

Forslund, Julie J. McGowan, Tom OíBrien, Lela

Folkers, Maria Teresa Cerqueira, Robert E. Quick,

James Kanu, Gauden Galea, EliasAbrutyn, Ann Marie

Kimball, Carrie Horwitch, Patrick OíCarroll,

Sumarjati Arjoso, Chaiyos Kunanusont, Ya-Shin Lin,

Clifford Meyer, Laura Schubert, Phillip Dunham,

David Bell, Gail Cassell, D. A. Henderson, Joseph

McDade, David Franz, Stanley Falkow, George

Alleyne, May C. Chu, Alexandra Levitt, Karl Western

Type of publication: Peer-reviewed journal

Pages: 164

Intended audience: United States; policy-makers,

government agencies, hospital personnel

Study timeframe: Varies

Study process: Varies

Type of organization: Federal Government

Languages (published in): English

Key contact

Ordering information: EID Editor, CDC/NCID/

MS C12, 1600 Clifton Road, NE, Atlanta, GA

30333

Available on the web at: http://www.cdc.gov/ncidod/

eid/vol4no3/contents.htm
113

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

(17) Preventing Emerging Infectious

Diseases: A Strategy for the 21st

Century

Organization: Centers for Disease Control and Prevention, National Center for Infectious Diseases

Year published: 1998

Selected key findings

• New developments since 1994 that necessitated

an update of Preventing Emerging Infectious Diseases include: new emerging threats; advanced

scientific findings; new methods of discovering,

tracking, and communicating outbreaks;

changes in health care delivery; and increased

public awareness and government response.

• Implementation of CDC guidelines on group B

streptococcal disease helped to reduce its incidence by over 40% between 1993 and 1995 in

the communities that followed the guidelines.

• A combination of improved practices in the food

industry, surveillance, and public education decreased the incidence of invasive listeriosis by

44% between 1989 and 1993; the reduction was

maintained through 1996, the last date cited in

the report.

Key recommendations

Surveillance

• “Strengthen infectious disease surveillance and

response;

• Improve methods for gathering and evaluating

surveillance data;

• Ensure the use of surveillance data to improve

public health practice and medical treatment;

• Strengthen global capacity to monitor and respond to emerging infectious diseases.”

Applied research

• “Develop, evaluate, and disseminate tools for

identifying and understanding emerging infectious diseases;

• Identify the behaviors, environments, and host

factors that put people at increased risk for infectious diseases and their sequelae.

• Enhance epidemiologic and laboratory capacity;

• Improve CDC’s ability to communicate electronically with state and local health departments, USA quarantine stations, health care

professionals, and others;

• Enhance the nation’s capacity to respond to complex infectious disease threats in the United

States and internationally, including outbreaks

that may result from bioterrorism;

• Provide training opportunities in infectious disease epidemiology and diagnosis in the United

States and throughout the world.”

Prevention and control

• “Implement, support, and evaluate programs for

the prevention and control of emerging infectious diseases;

• Develop, evaluate, and promote strategies to help

health care providers and other individuals

change behaviors that facilitate disease transmission;

• Support and promote disease control and prevention internationally.”

Implementation suggestions

Surveillance

• “Extend the ELC [Epidemiology and Laboratory Capacity] program to all state, territorial,

and large local health departments;

• Strengthen the EIP [Emerging Infections Program] network by increasing its demographic

and geographic representativeness and enhancing its laboratory and epidemiologic capacity;

• Use the existing provider-based sentinel networks

to monitor syndromes and diseases, and establish at least one additional network;

• Integrate public health information and surveillance systems;

• Use surveillance data to analyze questions of

public health importance;

• Facilitate access to surveillance data that can be

used in clinical practice;

• Assist global surveillance and response efforts

through increased support of CDC-based WHO

Collaborating Centers;

• Help monitor conditions that favor the emergence or spread of infectious diseases.”

Applied research

• “Develop, evaluate, and disseminate testing

methods for infectious agents;

• Identify factors that influence the risk of developing infectious diseases;

• Assess the role of infectious agents in causing or

exacerbating chronic diseases and syndromes for

which the causative agents are unknown;

• In collaboration with other organizations, support research to develop and evaluate new antimicrobial drugs and prophylactic agents, as well

as methods to control disease vectors and reservoirs;

• Support research to develop new methods of

disinfection;
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

114

• Support social science and behavioral research

to develop better prevention programs.”

Infrastructure and training

• “Define core public health functions and capacities needed for monitoring the spread of

microbes and responding to infectious disease

outbreaks, and provide personnel in state and

large local health departments with essential

equipment and training;

• Strengthen CDC’s capacity to serve as the national and international reference laboratory for

diagnosis of infectious diseases and for drugresistance testing;

• Promote the development and production of

diagnostic and reference reagents for use by public health laboratories;

• Work with state health departments to standardize new diagnostic techniques and facilitate

their use throughout the United States;

• Assist other USA agencies, international organizations, and other nations in building global

capacity for disease surveillance and response;

• Enhance national surge capacity for responding

to outbreaks of unusual size, duration, and

severity;

• Ensure the continued training of epidemiologists in problems related to emerging infectious

diseases;

• Increase the number of laboratory scientists

trained in infectious diseases through the Emerging Infectious Diseases (EID) Laboratory

Fellowship Program and add a track for international students;

• Expand CDC’s efforts to train counterparts in

developing countries in the use of epidemiologic

and laboratory methods for combating emerging infectious diseases.”

Prevention and control

• “Expand existing community-based programs;

• Develop and support new community-based

demonstration programs in the target areas.

• Evaluate the impact and cost-effectiveness of

alternative approaches to reducing infectious

diseases;

• Increase the use of vaccines to prevent and control emerging infectious diseases;

• Work with health care providers, hospitals, managed care organizations, and others to improve

patient outcomes related to infectious diseases;

• Work with private industry, government agencies, and others to develop systems that promote

prompt identification of infectious disease problems and rapid implementation of control measures;

• Develop, implement, and evaluate disease prevention guidelines that can be used by the public, health care providers, and health care systems;

• Work with foreign governments, WHO, the

USA-European Union Task Force on Communicable Disease, other international partners, and

the CISET Emerging Infectious Disease Task

Force to promote global programs for the prevention and control of infectious diseases;

• Provide technical assistance and transfer costeffective technologies to other countries, using

governmental and nongovernmental channels;

• Participate in bilateral and multilateral initiatives

to improve global infectious disease prevention

and control;

• Work with WHO and other partners to complete the revision of International Health Regulations;

• Work with developing countries to sustain health

care improvements and surveillance efforts after

outbreaks.”

Conclusions/Executive Summary

“Achievement of the objectives described in this

plan will improve our ability to understand, detect, control, and prevent infectious diseases. The

outcome will be a stronger, more flexible USA public health infrastructure well-prepared to respond

to well-known disease problems and to address the

unexpected, whether it is an influenza pandemic, a

disease caused by an unknown organism, or a

bioterrorist attack.”

Authors: Sue Binder, M.D., Alexandra M. Levitt,

Ph.D., Judith R. Aguilar, David M. Bell, M.D., Martin S. Cetron, M.D., Mary E. Chamberland, M.D.,

Mark L. Eberhard, Ph.D., Duane J. Gubler, Sc.D.,

Meredith A. Hickson, M.P.H., Jonathan E. Kaplan,

M.D., Rima F. Khabbaz, M.D., James W. LeDuc,

M.D., Susan A. Maloney, M.D., William J. Martin,

Ph.D., Alison C. Mawle, Ph.D., Patrick McConnon,

M.P.H., Martin I. Meltzer, Ph.D., Siobhan O’Connor,

M.D., Alan J. Parkinson, Ph.D., Anne Schuchat,

M.D., Steven L. Solomon, M.D., Robert V. Tauxe,

M.D., Fred C. Tenover, Ph.D., Theodore F. Tsai,

M.D., Robert B. Wainwright, M.D., Helene D. Gayle,

M.D., Walter A. Orenstein, M.D., Barbara R.

Holloway, M.P.H., James S. Marks, M.D., M.P.H.,

Edward J. Sondik, Ph.D., Linda Rosenstock, M.D.,

M.P.H., Walter W. Williams, M.D., M.P.H., Stephen

B. Blount, M.D., M.P.H., Karen K. Steinberg, Ph.D.,

Edward L. Baker, M.D., M.P.H.
115

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Type of publication: Report

Pages: 75

Intended audience: United States; physicians and

other health care providers; policy-makers

Study timeframe: The Steering Committee reviewed

scientific literature from 1982 to 1998, with the

bulk of material from the mid- to late-1990s.

Study process: The Committee evaluated and updated CDC’s plan from 1994, Preventing Emerging

Infectious Diseases.

Type of organization: Federal Government

Languages (published in): English

Key contact

Ordering information: Office of Health Communication, National Center for Infectious Diseases,

Centers for Disease Control and Prevention,

Mailstop C-14, 1600 Clifton Road, Atlanta, GA

30333. Available online at http://www.cdc.gov/

ncidod/emergplan

(18) Human Health Safety Criteria.

Guideline 18.

Organization: Food and Drug Administration, Center

for Veterinary Medicine; USA Department of

Health and Human Services

Year published: Updated on July 28, 2000.

Selected key findings

No findings are presented.

Key recommendations

Antibacterial drugs that are used in the treatment

of animals and have not been found to transfer

resistance to antibacterial drugs that are used in

human clinical medicine must undertake the following studies:

• Controlled studies to determine whether or not

the antibacterial drug, given at subtherapeutic

levels, causes “an increase in the relative quantity or prevalence of Salmonella in animals or

the duration of shedding of these Salmonella as

compared to controls; and/or an increase in the

proportion of resistant Salmonella, the degree of

resistance, and the resistance spectrum;”

• Controlled studies to determine whether or not

antibacterial drugs administered to animals increase the number of coliforms that are resistant

to antibacterial drugs that are used in human

clinical medicine and may transfer that resistance to human intestinal tracts;

• Controlled studies “to determine whether the

consumption of food produced by animals

receiving antibacterial drugs will result in: a. An

increase in the intestinal flora of the prevalence

of pathogenic bacteria; b. An increase in the

degree and spectrum of resistance of the intestinal flora to drugs used in human clinical medicine.”

The guideline also recommends the conducting

of a literature survey, “to determine the incidence

of reports of hypersensitivity resulting from antibacterial drugs in food.”

Implementation suggestions

The criteria are guidelines for implementing the

policies and complying with the regulations mandated by Congress and FDA.

Conclusions/Executive Summary

“The...criteria must be satisfied in order to establish that the use of low and/or intermediate levels

of an antibacterial drug in animal feeds is a safe

practice from the aspect of human health. In general terms, such drug use should not result in: (1) a

significant adverse effect in the relative quantity,

prevalence and shedding of Salmonella organisms

in animals, (2) a significant increase of Salmonella

organisms resistant to drugs used in human clinical medicine in the animal, (3) a significant increase

in the resistance of coliforms to antibacterial drugs

used in human clinical medicine provided this resistance is transferable to bacteria in man, (4) enhancement of pathogenicity of bacteria, or (5)

adverse effect to humans due to ingestion of residues

of the antibacterial drug, metabolites, or degradation products.”

Authors: Not identified

Type of publication: One of 98 guidance documents

created by the Center for Veterinary Medicine to

clarify the laws made by Congress or the Food and

Drug Administration that affect regulated industries. They include guidance on testing procedures,

manufacturing processes and scientific protocols.

Pages: 3

Intended audience: United States; regulated animal

health/food production industries, FDA employees responsible for enforcement

Study timeframe: N/A

Study process: N/A

Type of organization: Federal Government
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

116

Languages (published in): English

Key contact

Ordering information: Food and Drug Administration, Center for Veterinary Medicine, Communications Staff, 7500 Standish Place, HFV-12,

Rockville, Maryland 20855; Telephone: (301) 594-

1755

Available on the web at: http://www.fda.gov/cvm/fda/

TOCs/guideline18.html

Comments and questions to: Policy and Regulations, Team (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500

Standish Place, Rockville, MD, 20855

(19) The Path of Least Resistance

Organization: United Kingdom Department of

Health, Standing Medical Advisory Committee,

Sub-Group on Antimicrobial Resistance

Year published: 1998

Selected key findings

• Although only 20% of prescriptions of antimicrobials for human use in the UK are for

hospital use, they are the site of the greatest resistance problems.

• Of the 50 million antibiotic prescriptions

written each year in the UK, about 50% are for

respiratory tract infections; about 15% are for

urinary tract infections.

• Incidence of methicillin-resistant Staphylococcus

aureus (MRSA) increased dramatically between

1989 and 1997: 1.5% of the organisms were

resistant in 1989, compared to 31.7% in 1997.

• There is every reason to anticipate the further

spread of resistance to currently susceptible

organisms. The most likely of these would be

vancomycin-intermediate MRSA, quinolone

resistant E. coli, and the resistance of gramnegative bacteria to carbapenems. The emergence of penicillin resistant Neisseria meningitidis

and Streptococcus pyogenes are also possible.

• The pressures of time and volume of patients in

hospital emergency wards often increases the

likelihood of inappropriate antibiotic prescriptions.

• A lack of clinical trials on antibiotic use in longterm care facilities, combined with the vulnerable nature of the population and inadequate

diagnostic capabilities, have hampered efforts to

control antibiotic resistance in such facilities in

the UK and the USA.

Key recommendations

The Sub-Group recommends:

• The implementation of a two-tiered national

campaign to improve community prescribing of

antibiotics: a Campaign on Antibiotic Treatment

for general practitioners, and a National Advice

to the Public campaign for patients and consumers;

• “That further support for appropriate prescribing in primary care be provided by developing

and promulgating evidence-based national

guidelines for the management of certain infections, under the aegis of the National Institute

for Clinical Excellence [and] that such national

guidelines are adapted for local use during the

development of Health Improvement Plans;

• That [guidelines] should be integrated within

computerized decision-support systems as soon

as possible. These guidelines should also be

promulgated widely through the medical literature;

• That studies be undertaken in selected hospitals

to develop and test one or more prototype decision-supported systems. To be fully effective,

these computer-based advisory systems should

include information from local antimicrobial

sensitivity profiles. These in turn should feed into

regional and national surveillance databases;

• That local prescribing information should,

whenever possible, be harmonized with that in

the British National Formulary (BNF) and other

formularies. Guidelines and formularies should

also take account of the proposed national evidence-based guidelines to be produced under the

aegis of the National Institute of Clinical Excellence all such local guidelines should include,

as a minimum, certain standard items of information on the drug, dosage and duration of

therapy;”

• That greater emphasis be placed on the teaching of guidelines for antimicrobial prescribing

to medical, dental, pharmaceutical, nursing and

veterinary students;

• “That a strategic system for resistance surveillance of antimicrobial resistance should be developed as swiftly as possible, and that this

should cover the whole of the UK;

• That research into antimicrobial resistance

should become a high priority for all funding

bodies concerned with health care and biomedical research;”

• That existing guidelines for hospital infection

control be more closely adhered to, and that
117

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

guidelines for infection control in the community be developed;

• “That the use of antibiotics in animals should

be guided by the same principles as those for

prescribing in humans—namely, they should be

used only for those clinical conditions where

their use is likely to provide a genuine health

benefit;

• That alternative means of animal husbandry be

developed so that the use of antibiotics as growth

promoters can be discontinued;

• That consideration be given by the appropriate

bodies to finding ways through pricing and other

mechanisms of ensuring that investment in the

development of new antibiotics remains commercially viable for the industry;

• That industry should be encouraged to undertake studies of optimum prescribing regimens

for new antimicrobial agents, for each indication and in adults and children as appropriate;

• That every effort is made by the Government to

raise the profile of antimicrobial resistance as a

major public halt issue meriting priority action

from all Member States of the European

Union.”

Implementation suggestions

The committee recommends the establishment of

a National Steering Group to institute the first phase

of the national strategy to counter the development

of antibiotic resistance. The NSG’s mandate is to

form sub-groups consisting of experts who can focus on particular aspects of the problem, and then

to report to the Chief Medical Officer within a year.

The CMO in turn may request that the Standing

Medical Advisory Committee reconvene the Antimicrobial Resistance Sub-Group in order to develop

the strategy’s next phase.

Conclusions/Executive Summary

“The recommendations in this Report are directed

towards ensuring that best practice in antimicrobial prescribing becomes routine practice. This will

require a willingness, on the part of health care

professionals and the public alike, to treat antimicrobial agents as a valuable and non-renewable

resource, to be treasured and protected in their own,

and everyone else’s interest.”

Authors: Sub-Group Members: Dr. Diana Walford, A.

Close, Dr. A. Dearmun, Professor T. Duckworth, A.

Ewing, Dr. J. Gilley, Dr. R. Horne, Professor A.

Johnson, Professor C. Peckham, Dr. S. Willatts, Dr.

G. Youngs, Dr. A.M. Johnston, Professor P. Littlejohns,

C. Murphy, Dr. G. Patou, Dr. M. Powell, Dr. P. Wilkie,

Professor R. Wise, Dr. P. Clappison, I. Cooper, Professor B.I. Duerden, R. Fenner, Dr. J. Leese, Dr. K.

Ridge, Dr. W. Smith, M. Hart, Dr. D.M. Livermore,

Dr. J.R. Weinberg

Type of publication: Report

Pages: 152

Intended audience: Primarily United Kingdom, but

also implications for global audience; policymakers, prescribers, consumers and patients

Study timeframe: The Sub-Group reviewed literature

dating from 1969 to 1997, with a few references

from the 1930s and 40s.

Study process: Review of case-studies, review of the

basis and impact of resistance, commission of an

independent review of evidence

Type of organization: Government

Languages (published in): English

Key contact: Available on the web at http://www.

doh.gov.uk/smac1.htm

and from: Publications Unit, PHLS, Headquarters

Office, 61 Colindale Avenue, London NW9 5DF;

tel: 0181 200 1295

(20) Antimicrobial Resistance: A special

edition of the British Medical Journal

Organization: British Medical Journal

Year published: 1998

Selected key findings

• Butler, et al., assessed the attitudes of physicians

and patients in South Wales when prescribing

or withholding antibiotics for sore throats.

Patient expectations for antibiotics were found

to be a compelling factor for prescription, even

though the drugs are largely ineffective for the

condition.

• Ferranti, et al., demonstrated that amoxycillin

and folate inhibitors are just as effective as newer,

more expensive broad-spectrum antibiotics in

the treatment of uncomplicated acute sinusitis.

Key recommendations

• Increase patient and prescriber education, surveillance, and research.

• For developing countries: improve prescription

regulation, access to diagnostic tools, surveillance, and education of the public, doctors and

veterinarians.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

118

• For international organizations: achieve international consensus standards for resistance surveillance, and create a global repository of

information on resistance in key pathogens.

• For hospitals: encourage multidisciplinary

cooperation in policy implementation, timely

detection and reporting of antibiotic resistant

strains, and aggressive control of the transmission of epidemic resistant bacteria.

Implementation suggestions

Developing countries: Not specified.

International organizations: Adoption of resolution

on antimicrobial resistance that was presented at

1998 World Health Assembly.

Hospitals: Needs and resources vary from hospital

to hospital; programs for infection control or the

development of policies should be tailored with

those differences in mind.

Conclusions/Executive Summary

“The increasing resistance problems of recent years

are probably related to the use of increasingly broad

spectrum agents (cephalosporins and fluoroquinolones) and crowding of the most vulnerable

members of society in daycare centers and nursing

homes. These problems are compounded by the

worldwide phenomena of pressure on health care

systems for greater efficiency, with higher bed

occupancies and stretched nursing and medical care.

Added to this are pressures to allow over-thecounter use of antibiotics in western countries so

as to reduce health care costs. To effect change much

will be required by the medical profession, politicians, the pharmaceutical industry, and not least

patients.”

Authors: Richard Wise, Tony Hart, Otto Cars, Reinen

Helmuth, Pentti Huovinen, Q. A. McKellar, David

M. Livermore, Alasdair P. Macgowan, Martin C. J.

Wale, Stef L. A. M. Bronzwaer, Richard Coker, BjornErik Kristiansen, Yngvar Tveten, Andrew Jenkins,

David Wilkinson, S. B. Squire, Paul Garner, Alan P.

Johnson, Marina Warner, Neil Woodford, David C.

E. Speller, Valerie Schwoebel, Benedicte Decludt,

Anne-Claire de Benoist, Sylvie Haeghebaert, Gabriela

Torrea, Veronique Vincent, Jacques Grosset, Sarah D.

de Ferranti, John P. A. Ioannidis, Joseph Lau, William

V. Anninger, Michael Barza, Christopher C. Butler,

Stephen Rollnick, Roisin Pill, Frances Maggs-Rapport,

Nigel Stott, John Turnidge, C. A. Hart, S. Kariuki, R.

J. Williams, M. J. Ryan, Marc J. Struelens, Herman

Goossens, Marc J. W. Sprenger, Peter M. Hawkey,

Deenan Pillay, Maria Zambon, Claude Carbon, Richard P. Bax, A. M. Johnston, Christopher C. Butler,

Edward A. Belongia, Benjamin Schwartz, Paul Farmer,

Jim Yong Kim

Type of publication: Peer-reviewed journal

Pages: 90

Intended audience: Global; physicians, other health

care providers

Study timeframe: varies

Study process: varies

Type of organization: Private company

Languages (published in): English, and local editions

in Belgium, Brazil, China, Greece, Hungary, Latin

America, Middle East, Netherlands, Pakistan,

Poland, Portugal, Romania, Scandinavia, South

Africa, South East Asia, Turkey and West Africa

Key contact

Editor, Richard Smith: editor@bmj.com;

Telephone: +44 (0) 171 387 4499

(21) Select Committee on Science and

Technology: Resistance to Antibiotics

and Other Antimicrobial Agents

Organization: House of Lords

Year published: 1998

Selected key findings

• Drug formularies and policies vary widely

throughout the United Kingdom’s hospital system; they are often created without input from

junior staff, and new staff are not well informed

of existing policies.

• Increased hospital infections may be linked to a

decline in hygiene, staffing shortages, and a

National Health Service policy of maximum

occupancy for beds.

• Reporting of resistance to the Public Health

Laboratory Service is voluntary and informal.

The PHLS favors mandatory reporting of certain resistances and of any unusual or unexpected

resistance markers in any microorganisms.

Key recommendations

• “The Royal Colleges should increase the attention paid to antimicrobial therapy in their programs of postgraduate education and vocational

training.

• Health authorities should step up their efforts

in the areas of prescribing audits, feedback and
119

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

educational outreach (including communication

skills).

• The pharmaceutical industry and grant-giving

bodies should give priority to work on rapid

affordable systems for diagnosis and susceptibility testing.

• The Medicines Control Agency should consider

whether the drug licensing system could be used

more effectively to encourage prudent use in the

interest of public health.

• Antibiotic growth promoters, such as virginiamycin, which belong to classes of antimicrobial

agent used (or proposed to be used) in man and

are therefore most likely to contribute to resistance in human medicine, should be phased out,

preferably by voluntary agreement between the

professions and industries concerned, but by

legislation if necessary.

• The UK National Health Service should set itself targets for controlling MRSA in hospitals,

and publish its achievements. The NHS should

also draw up national standards and guidelines

for community infection control management.”

Implementation suggestions

Responsibilities were delegated to various government agencies and departments of the United Kingdom.

Conclusions/Executive Summary

“This enquiry has been an alarming experience,

which leaves us convinced that resistance to antibiotics and other anti-infective agents constitutes a

major threat to public health and ought to be recognized as such more widely than it is at present.

We commend the current trend towards local antibiotic formularies and evidence-based clinical

guidelines, giving professionals agreed definitions

of prudent practice in particular situations. But the

issuing of documents is not enough to turn policy

into practice; it must be followed through in professional education, and continuing professional

development. We do not recommend that GPs

should be required to establish antimicrobial

susceptibility before prescribing. This, we believe,

would at present be impracticable, and would overload diagnostic series which are already stretched.

But improved access to microbiological testing

clearly reduces uncertainty in prescribing. Potent

agents important to human medicine, such as the

fluoroquinolones, deserve extreme economy of use

in veterinary practice. There is still much that needs

to be done to increase understanding of the mechanisms of resistance and the action of antimicrobials

and, in the clinical sphere, methods of using agents

to best advantage.”

Authors: Sub-Committee members: Lord Dixon-Smith,

Lord Gregson, Lord Jenkin of Roding, Baroness

McFarlane of Llandaff, Baroness Masham of Ilton,

Lord Perry of Walton, Baroness Platt of Writtle,

Lord Porter of Luddenham, Lord Rea, Lord Soulsby

of Swaffham Prior, Lord Walton of Detchant, Lord

Winston; with Specialist Advisors Professor Harold

Lambert and Professor Richard Wise

Type of publication: Report

Pages: 108

Intended audience: United Kingdom; policy-makers,

general public

Study timeframe: July 1997 to March 1998

Study process: Sub-Committee members conducted

interviews at the Headquarters of the Public Health

Laboratory Service, King’s College Hospital, and

with individual experts in the United States and

United Kingdom. Members also gathered evidence

from the agricultural and pharmaceutical industries,

international and regional health organizations, and

professional medical and scientific societies.

Type of organization: Government

Languages (published in): English

Key contact

The Publications Centre: PO Box 276, London

SW8 5Dt; Tel. +44 0345 58 54 63; fax +44 0170

873 8200; Web site: http://www.hmso.gov.uk/

(22) Antimicrobial Resistance: Issues and

Options. Workshop Report from the

Forum on Emerging Infections

Organization: Institute of Medicine

Year published: 1998

Selected key findings

• The global effort to control antibiotic resistance

lacks adequate surveillance mechanisms and

comprehensive databases.

• There is a lack of research on the greater impacts of antibiotic use in animals, including the

transfer of resistance.

• There has been insufficient analysis of the reservoir of antimicrobial drug-resistant genes.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

120

Key recommendations

Surveillance:

• “Funding, implementation, assumption, or

assignment of leadership, and formation of partnerships for implementing the 1995 American

Society of Microbiology’s detailed recommendations for a comprehensive resistance surveillance program;

• Improving data gathering and analysis, perhaps

through national systems that would continuously monitor antimicrobial usage in hospitals,

community and farm environments;

• Including information about the effects of

resistance on the outcome of infections in data

collection systems;

• Selecting and strengthening the laboratories in

a set of sentinel hospitals as bases for global

assessment of the prevalence and transmission

of the most critical antibiotic-resistant genes,

including training laboratory personnel in sentinel hospitals in standardized methodologies;

• Designing categories and pathways for reducing

data sets into comprehensive packages for use

by clinicians and researchers;

• Expanding distribution of NCCLS Guidelines

and perhaps increasing the frequency with which

they are updated.”

The use of antibiotics in food production

• “Collaborative access to data from veterinary

reference laboratories;

• Systematic, collaborative development, by the

United States Department of Agriculture, the

American Veterinary Medical Association, the

Food and Drug Administration and producer

organizations, of strategies and educational

materials toward expanding ecological understanding;

• Developing cost-benefit and cost-effectiveness

models of different on-farm antibiotic usages to

enhance the public health community’s understanding of farmer perspectives.”

Prolonging antibiotic effectiveness

• “Implementing a joint project involving all pertinent professional societies in developing unitary guidelines (including checklists for providers

to use in clinical settings) for antimicrobial use,

implementing their extensive dissemination,

and, very importantly, updating them periodically based on annual data from longitudinal

studies;

• Quantifying the risks of injudicious antimicrobial use and developing descriptive and predictive models of the differences that judicious use

would make, to help in policy development,

advocacy, and action;

• Designing and implementing research on clinical outcomes from shorter courses of therapy and

different dosing regimens, as the basis for updating practice guidelines and revising labeling.”

Developing new products

• “Conduct studies of gene flow in order to

understand the diversity and prevalence of resistant gene families and to discern the origins

of resistant genes and how they spread from one

organism to another.”

Legal and regulatory approaches

• “Exploring whether increased resistance and

rapid diminution of effectiveness of existing antibiotics might justify awarding greater authority to the CDC to monitor and enforce legal

duties regarding resistance, and consideration of

the means by which this might be accomplished;

• Developing alternative ways to define efficacyfor example, surrogate markers, in vitro technologies, and animal models-to address the lack

of well-defined populations for clinical trials.”

Implementation suggestions

Existing projects of various government agencies

and departments of the United States are cited as

foundations for implementing the above recommendations, including: a surveillance project

being conducted by CDC, USDA and FDA; the

USDA’s reports on food safety and antibiotic resistance; and the EPA’s considerations of the use of

antibiotic pesticides. The food-production industry is also cited as a potential source of funding,

research, and the development of guidelines for

prudent antibiotic use in food-producing animals.

Conclusions/Executive Summary

“The evidence and opinions presented at this workshop suggest...that the transition from a historically generous armamentarium to one at least

temporarily much less lavish could be mitigated by

wiser policies, both to conserve what remains and

to plan for what is to come; policies for the most

cost-effective use of antibiotics; evidence-based

regulation, with transparent balancing of risks and

benefits; and as already exemplified in genome

projects, social investment in the underlying science needed to develop new antimicrobial agents.

Also, because antimicrobial drug resistance is increasingly known to be a global problem, it can be
121

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

addressed only with international cooperation, at

a minimum in the acquisition and sharing of information. Whatever frictions might ensue from

shaping and implementing such policies would be

more than offset by the savings in medical and hospital costs and, most importantly, by the deaths and

disability avoided.”

Authors: Editors: Polly F. Harrison and Joshua

Lederberg. Forum Participants: Joshua Lederberg, Vincent I. Ahonkhai, Steven J. Brickner, Gail H.

Cassell, Gordon H. Defriese, Nancy Carter Foster,

Renu Gupta, Margaret A. Hamburg, Dieter

Hinzen, James M. Hughes, J. Stanley Hull, Samuel

L. Katz, Kenneth W. Kizer, William Kohlbrenner,

John R. LaMontagne, Carlos Lopez, Stephen S.

Morse, Solomon Mowshowitz, Stuart L. Nightingale, Michael T. Osterholm, David M. Shlaes, John

D. Siegfried, P. Frederick Sparling. Forum Liaisons:

Barry R. Bloom, Enriqueta C. Bond, Gary

Christopherson, Michael Hughes, Stephanie James,

C. Michelle Limoli, Stephen M. Ostroff, Gary

Roselle, Fred Tenover. Study Staff: Jonathan R. Davis,

Polly F. Harrison, Gretchen G. Kidder, Christina

Thacker

Type of publication: Workshop Report

Pages: 115

Intended audience: United States; policy-makers, government

Study timeframe: Workshop conducted in July of

1997

Study process: Workshop discussion, with participants from government, industry and academia

Type of organization: Non-profit public health and

advisory organization; advisor to Federal Government on issues of public health

Languages (published in): English

Key contact

Ordering information: National Academy Press,

http://www.nap.edu

Content: Joshua Lederberg, Chair, Forum on

Emerging Infections

(23) Protecting the Crown Jewels of

Medicine: A Strategic Plan to Preserve

the Effectiveness of Antibiotics

Organization: Center for Science in the Public Interest

Year published: 1998

Selected key findings

No original key findings; report cites findings from

original sources of research.

Key recommendations

• Congress should allocate funding for an antibiotic use initiative (including public and professional education, national surveillance, research

and development, etc.).

• The Department of Health and Human Services

should include goals for decreasing inappropriate use of antibiotics and antibiotic resistance in

its Healthy People 2010 initiative.

• The FDA should change its policies on antibiotic advertising to curtail inappropriate antibiotic use.

• The FDA should ban all subtherapeutic uses of

antimicrobial agents that are used in human

medicine or might select for cross resistance to

antimicrobials used in human medicine.

Implementation suggestions

• Increased funding from Congress to implement

national education programs and surveillance.

• Government health care facilities should serve

as models for the prudent use of antibiotics.

Conclusions/Executive Summary

“Despite antibiotics’ extraordinary value, the overuse of those miracle drugs in medicine and agriculture endangers their continued effectiveness. The

more antibiotics are used, the more likely it is that

bacteria will develop mechanisms to evade them.

The development of new antibiotics has not kept

up with the development of antibiotic resistance.

The time has come when public and private institutions, as well as the general public, must change

their policies and practices to prevent further increases in antibiotic resistance. Rather than believing that new drugs continually can be developed

to treat antibiotic-resistant infections, public-health

prevention measures should be adopted.”

Authors: Patricia B. Lieberman, Ph.D., Margo G.

Wootan, D.Sc.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

122

Type of publication: Booklet

Pages: 27

Intended audience: United States; general public

Study timeframe: Works cited incorporate research

findings from 1972 to 1998.

Study process: Compilation of statistics and information from other sources (USDHHS, CDC,

American Society for Microbiology, scientific journal articles, etc.).

Type of organization: Non-profit, public health organization

Languages (published in): English

Key contact

Center for Science in the Public Interest, 202-332-

9110

(24) The Agricultural Use of Antibiotics

and Its Implications for Human

Health

Organization: United States General Accounting Office

Year published: 1999

Selected key findings

Experts from the Department of Health and

Human Services, CDC and FDA “believe that resistant strains of three specific organisms that cause

illness or disease in humans—Salmonella, Campylobacter, and E. coli—are linked to the use of antibiotics in animals.”

There is only one federal program that specifically tests for antimicrobial resistance related to

agriculture: the National Antimicrobial Resistance

Monitoring System’s Enteric Bacteria program. The

program tests samples of Campylobacter and

Salmonella from humans and animals for susceptibility to 17 antibiotics.

“About 95 percent of Salmonella DT-104 strains

are resistant to five antimicrobials—ampicillin,

chloramphenicol, streptomycin, sulfonamides, and

tetracycline.”

Between two and four million people each year

contract Campylobacter infections; out of every

1,000 reported cases, one will develop into GuillainBarré Syndrome, which may result in paralysis.

Key recommendation

Development and implementation of a plan by the

Secretaries of Agriculture and of Health and

Human Services that creates a framework for evaluating the risks and benefits of the current and

future uses of antibiotics in agriculture.

Implementation suggestions

The Departments of Agriculture and Health and

Human Services would create the plan, devising

the goals and timeframes, and identifying the resources necessary to determine the safest uses of

antibiotics in agriculture. The Departments will also

see to the filling of the existing gaps in data and

research.

Conclusions/Executive Summary

“Although research has linked the use of antibiotics in agriculture to antibiotic-resistant strains of

specific foodborne pathogens that affect humans,

agricultural use is only one factor in the emergence

of antibiotic resistance in non-foodborne pathogens. Debate exists over whether the role of

agricultural use in the overall burden of antibioticresistant infections of humans warrants further

regulation or restriction. CDC believes the potential human health risks call for action to restrict

antibiotics for growth promotion in animals. We

first raised concerns in 1977 about the potential

human health risks of this practice. Today, more

than two decades later, federal agencies have not

reached agreement on the safe use of antibiotics in

agriculture. In developing a federal response, both

human health concerns and the impact on the agriculture industry are factors to consider.”

Authors: Major Contributors: Robert E. Robertson, Erin

Lansburgh, Stuart Ryba, Natalie Herzog, Jerry

Seigler, Shannon Bondi.

Type of publication: Report to Senator Tom Harkin,

Ranking Minority Member, Committee on Agriculture, Nutrition, and Forestry.

Pages: 33

Intended audience: United States

Study timeframe: The review was conducted between

May 1998 and April 1999. It covered material from

1969 through 1999.

Study process: The authors conducted interviews with

representatives from USA government agencies, the

agricultural industry, and agricultural associations.

They also reviewed existing research on the subject

and consulted with experts and officials from CDC,

FDA, USDA, and others to get their opinions on

the material.
123

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Type of organization: Federal Government

Languages (published in): English

Key contact

Ordering information: USA General Accounting

Office, P.O. Box 30750, Washington, D.C., 20013;

tel.: (202) 512-6000; fax: (202) 512-6061

Available on the web at: http://www.gao.gov/

(25) The Use of Drugs in Food Animals:

Benefits and Risks. Report by the

Committee on Drug Use in Food

Animals and the Panel on Animal

Health, Food Safety, and Public

Health

Organization: National Research Council

Year published: 1999

Selected key findings

• “Use of antibiotics increases the risk of emergence of microorganisms that are resistant to

specific, and perhaps other, antibiotics. Development of this kind of resistance is not restricted

to antibiotic use in food animals; it is far more

prevalent because of misuses in human medicine;

• A link can be demonstrated between the use of

antibiotics in food animals, the development of

resistant microorganisms in those animals, and

the zoonotic spread of pathogens to humans. The

incidence of the spread of human disease in that

way is historically very low, but data are seriously

inadequate to ascertain whether the incidence

is changing;

• A major impediment to determining the effect

of antibiotic use in food animals on human

health risk is the complexity of food animal drug

treatment and subsequent food-processing and

handling interactions. Post-farm good processing, storage and improper handling and cooking are major contributors to the chain of events

that allows the pathogen to contaminate the

product, proliferate on or in the food, and attain the large numbers that cause disease;

• Substantial information gaps contribute to the

difficulty of assessing the effect of antibiotic use

in food animals on human health.”

Key recommendations

• “The Center for Veterinary Medicine should

continue procedural reform to expedite the drug

approval review process and broaden its perspective on efficacy and risk assessment to encompass review of data on products already approved

and used elsewhere in the world;

• To improve drug availability, worldwide harmonization of requirements for drug development

and review should be considered and further

enhanced among the federal agencies that are

responsible for ensuring the safety of the food

supply;

• The Center for Veterinary Medicine should base

drug use guidelines on maximal safe dosage regimens for specific food animals, consider greater

emphasis on the pharmacokinetics of drug elimination from tissues that are consumed in large

quantity, and set drug withdrawal times accordingly;

• Increased funding for basic research that explores

and discovers new or novel antibiotics and

mechanisms of their action, including the development of more rapid and wide-screen diagnostics to improve the tracking of emerging

antibiotic resistance and zoonotic disease;

• Establishment of integrated national databases

to support a rational, visible, science-driven decision-making process and policy development

for regulatory approval and use of antibiotics in

food animals, which would ensure the effectiveness of these drugs and the safety of foods of

animal origin;

• The committee recommends that further development and use of antibiotics in both human

medicine and food animal practices have oversight by an interdisciplinary panel of experts

composed of representatives of the veterinary

and animal health industry, the human medicine community, consumer advocacy, the animal production industry, research, epidemiology,

and the regulatory agencies;

• Increased public- and private-sector research on

the effect of nutrition and management practices on immune function and disease resistance

in all species of food animals;

• Increased public- and private-sector research on

strategies for the development of new vaccination techniques, on a better understanding of

the biochemical basis of antibody production,

and on genetic selection and molecular genetic

engineering for disease resistance.”

Implementation suggestions

Issues concerning antibiotic use in food animals and

humans should be coordinated with regard to use

patterns, resistance trends, surveillance data, and
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

124

recommendations for use in a partnership of regulatory agencies, pharmaceutical companies, the food

animal industry, and animal and human health care

professionals.

Conclusions/Executive Summary

“The committee concludes that the use of drugs in

the food animal production industry is not without some problems and concerns, but it does not

appear to constitute an immediate public health

concern; additional data might alter this conclusion. The greatest concern is associated with the

use of antibiotics in food animals in such a way

that there is a potential for antibiotic resistance to

develop in or be transferred to pathogens that can

cause disease in humans. This report acknowledges

that there is a link between the use of antibiotics in

food animals, the development of bacterial resistance to these drugs, and human disease—although

the incidence of such disease is very low. A substantial change in the human health risk posed by

antibiotic use would affect not only how animal

drugs are reviewed, approved, and used, but also

how food animals are produced. It should be noted

that antibiotics are still effective for their intended

purposes at the recommended dosages. New antibiotic drugs are needed to combat emerging

animal diseases that do not respond to traditional

drugs and so threaten public confidence in animal

agriculture and human medicine. Professionals in

human health care should be concerned that they

do not have enough specialty antibiotics to treat

resistant and emerging infections in humans, as

should veterinarians. The question is, should newly

discovered medications be held in reserve for

human or animal use only? Antibiotics should be

available to treat specific human and animal disease with proper accountability and oversight of

the drugs used.”

Authors: Committee on Drug Use in Food Animals: James

R. Coffman, George W. Beran, Harvey R. Colten,

Connie Greig, Jean Halloran, Dermont Hayes, John

B. Kaneene, Kristin McNutt, David Meeker, Stephen

C. Nickerson, Thomas Seay, R. Gregory Stewart. Panel

on Animal Health, Food Safety, and Public Health: John

A. Shadduck, Kenneth Berns, Michael P. Doyle, Hollis

N. Erb, John Ferry, Jere E. Goyan, Werner Heuschele,

Helen H. Jensen, Franklin M. Loew, Joy A. Mench,

Harley Moon, Wilson G. Pond, R. Gregory Stewart.

Board on Agriculture: Dale E. Bauman, John M. Antle,

Sandra S. Batie, May R. Berenbaum, Leonard S. Bull,

William B. Delauder, Anthony S. Earl, Essex E.

Finney, Jr., Cornelia Flora, George R. Hallberg, Richard R. Harwood, t. Kent Kirk, Harley W. Moon,

William L. Ogren, George E. Seidel, John W. Suttie,

James J. Zuiches. Food and Nutrition Board: Cuthberto

Garza, John W. Erdman, Lindsay H. Allen, Benjamin

Caballero, Fergus M. Clydesdale, Robert J. cousins,

Michael P. Doyle, Johanna T. Dwyer, Scott M.

Grundy, Charles H. Hennekens, Janet C. King,

Sanford A. Miller, Ross L. Prentice, A. Catharine Ross,

Robert E. Smith, Virginia A. Stallings, Vernon R.

Young.

Type of publication: Report

Pages: 253

Intended audience: United States; food-production

industry, policy-makers, veterinarians

Study timeframe: The report considers information

from 1968 to 1998.

Study process: The Committee reviewed the major

classes of drugs used in food animals; reviewed scientific literature; heard testimony on animal-drugrelated issues; reviewed federal regulations that

provide guidelines and list mandatory practices for

drug use, monitoring capabilities for drugs and

residues in foods, veterinary oversight in prescription drug use, rates of violations, and instances of

documented health problems.

Type of organization: Non-profit organization, the

working arm of the National Academy of Sciences

and the National Academy of Engineering

Languages (published in): English

Key contact

Ordering information: National Academy Press,

http://www.nap.edu

Content: James R. Coffman, Chair, committee on

Drug Use in Food Animals
125

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

APPENDIX B

Local action around the world

Activities of the APUA Latin American Initiative

The Latin America Initiative increases the impact

and reach of chapter work by providing a mechanism to link countries and share resources, information, and expertise. Activities supported through

the initiative include country-specific projects as

well as efforts to develop regional communications

and region-wide research and educational activities. These activities are coordinated to build on

PAHO activities at the country and regional levels.

This section includes a list of activities in the region supported by APUA or conducted in collaboration with WHO, PAHO, ministries of health,

and other institutions and organizations.

Chapter development activities

The Latin America Initiative has grown from the

initial group of five country chapters to include the

following countries: Argentina, Chile, Colombia,

Cuba, Dominican Republic, Ecuador, Guatemala,

Mexico, Venezuela and Uruguay. Efforts are currently underway to establish APUA chapters in the

following countries:Bolivia, Brazil, Costa Rica, El

Salvador, Honduras, Nicaragua, Paraguay and Peru.

Research activities

• A study conducted by our Uruguay chapter in

1999 compared the rate at which antibiotics were

prescribed for children with pharyngitis to the

actual need for antibiotics, based on the percentage who tested positive for Streptococcus pyogenes.

The study showed that while 75% of the 212

children who presented with pharnygitis at an

outpatient clinic were prescribed antibiotics,

only 15% tested positive for Group A Streptococcus pyogenes (GAS). By demonstrating the

overuse of antibiotics for children with pharyngitis, the study aims to persuade pediatricians

to modify their prescribing habits. The study was

funded by the Ministry of Health, PAHO, and

APUA.

■ APUA Latin American Initiative

Report prepared by APUA

The mission of APUA is to promote the prudent

use of antibiotics in order to preserve their power

for future generations. The establishment of foreign-affiliated chapters to conduct research and

education activities tailored to local needs is an

important vehicle for achieving this goal. APUA’s

Latin America Initiative was developed to

strengthen and expand existing APUA country activities to curb the development of antibiotic resistance and to coordinate these activities with

related activities in the region. Through the Initiative, APUA’s regional network of chapters has grown

from five to ten, with eight additional countries in

the process of developing chapters. This regional

initiative has been funded largely by the United

States Agency for International Development

(USAID) and the Pan American Health Organization (PAHO) and is being implemented in collaboration with PAHO’s IMCI (Integrated

Management of Childhood Illness) Unit.

A key feature of the Initiative is the network of

APUA country chapters. With a strong foundation

in microbiology and infectious disease, chapter

members work at the grassroots level to tailor interventions to local situations and to provide a link

between data and action within their countries.

Through the Initiative, APUA is collaborating with

PAHO and its Member States to develop interventions to curb antibiotic resistance. PAHO, with

APUA and other partners, has been involved in

developing a strategic plan for the surveillance of

antibiotic resistance as well as laboratory training

activities to support a regional surveillance network.

APUA has also been working with the IMCI Unit

of PAHO to develop and implement projects to

curb antibiotic resistance within the context of

IMCI. APUA will continue to expand its network

of chapters in Latin America and support existing

chapters as they work more aggressively towards

documenting, understanding, and containing antibiotic resistance.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

126

• In 2000, APUA funded a study by its Guatemalan chapter titled “Study of the Risk Factors for

Antibiotic Resistance of S. pneumoniae among

Guatemalan Children from Different SocioEconomic Strata and Health Care Delivery Systems”, to be completed in 2001.

• APUA, in collaboration with PAHO, is conducting a regional survey of physician’s knowledge,

attitudes, and practices (KAP) regarding antibiotic resistance and use. The survey, developed

by APUA and pilot-tested in Argentina, will

initially be conducted in 9 countries, and will

inform the development of appropriate treatment guidelines and provider educational

materials.

• APUA provides technical assistance to chapters

in the region, including help with meeting and

conference planning, providing speakers, supporting the south-to-south exchange of expertise, and proposal development for grants from

APUA and other funding sources.

• Five chapters were awarded grants from the 2000

Joint Initiative to conduct research on antibiotic use. APUA provided technical support

during proposal development.

• APUA chapters contributed to the IMCI News

bulletin produced by PAHO.

• The new APUA chapter in Colombia has plans

to develop a surveillance and reporting network

for antibiotic resistance in tertiary hospitals

throughout the country using WHONET software. The plan includes the dissemination of

regular reports on resistance to hospitals and

national health authorities, including a formal

annual report from the network.

Training and educational activities

• APUA conducted a Continuing Medical Education session on “Improving Antibiotic Use in

the Management of Childhood Illnesses” held

in June 2000 at the Global Health Council annual meeting in Washington, DC. This session,

attended by clinicians, public health professionals and policy makers, featured background information on the antimicrobial resistance

problem, specifically as it relates to children’s

health in Latin America. It also described the

APUA-PAHO/ IMCI partnership as a model for

collaborative work to contain resistance and

other related projects sponsored by the two

organizations, such as surveillance, capacitybuilding, and provider trainings.

• APUA provided assistance in the design of a

comprehensive one-week training course in testing organisms for susceptibility to antibiotics and

resistance surveillance, which was conducted by

the Ministry of Health in Argentina, in collaboration with PAHO and the APUA-Argentina

chapter. APUA plans to adapt the course for use

in other countries in the region, in collaboration with PAHO.

• In collaboration with PAHO, APUA produced

a Spanish version of the APUA patient education brochure and health care provider wall

poster for distribution via PAHO and APUA

chapters throughout Latin America.

• APUA supported the development or translation of articles in Spanish on otitis media and

the prevention and treatment of pneumococcal

infections, that were published on the APUA

Web site and in the monthly bulletin of PAHO’s

IMCI programme.

• A week-long Latin America regional training

course on laboratory surveillance methods for

detecting antimicrobial resistance, was held in

April 2000 in Buenos Aires, Argentina. The

course was organized and designed by the

Argentine Ministry of Health and founding

members of APUA-Argentina, with assistance

from PAHO and APUA. One hundred microbiologists from Argentina, as well as 20 participants from other Latin American countries,

attended this hands-on training to improve and

update their skills and knowledge in susceptibility testing techniques, specific organisms,

interpreting test results, quality control, and the

management of susceptibility data. Participants

will take these newly-acquired skills and knowledge back to their colleagues. APUA and PAHO

plan to sponsor similar trainings in other Latin

American countries, after adapting the course

to address challenges faced by less developed

countries in the area. The refined curriculum

will also serve as a model for other countries with

limited resources outside of the region.

Conference and networking activities

• APUA, in collaboration with PAHO and the Pan

American Association for Infectious Diseases,

organized a symposium on “Prudent Use of

Antibiotics in the Developing World” during the
127

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

International Congress on Infectious Diseases

(ICID) in Buenos Aires in April 2000. The symposium covered partnerships to address antibiotic resistance, the application of community

research results to clinical practice, effective strategies for provider education, and the process of

designing clinical guidelines for antibiotic use.

• APUA has established a Spanish-language

listserve for the Latin America region. The

listserve, moderated by APUA’s Latin America

Project Director, allows Latin American health

professionals to regularly exchange information

on research related to antibiotic resistance and

use, offer or seek technical assistance from other

participants, and post announcements of upcoming meetings and funding opportunities.

■ Moldova: Nongovernmental

organizations and antibiotic

programmes

Report prepared by Natalia Cebotarenco, Ph.D., Director

of the Association Drugs, President APUA Moldova,

“natalie”@drugs.mldnet.com or

natalie@drugs.moldova.su

Antibiotics have revolutionized the treatment of

common bacterial infections and have a vital role

in reducing child mortality. Since antibiotics were

first introduced, their consumption has increased

dramatically in most parts of the world. Resistant

bacterial strains have emerged and spread throughout the world because of the remarkable genetic

plasticity of the microorganisms, heavy selective

pressures of antibiotic use, and the mobility of the

world’s population.

The problem of resistance to antimicrobial drugs

is particularly troublesome in a country like the

Republic of Moldova that also has economic and

societal problems. After the collapse of the Soviet

system, Moldova instituted an economic reform

that tried to establish a market economy. The economic changes led to increasing numbers of

private pharmacies. Moldova has 4.35 million citizens and 1500 registered pharmacies. More than

85% of the pharmacies are private. This situation

brought a flood of medicines on the market in

Moldova and created a situation of uncontrolled

dispensing of medicines.

Increasing the availability of antibiotics and enhancing their appropriate use are two interrelated

aims. With the increasing quantity and variety of

pharmaceuticals available today in Moldova, the

potential inappropriate use of antibiotics is a growing concern. The sale of medicines by prescription,

including antibiotics, has almost ceased in Moldova.

Officially, antibiotics are prescription-only drugs

in Moldova. In practice, they are widely available

in many pharmacies and even on the streets. The

doctors’ recommendations are often ignored as patients are lured by drug store offers. On the other

hand, doctors are extremely underpaid in Moldova

and can gain some money by selling or prescribing

antibiotics. Thus it is often hard to discuss the concept of a rational choice of an antibiotic with health

care providers and the general public.

The situation in Moldova shows several problems associated with the use of antibiotics including widespread inappropriate antibiotic use, young

children frequently medicated with antibiotics for

too short a course, and a vast majority of self-medicated treatment regimes. Only one-sixth or oneseventh of the antibiotics are recommended by a

doctor and resistant respiratory pathogens are widespread among the children.

A non-governmental medical organization is formed to

provide drug information

With new political possibilities in 1995, a medical

non-government organization, Association

DRUGS, was established in Moldova. The Association DRUGS provides unbiased, up-to-date

information on the safety and efficacy of drugs to

interested health professionals, consumers and

government institutions such as the Ministry of

Health, the National Institute of Pharmacy, the

Moldavian Medical and Pharmacy University

“N.Testemitanu”.

The first project by the Association DRUGS in

1995 was the establishment of the Information

Centre with the goal of promoting rational drug

use and the Essential Drugs concept in Moldova.

Since its beginning, the Association DRUGS has

provided 47 seminars and training sessions on various aspects of rational drug use at the hospitals in

Chisinau (capital of Moldova) and in regions of

Moldova, as well as the Postgraduate Faculty of the

Medical and Pharmacy University of the Republic.

More than 2,700 physicians and pharmacists took

part in its educational programmes. Since January

1996, 34 issues of the independent Drug Bulletin

were published with 1,500 samples distributed freeof charge for physicians and pharmacists. Through

the activity of Association DRUGS, a network was

created for rational drug use in Moldova, which
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

128

included authorities from the Ministry of Health,

the National Institute of Pharmacy, Medical and

Pharmaceutical University of Moldova, pharmacists, physicians, journalists and non-governmental organizations.

From the beginning of the activity in 1995, the

Association DRUGS analysed 1500 records from

the children’s hospital “V. Ignatenco” in Chisinau

(the capital of Moldova), focusing on physicians’

antibiotic prescriptions. The most common

pediatricians’ problems were inappropriate antibiotics prescriptions that included polytherapy and

the overprescribing of antibiotics:

• Acute respiratory infections were treated with

1–2 antimicrobials

• Acute pneumonia was treated with 2–3 antimicrobials, occasionally 4 antimicrobials

• Predominance of antibiotic injections

• Duration of treatment too short (fewer than 3

days) or too long (more than 15 days)

• Overuse and too high a dose of antimicrobials

• Inappropriate choice of antibiotic group

• Predominance of gentamicin and cefalosporins

of the second or third generation

• Non-consideration of microbiology control

before or during treatment course by antibiotic

• Non-consideration of the problem of antibiotic

resistance in daily work.

The survey showed that there was no professional

awareness of the problem of antibiotic resistance.

Antibiotic resistance problems have not been and

are not identified as national priorities of the health

care system.

Was education of pediatricians carried out continually?

Were guidelines for treatment developed?

Given the chronic state of deficient funding that

covers only 5–7% of the hospitals’ needs, the antibiotic resistance problem must be approached by

changing the educational system for physicians.

However, the education programmes in the medical school and University of Moldova do not include the themes “Formulary system in the

hospital”, “Analyzing the cost-effectiveness of treatment”, “Essential Drugs Lists development”,

“Rational drug use” and other items in the update.

In Moldova, the guidelines for the treatment of

the most common infectious diseases were developed and distributed without general discussion or

follow-up; a few scientific seminars were formalized but were not necessarily interactive. Practically

speaking, the treatment guidelines are not available

to many physicians. Many Moldavian pediatricians’

English knowledge is not good enough to allow

them to get information or enable them to follow

international recommendations and guidelines. For

these reasons the guidelines do not work in Moldova

yet.

Considering that the incorrect prescribing of

antibiotics by physicians is one of the factors that

stimulates the development of antimicrobial resistance, it is necessary to create an appropriate educational strategy.

How can the behaviour of pediatricians be changed?

As poor prescription practices were originally

attributed to a lack of appropriate prescribing information, the main strategy focused on providing

up-to-date information regarding appropriate prescriptions of antibiotics and the antimicrobial

resistance problem. Education on the proper use

of antibiotics has a limited effect if the existing drug

distribution patterns and information sources are

not rationalized. Health workers who try to change

patterns of antibiotic use realize more and more

that what is rational depends very much on what

people think is rational, what their living conditions are and what drugs and diagnostic tools are

available in the health care context.

In order to improve the situation with inappropriate antibiotic prescriptions, a training programme has been developed with the support of

the APUA and United States Pharmacopoeia in

collaboration with the Association DRUGS in

Moldova. The health training programme was

created in 1998-1999 to help middle and lower level

health workers, especially pediatricians, learn to use

antibiotics more wisely and to help prevent antibiotic resistance.

A pilot training programme was conducted at

the Moldavian Medical and Pharmacy University

to explore the practicalities, acceptance and educational value of the postgraduate department’s

pediatricians. During a needs assessment period,

meetings were held with authorities from the Ministry of Health, pediatricians from the different levels of the health system, and pharmacists to help

identify barriers to rational antibiotic use. In addition, teachers from academic institutions became

involved. These groups see the need to change the

medical curriculum to include the antibiotic resistance problem and to monitor prescribing practices
129

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

in different health care facilities. Concerns expressed

included the high number of prescriptions, inadequate information about antibiotic use, and problems with the poor quality of donated antibiotics.

The educational programme had five components:

1. Questionnaire assessment of Knowledge,

Attitude and Practice Survey (KAPS) of middle

and lower level pediatricians.

2. “Improving Antibiotics Use” Training.

3. Distribution of the manual, “Antibacterial

Therapy”, in Russian to the participants of the

training issued by the United States Pharmacopoeia.

4. Distribution of the APUA Newsletter among

pediatricians and publishing the result of the

KAPS-survey in the informational bulletin of the

Association DRUGS.

5. Using mass media to attract the public’s attention to the topics of antibiotic rational use and

antibiotic resistance.

The session of the training “Improving Antibiotics Use”consisted of:

• How to choose the most cost-effective antibiotics for essential drug list and formulary

• Control the rise of antibiotic resistance

• Limit antibiotic over-prescribing

• Limit over-prescribing due to patient pressure

• Guidelines for drug donations

• Risks of using antibiotics for the treatment

of acute respiratory infections.

The effectiveness of the training in increasing

the students’ knowledge of rational antibiotic use

and antibiotic resistance problems was measured

by a pre-test and post-test multiple choice examination. Evaluations showed that the course increased the knowledge and understanding of

pediatricians, helped them develop more positive

attitudes, and demonstrated the importance of

multiprofessional teamwork and communication

among the physicians’ different specialities. Participating pediatricians believed that postgraduate

courses should include early and regular opportunities for shared learning.

The key principle underpinning this framework

is that a range of educational transactions may need

to occur for learning to be effective.

The development of training programmes in

hospitals is still largely at a rudimentary level in

Moldova. Appropriate training experiences in managed care organizations may be a valuable strategy

to address the current disconnect between the

traditional hospital-based education of pediatricians

and the expanded competencies necessary to practice in intensively managed, integrated and accountable health systems. A main assumption is that a

new learning strategy will either fit into existing

patterns or trigger changes in the way that teachers/trainers and learners talk together.

References

1. Kunin CM. Ann Intern Med 1993 Apr 1;118(7):

557–61.

2. Ansari MZ. JPMA J Pak Med Assoc 1995 Jan;

45(1):18–23.

3. Ireland LM; Powell C. Br J Nurs 1997 JUN 26–Jul

9;6(12):686–90.

4. Parsell G; Spalding R; Bligh J Med Educ 1998 May;

32(3):304–11.

5. Okeke IN; Lamikanra A; Edelman R. Emerg Infect

Dis 1999 Jan-Feb;5(1):18–27.

6. Quick JD et al., eds. Managing Drug Supply, 2nd

ed. USA Kumarian Press 1997

■ Nepal: Developing a national

antibiotic policy

Report prepared by Mr. Shyam P. Lohani, M. Pharm.,

Programme Coordinator, United Hands to Nepal,

Chapter Coordinator, APUA Nepal. Contact:

uhn@mos.com.np

Background

The Drug Act was promulgated in Nepal in 1978

to 1) control the production, distribution, sale,

export and import of drugs and 2) to ensure the

availability of safe, quality and efficacious drugs to

the general public. Its first amendment was added

in 1988. To prevent misuse and abuse of drugs, all

of the available drugs are classified into three categories according to their composition, efficacy and

use as per the provision of the Drug Act. The three

categories are:

1. Group ‘Ka’—Narcotic, psychotropic drugs and

potent active therapeutic agents.

2. Group ‘Kha’—Antibiotics, hormones and general therapeutic agents.

3. Group ‘Ga’—Other common drugs which are

safer.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

130

Drugs in groups ‘Ka’ and ‘Kha’ are prescriptive

drugs while those in group ‘Ga’ are over the counter drugs. According to the Drug Act, drugs placed

in the ‘Ka’ and ‘Kha’ categories are to be prescribed

by practitioners registered with the Nepal Medical

Council.

His Majesty’s Government (HMG) of Nepal

published a National Essential Drug List in 1986,

which was revised in 1992 and again in 1997. To

promote appropriate use of anti-infective drugs, the

National Essential Drug List categorized the drugs

according to the different levels of health care.

• Sub-health posts (the most peripheral health care

facilities, which are a part of each Village Development Committee): amoxicillin, cotrimoxazole

and tetracycline.

• Health posts (775 health care facilities): amoxicillin, procaine benzyl penicillin, chloramphenicol, cotrimoxazole, and tetracycline.

• District level (75 public health offices and 50 district hospitals): amoxicillin, benzathin penicillin, benzyl penicillin, cloxacillin, procaine benzyl

penicillin, chloramphenicol, ciprofloxacin,

erythromycin, gentamicin, metronidazole, tetracycline, rifampicin, streptomycin, ethambutol, sulfaacetamide, doxycycline and

nitrofurantoin.

• National List: The national list includes all the

drugs from the district level plus Cefotaxime.

In addition to the antibiotics in the national list,

other antibiotics available in the private sector retail shops need to be registered with the Department of Drug Administration (DDA), Nepal. A

new molecule, including an antibiotic, is not registered in Nepal until it is included in the recognized

pharmacopoeia as per the convention adopted by

the Drug Advisory Committee.

Antibiotic use pattern in Nepal

Several research studies examined the prevalence

of antibiotic prescriptions:

• In 1994, in collaboration with the WHO, the

DDA studied the prescribing habits of private

practitioners; this study showed that antibiotics

were prescribed in 49.85% of all cases.

• In 1997, in collaboration with PHCP/GTZ,

another DDA study (the Rapid Assessment of

Pharmaceutical Management and Utilization)

showed that antibiotics were prescribed in 59%

of all encounters in health facilities.

• In 1998, PHON conducted a study on Priority

and Misused Drugs in health facilities and private sector practitioners which showed that

antibacterials were prescribed in 50.7% of all

encounters.

Research on dispensing practices showed recommendations of antibiotics for diarrhoeal diseases,

fevers and viral infections.

Large amounts of antibiotics are used in animals

not only as curative agents, but also as prophylactic agents and as growth promoters. The total

amount of antibiotics used in food animals and in

feed in Nepal is not known. However, restricting

attention to the human use of antibiotics is not

enough to curb bacterial resistance.

The participants of a regional drug information

workshop at Nepalgunj and Pokhara on January

9–14, 1999, advocated for the need for a separate

policy for antibiotics. It was felt that a policy should

be developed for prescribing of antibiotics and raising the general public’s awareness of bacterial resistance to antibiotics.

In response to this, the APUA-Nepal chapter,

on the request of the Department of Drug Administration and the Ministry of Health, prepared a

draft of a National Antibiotic Policy developed by

a committee of experts from the health, veterinary,

agriculture and other fields. The initial draft of the

National Antibiotic Policy was presented in a workshop on May 18–20, 2000, at Dhulikhel, Nepal.

The participants presented their comments and

suggestions on the draft. These comments were used

to prepare a final draft which is pending at the

Ministry of Health for approval.

Details of the proposed national antibiotic policy

(2000)

The draft policy has nine sections: the preamble,

definition, main policy, objectives, strategic guidelines, national antibiotic control committee,

research and development, technical cooperation

and monitoring and supervision. The draft recommends:

• Classifying antibiotics into three categories:

reserved, restricted, and semi-restricted.

• Dispensing antibiotics only with a prescription

or within a nationally approved protocol.

• Establishing interagency cooperation among

governmental, non-governmental and private

institutions to promote the prudent use of antibiotics by health care professionals and the gen-
131

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

eral public, with the assistance of His Majesty’s

Government (HMG) of Nepal.

• Creating a National Antibiotic Control Committee comprised of concerned experts from

human and animal health, agriculture, professional organizations, and organizations involved

in consumer rights and awareness under the

auspices of HMG.

• Establishing a national antibiotic surveillance

system.

• Developing curricula for training and education

on the prudent use of antibiotics, and incorporating them at all levels of prescribers’ and dispensers’ education.

• Promoting prudent use of antibiotics by implementing periodic training of health care workers who are eligible to prescribe drugs.

• Creating and regulating a National Antibiotic

Therapeutic Advisory Committee (NATAC)

comprised of concerned experts from relevant

sectors, under the auspices of HMG.

• Facilitating research on prescribing, dispensing,

and use of antibiotics as well as antibiotic resistance.

• Encouraging the involvement of national and

international agencies in technical training, education, and research related to the prudent use

of antibiotics.

• Creating subcommittees of the National Antibiotic Control Committee to be responsible for

effective implementation of the antibiotic policy

as well as for monitoring and supervising its implementation.

• Requiring that antibiotics used for therapeutic

purpose in humans and animals not be used as

growth promoters or prophylactic agents in animal feed.

• Developing national antibiotic guidelines, which

will assist individual health and veterinary institutions to formulate local antibiotic guidelines.

• Developing facilities for antimicrobial resistance

testing and detection of antibiotic residue in livestock products in health and veterinary institutions, with the help of HMG.

■ Viet Nam: Hospital case study and

national antibiotic policy

Report prepared by Dr. Hoang Thuy Long, Director of

National Institute for Hygiene and Epidemiology,

Vietnam. Chapter Head, APUA Vietnam.

Contact: daihocyhn@hn.vnn.vn

Policy of the Ministry of Health on the rational, safe,

and effective use of drugs

In 1997–1998, the Vietnamese Ministry of Health

enacted a set of regulations to ensure the rational,

safe, effective and economic use of drugs. These

regulations:

• Established a Drug and Therapeutic Committee (DTC) in each hospital whose function was

to oversee correct drug provision, management,

and use.

• Strengthened the policy of rational, safe and economic use of drugs in the clinic and polyclinic

institutions.

The Drug and Therapeutic Committee’s tasks are:

• To implement the national policy of using drugs

in hospitals.

• To set up basic regulations concerning the supply, management, and use of drugs in hospitals

and then submit the regulations to the hospital’s director for approval.

• To set up the lists of drugs used in hospitals and

submit the lists to the hospital’s director for

approval.

• To set up the drugs’ distribution procedure, submit the procedure to the hospital’s director for

approval and help the director to implement the

procedure.

• To help the hospital’s director carry out the following activities:

— Supervise rational prescription of drugs:

— Set a rational prescription standard.

— Check the contents of case histories that

refer to the drug use process.

— Supervise adverse drug reactions in the hospital.

— Organize drug information.

— Organize scientific research and training on

current knowledge of drugs.

— Set up a cooperative relationship between the

pharmacist and the physicians and nurses for

drug use in patients.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

132

Prior enactment, these Instructions were tested

for a year in four city or provincial hospitals in

North Vietnam. In 1999, the Ministry of Health

organized a conference to evaluate the impact of

the Drug and Therapeutic Committees after two

years of operation.

The results of this evaluation showed:

• Active participation by the Drug and Therapeutic Committee in the drug regulation in the

hospitals.

• Enhanced supervision of adverse drug reactions.

• The Pharmacy Departments supplied a sufficient

quantity of drugs of good quality.

• In some hospitals:

— The Pharmacy Department was able to

advise and provide drug information.

— A good working relationship was established

between physicians, pharmacists and nurses

to consult about drug use in patients.

• In many hospitals the Drug and Therapeutic

Committee had just been established and is not

yet a fully functioning entity.

Lessons learned from this experience

• Instruction and management by the Ministry of

Health of the activities of the Drug and Therapeutic Committee

• Instructional activities of the Drug and Therapeutic Committees and of the provincial health

service

■ Utilization and management of

antibiotic use in Hospital GynecologyObstetric Hanoi (1995–1999)

Bui Suong, MD, Hospital Gynecology-Obstetric Hanoi

and Nguyen Thi Vinh PhD, Medical College Hanoi,

Viet Nam

This article is from the report of the workshop

“Rational, safety use of antibiotics” held on February 28–29, 2000 in Hanoi.

Bacterial infection remains one of several factors leading to high mortality rates. Antimicrobial

agents play a decisive role in reducing the mortality and the incidence of bacterial infections. Today

antibiotics are widely and inappropriately used.

Anybody can buy antibiotics without a prescription. Hundreds of different brands of antibiotic

products are on the market and lack of information favours their misuse, such as unnecessary use,

incorrect choice, incorrect dose, incorrect administration, or poor drug quality. This misuse is the

reason for increasing bacterial resistance, leading

to prolonged treatments in hospitals and increased

expenses for drugs and services.

In March 1996, as one of the four pilot projects,

the Ministry of Health established the Drug and

Therapeutic Committee (DTC) at the Hospital

Gynecology-Obstetric Hanoi (HGOH). The

HGOH is a top-ranked hospital in Gynecology and

Obstetrics in Hanoi City. The HGOH treats

gynecological diseases and pathologic pregnancies,

provides sterility treatment, family planning and

obstetric services. The registered capacity of the

hospital is 200 beds, but it is always working at

overcapacity with both out- and in-patients. The

hospital is a reliable institution for women in Hanoi and surroundings.

After being established, the HGOH Drug and

Therapeutic Committee organized regular meetings

to encourage appropriate prescribing models and

drug choice for each patient. As time went on,

models were reviewed and improved as needed. The

appropriate choice of antibiotic:

• Was specific for the pathogen germ.

• Was quickly and well absorbed at the infection

site.

• Was appropriate to the treatment goal:

gynecological, obstetric, post- obstetric, newborn, inpatient, or outpatient.

• Was appropriate to the treatment subject, i.e,

pregnant, newborn.

• Minimized adverse drug reactions.

• Was of reasonable cost and acceptable to patients.

The HGOH’s Drug and Therapeutic Committee has observed changes in antibiotic use since the

Committee was implemented.

1. The proportion of patients using antibiotics

in the hospital

About 90% of patients used antibiotics. The remaining 10% included pregnant patients planning

to nurse their newborns and some doubtful cases

of ex-uterine pregnancies; antibiotics were not used

in these cases.
133

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

TABLE 3. PROPORTION OF PATIENTS USING ANTIBIOTIC COMBINATION THERAPY

1995 1996 1997 1998 1999

Percent of patients using antibiotics 91.7% 91% 90.8% 90.5% 80.5%

Percent of patients using one antibiotic 50.8% 57.4% 71.4% 74.6% 68.6%

Percent of patients using two antibiotics 30.3% 25% 15.3% 12.3% 10.5%

Percent of patients using ≥ 3 antibiotics 10.6% 80.6% 4.1% 3.6% 1.4%

• Generally, only one antibiotic was used for

prophylaxis after abortion or delivery with episiotomy.

• When necessary, antibiotic combination therapy

was used as follows:

— β-lactam (ampicillin) + aminoglycoside (gentamicin) were the main combination used

— β-lactam (cephalosporine) + metronidazole

— β-lactam + aminoglycoside + metronidazole

— Quinolone + aminoglycoside (few/gynecoTABLE 1. OUT- AND IN-PATIENTS AT HOSPITAL GYNECOLOGY-OBSTETRIC HANOI

1995 1996 1997 1998 1999

1. Total number of patients examined 46,030 52,147 60,868 74,974 75,068

Total number of examinations 68,902 78,061 90,746 105,886 105,021

Total number of abortions 4,931 5,417 6,150 7,099 7,619

2. Total number of inpatients 10,487 12,007 12,342 13,061 14,600

Total number of deliveries 5,778 6,139 6,924 7,204 7,682

* Difficult 2,419 2,893 2,992 3,207 3,057

* Normal 3,359 3,246 3,932 3,997 4,625

Total number of operations 1,943 2,393 2,540 2,979 3,100

* Gynecological 593 784 976 1,193 1,142

* Obstetric 1,353 1,609 1,549 1,777 1,958

3. Average duration of therapy (days) 6.7 6.3 6.0 6.4 5.8

TABLE 2. ANTIBIOTIC USE BY PATIENTS

1995 1996 1997 1998 1999

Number of patients using antibiotics 9,616 10,926 11,207 11,820 11,753

Total number of patients 10,487 12,007 12,342 13,061 14,600

% 91.7% 91% 90.8% 90.5% 80.5%

logic)

— Antibiotic + antifungi

• Antibiotic combination therapy was reduced in

1999 because antibiotic prophylaxis was introduced in surgery in 1996 and was implemented

hospital-wide in 1998.

• Antibiotic use was greatly reduced in 1999

(19.5%) because antibiotic use was removed for

all cases of normal delivery with tidy amniotic

fluid, entire placenta, no episiotomy.

TABLE 4. PROPORTION OF EXPENDITURE FOR ANTIBIOTICS

1995 1996 1997 1998 1999

Expenditure for antibiotics (thousands Vndong) 322,127 646,867 905,159 1,010,433 1,043,799

% of total drugs expenditure 45.8% 45.6% 44.3% 43.8% 43.5%
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

134

• The expenditure for antibiotics is appropriate

for a top-ranked hospital for Gynecology and

Obstetric Surgery in Hanoi City.

• The proportion of antibiotic expenses was gradually reduced from 1995 to 1999.

Today about twenty antibiotics are being used,

with ten in common use. The Drug and Therapeutic Committee considers every sort of antibiotic.

To be chosen, the antibiotic must be therapeutically effective, have few adverse drug reactions, and

be manufactured by a reliable firm. Only one brand

product of every antibiotic is used, making supervision and management easier. While the kinds of

antibiotics may be increased or decreased, the quantity of expensive antibiotics was reduced from 1995

to 1999.

2. Antimicrobial prophylaxis

From 1996 the hospital has used cefuroxime 0.75g

x 03 (or 04) ports/case to test for prophylaxis in

surgery (gynecological and obstetric) due to the

short duration. Hygienic measures, sterilization and

disinfection methods reduced the post-operative

infection rate considerably (from 19.8% to 11.7%

in the period studied). Because of its success, this

is now the standard order for antimicrobial prophylaxis in the hospital. The post-operative infection

rate is 5% (fever 38.5–39 °C, inflammation at incision site) with no cases of serious post-operative

infection.

Today, antimicrobial prophylaxis achieves good

results, reducing pain for patients, shortening antibiotic duration, avoiding drug complications, reducing the effect on the mother’s milk (childbirth

operation). In addition, good economic results were

achieved, reducing medical service and reducing

total expense for treatment in comparison to longterm therapy with antibiotics. The antimicrobial

prophylaxis regimen could help to reduce the rise

and spread of antibiotics resistant pathogens also.

3. Managing measures for rational, safe use of

antibiotics by the Drug and Therapeutic

Committee

In 1998, the HGOH’s Drug and Therapeutic Committee became a full-fledged, independent entity

in the hospital. The Committee has eight members, with the director as the chairman and the head

of Pharmacy Department as the permanent secretary. Since its establishment, the Committee has

been advising the director on the rational, safe and

effective use of drugs, including antibiotics. All leaders of the hospital understand the necessity of the

rational, safe and effective use of drugs for therapy,

as promoted by the Ministry of Health.

The Drug and Therapeutic Committee guidelines for the Pharmacy Department and the

Planning Department are:

Drug providing

• The Pharmacy Department provides sufficient

drugs on time and at high quality. Drugs are

generally obtained from state pharmaceutical

firms.

• Only one of several products under the same

generic name is used; this product must be of

good quality and meet the therapeutic demand

to facilitate the management and supervision of

antibiotic use in the hospital.

Prescribing

• On a yearly basis, experts are invited to give lectures on special topics in clinical pharmacy, such

as antibiotics, vitamins, drug interactions,

adverse drug reactions. The audience is made

up of physicians, pharmacists and nurses from

the whole hospital.

• One pharmacist and two physicians (special first

level) revise, advise and help the physicians to

prescribe rational, safe, effective antibiotics.

• A clinic pharmacist helps physicians choose

appropriate drugs for treatment of patients.

• At the weekly general meeting of the hospital,

the Pharmacy Department reports the case

histories of inappropriate drug use in order to

correct future problems.

• Monthly, if a sudden change in the quantity of

drug use is recognized, the Pharmacy Department reviews the case histories to find a reason

for the change. It reports to the Drug and Therapeutic Committee and makes suggestions for

solving the problem to gradually improve the

quality of treatment.

Drug use

• The Pharmacy Department regularly makes

guidelines and supervises the nurses and midwives in using drugs according to prescription.

The Pharmacy Department cooperates with the
135

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

clinical departments to watch the effectiveness

of drug use and report any decrease in effectiveness to the Drug and Therapeutic Committee.

The Pharmacy Department monitors any

adverse drug reactions in time to recover. In four

years, fifty cases of adverse drug reaction were

found, in which 38 cases were caused by antibiotics. All cases were treated in time with no complication.

• The physicians prescribe according to the guidelines and the list of drugs, which are rewritten

by the Drug and Therapeutic Committee each

year, so that the use of antibiotics in the hospital is becoming more rational, safe and effective. The post-operative infection rate is being

reduced. Therefore, although the number of

inpatients is increasing, the average duration of

treatment is decreasing (from 6.7 days in 1995

to 5.8 days in 1999).

Conclusion

Enacting the policies of the Ministry of Health with

the determination of the director of the board and

under the leadership of the Drug and Therapeutic

Committee, all physicians adhere strictly to the

prescribing regulations and therapeutic guideline.

Antimicrobial prophylaxis and the rational, safe use

of antibiotics showed a high degree of effectiveness.

To improve results, we will promote the effectiveness of the Drug and Therapeutic Committee

activity by:

• Strengthening science research activities in the

hospital.

• Encouraging and providing conditions for

personnel to improve their professional knowledge.

• Re-educating physicians on prescribing regulations, principles of drug use in general and of

antibiotic use in particular.

• Regularly providing to physicians, pharmacists

and nurses sufficient and up-to-date information about drugs in the drug list and their

administration.

• Reinforcing surveillance on therapeutical effectiveness of drugs being used in the hospital, finding out about drugs with bad activity and/or

adverse drug reactions in order to eliminate that

drug from the drug list.

• Strengthening supervision on rational, safe use

of drugs in the whole hospital (including in- and

out-patients) from the examination phase

through prescribing and realization of medical

orders to the final result. There could be punishment for infringed cases.

■ Greece: Hospital case study of an

antibiotic policy

Report prepared by Helen Giamarellou, MD, PhD,

Professor of Internal Medicine, Athens University School

of Medicine, Sismanoglio General Hospital, Athens,

Greece; President, APUA Greece; Anastasia Antoniadou,

MD, Nearchos Galanakis, MD, George Petrikkos, MD,

Erasmia Sarmi, Pharmacist. Contact Dr. Helen

Giamarellou at: hgiama@ath.forthnet.gr

This is a report on the encouraging results of our

implementation of an antibiotic resistance policy

in Laiko General Hospital during the period 1992–

1998.

In Greece, as in other settings, high antibiotic

resistance rates run in parallel with huge antibiotic

consumption in hospitals and in the community.

We implemented a antibiotic restriction policy in

a 500 bed University teaching hospital. In this hospital, antibiotic consumption before 1990 ranged

between 62–78% with the highest rates in the General Surgery and Urology Departments (75–100%).

The main overuse involved long-term surgical

prophylaxis, while one-third to one-half of antibiotic consumption involved the unjustified use of

third generation cephalosporins, carbapenems,

newer quinolones and vancomycin. Resistance rates

among Gram-negative isolates were already high

(Table 1) and the threat of losing all new active

compounds because of their unjustified overuse was

a reality.

 Since 1991, an antibiotic restriction programme

proposed by Professor Giamarellou and her team

was implemented by the Infection Control Committee of the Laiko General Hospital. According

to the programme, all new antimicrobials (third and

forth generation cephalosporins, aztreonam,

imipenem and later meropenem, vancomycin and

later teicoplanin and all newer quinolones) were

ordered to the hospital pharmacy only after physicians had completed a restricted antibiotic form,

which had to be inspected and signed by the hospital infectious diseases clinicians (Laiko Hospital

had 3 of them) or by physicians with a proven interest in infectious diseases. The programme was

also supplemented by enforcement of the rules of
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

136

hygiene (particularly of hand washing and appropriate use of gloves), educational programmes for

small groups of physicians belonging to different

clinics, “consensus agreements” regarding mainly

surgical prophylaxis, febrile neutropenia and nosocomial pneumonia (often in the form of clinical

protocols) and limited susceptibility reporting from

the hospital’s Central Diagnostic Laboratory. The

results were immediate and restricted antibiotic consumption was dramatically diminished (Table 2).

In order to improve further the quality of prescribing, an Antibiotic Team was formed in 1992,

composed of an infectious diseases physician, a

clinical microbiologist and a pharmacist, who undertook the mission to apply an audit programme

in close cooperation with the pharmacy, as an extension to the already active restriction policy. Three

times a week, an infectious diseases physician (who

rotated monthly) audited the antibiotic restriction

forms, before the pharmacy had delivered the required antibiotics (the pharmacy delivered drugs

to departments three times a week). Whenever an

order form was incomplete or the justification for

requiring any restricted antibiotic seemed irrational,

the infectious diseases physician visited the clinics

and discussed the case with the resident doctors.

Every justified order form was valid for five days,

after which a new complete and justified order form

TABLE 1. RESISTANCE RATES TO SEVERAL ANTIMICROBIAL AGENTS OF

5454 GRAM-NEGATIVE ISOLATES FROM 55 GREEK HOSPITALS

DURING A 3-MONTH PERIOD (SPRING 1989)

Antimicrobial Pseudomonas Acinetobacter Enterobacter Klebsiella

agent aeruginosa spp spp pneumoniae

Cephalothin — — 95% 63%

Cefotaxime — — 77% 51%

Ceftazidime 31% 92% 67% 46%

Imipenem 14% 1.1% 4.2% 0.5%

Ciprofloxacin 26% 59.6% 13% 10%

Amikacin 44% 91% 51% 45%

Gentamicin 45% 83% 43% 36%

Netilmicin 61% 90% 66% 45%

TABLE 2. THE INITIAL EFFECT OF A RESTRICTED ANTIBIOTIC POLICIES PROGRAMME ON RESTRICTED ANTIBIOTIC

CONSUMPTION

Number of patients on restricted antibiotics

Restricted antibiotic January 1988a September 1989 January 1990 March 1990 June 1990

Vancomycin 118 32 15 16 15

Imipenem 102 28 22 32 13

Ceftazidime 150 60 43 54 26

TOTAL 370 120 80 102 54

a

 control = consumption without restriction

TABLE 3. CONSUMPTION OF RESTRICTED ANTIMICROBIALS IN DIFFERENT CLINICS AFTER THE IMPLEMENTATION OF AN

AUDIT PROGRAMME

Percentage of patients on restricted antibiotics

Clinic November 1991 November 1992 November 1993 February 1994 February 1995

(without audit) (with audit) (with audit) (with audit) (with audit)

TOTAL 9.6%* 6.5% 6.2% 6.6% 5.8%

General surgery 12.2% 35 0.9% 1.4% 0.7%

Orthopedics 8.4% 1.9% 3.3% 1.8% 2.5%

Urology 2.7% 0.3% 0.9% 0.8% 1%

Transplant Unit 19% 18% 7% 12% 7.7%

Internal Medicine (neutropenics) 11.6% 12.8% 11.4% 11.4% 11.2%

(14%) (29%) (25%) (41%) (43%)

* before 1991 consumption exceeded 30%
137

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

needed to be sent to the pharmacy if the treatment

was further prolonged.

In addition, every two months the Antibiotic

Team organized scientific meetings with the staff

and the residents of each clinic to discuss irrational

order forms, case studies, and treatment guidelines.

Such meetings provoked large-scale discussion and

were considered to be the most effective educational

programme on antibiotic use. At the same time

surveillance of resistance and in-hospital antibiotic

consumption was performed every 3 months and

the results were released to physicians and discussed

during the above-mentioned meetings.

After the introduction of the audit programme

a further significant reduction in restricted antibiotics was observed (Table 3). The reduction was

mainly attributed to the implementation of

correct prophylaxis guidelines in the surgery

departments (single dose of a second-generation

cephalosporin perioperatively in clean-contaminated operations and three doses of vancomycin in

orthopedic and vascular surgery with the use of

prosthetic material). It is of interest that despite

the fear that restriction of advanced antibiotics

might increase the consumption of non-restricted

antibiotics, the overall antibiotics use was reduced

by more than 50%, ranging between 32% and

38.5% (= patients receiving antibiotics/patients

hospitalized x 100) (Table 4).

After three years of applying the audit programme, there was a significant reduction in the

resistance rates of several classes of antibiotics

(Table 5). In particular, for P. aeruginosa, a major

nosocomial threat, resistance to ceftazidime was

reduced from 45% before 1990 to 8% in 1995,

while for imipenem it remained low, at the same

levels as when the antibiotic was introduced into

the Greek market (5–10%). Interestingly, although

aminoglycosides as a group were not officially

restricted, their prescription in the hospital was selflimited due to the introduction of the newer βlactams and the fear of nephrotoxicity and were

confined only to septic or profoundly neutropenic

patients. As a result of this minimal use, mean

resistance rates for amikacin and gentamicin decreased from 55% and 85% respectively before

1990 to 12% and 19%. However, it should be

pointed out that resistance to quinolones was not

influenced by the antibiotic policy programme, but

showed a steady increase, with levels of 35% and

30% for P. aeruginosa, and Enterobacteriaceae, respectively, observed in the spring of 1995. Consequently, the Infection Control Committee and the

TABLE 4. TOTAL CONSUMPTION OF RESTRICTED AND NON RESTRICTED

ANTIBIOTICS

Year Restricted antibiotics Non restricted antibiotics

1991 12.5% 32%

1992 7.5% 36.5%

1993 7.3% 38.6%

1994 7.9% 34.7%

TABLE 5. INDICATIVE DECREASING RESISTANCE RATES

Antibiotic Indicative Resistance Rates (%)

P. aeruginosa Enterobacteriacea

1991 1994 1991 1994

Ceftazidime 45 8 — —

Imipenem 7 7.5 0 0

Ciprofloxacin 20 35 2 8

Gentamicin 61 28 18 10

Antibiotic Team decided that the quinolones should

be totally restricted in the hospital, prescribed only

in cases where a pathogen was exclusively susceptible to this class of antimicrobials and after consultation with an infectious diseases physician and the

approval of the Head of the Infectious Diseases

Department. As a result, consumption of quinolones decreased abruptly (by 80%) during the first

trimester, but it took two years of continuous

application of the restriction policy to observe a

marked decrease in quinolone resistance among the

Gram-negative nosocomial pathogens (Table 6).

The above-mentioned policy has been successTABLE 6. RESULTS AND IMPACT OF A TOTAL RESTRICTION PROGRAMME OF

QUINOLONES ON RESISTANCE RATES

1st trimester 1995 4th trimester 1996

Patients hospitalized 5181 5215

Number of patients taking

quinolones (%) 140 (2.7%) 30 (0.5%)

Defined Daily Dose (DDD) 1167 250

Sensitivity to Ciprofloxacin

E. coli 92% 95%

P. aeruginosa 66% 82%

P. mirabilis 70% 84%

K. pneumoniae 74% 94%

Acinetobacter baumannii 15% 50%
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

138

ful in decreasing resistance rates in the closed system within a university hospital, because:

• Although restriction and audit were the main

parameters of the policy, as an entity it was a

multidisciplinary programme including surveillance, education, treatment guidelines, limited

reporting sensitivity testing, consultation, and

implementation of hygiene measures;

• The audit was effective because infectious diseases physicians had the cooperation of the

microbiology laboratory and the pharmacy;

• The team that tried to apply it consisted mainly

of infectious diseases physicians who worked

with enthusiasm and belief, despite initial difficulties with their fellow doctors’ attitude;

• Respected opinion leaders in the field of infectious diseases guided the programme, a fact that

made the work of the Antibiotic Team easier.

The lessons we learned from this experience,

especially the fact that controlling and limiting

antibiotic use can reverse increased microbial resistance, can be applied to hospitals and the community. We are trying now to implement such a

policy in hospitals on a national scale. Of course a

prerequisite is the presence of an infectious diseases

physician in every hospital who will be responsible

for the implementation of the policy.

■ Russia: Hospital Case Studies of

Antibiotic Policies

Report prepared by Leonid S. Stratchounski, MD, PhD,

Director, Institute of Antimicrobial Chemotherapy (IAC),

Russian Federation, Smolensk; President, APUA Russia;

Roman S. Kozlov, MD, MSc, PhD, Deputy Director of

Science, Institute of Antimicrobial Chemotherapy (IAC),

Russian Federation, Smolensk; Coordinator, APUA Russia;

Alla S. Andreeva, MD, Clinical Pharmacologist, Smolensk

Regional Hospital, Russian Federation, Smolensk; and

Oleg L. Rozenson, MD, PhD, Assistant Professor,

Department of Clinical Pharmacology & Antimicrobial

Chemotherapy, Smolensk State Medical Academy,

Russian Federation, Smolensk.Contact Dr. Roman Kozlov:

roman@cliph.keytown.com

Antibiotic Policy: Introduction of an antibiotic policy

into a large regional hospital

This is a report of the implementation of an antibiotic policy in the Smolensk Regional Hospital

(SRH): 1,320 beds, 30 wards.

Background

The introduction of an antibiotic policy into hospitals has previously been shown to be an effective

tool in the curbing of antimicrobial resistance. Such

policies have not been used extensively in Russia

previously for a variety of reasons, including:

• Isolation of practicing doctors from modern

international trends in antimicrobial chemotherapy.

• The results of microbiological investigations

(including susceptibility testing) have little influence on clinical practice.

• Presence of a ‘gap’ between microbiologists and

clinicians.

Description of the antibiotic policy

• Clinicians were taught about rational antimicrobial chemotherapy on a regular basis via seminars, case discussions, distribution of literature,

participation in symposia and postgraduate

courses.

• Clinical pharmacologists were appointed to the

SRH and provided regular consultation with

physicians on the choice of antimicrobials.

• A Formulary Committee was established with

the introduction of a formulary and its regular

update.

• Microbiological services were improved by

means of:

— Continuous education of personnel in the

microbiological laboratory (including the

principles of selective reporting of susceptibility testing results);

— After-hours coverage;

— Implementation of internationally recognized guidelines (National Committee for

Clinical and Laboratory Standards

(NCCLS)) for susceptibility testing within

the microbiological laboratory;

— Establishment of resistance monitoring programmes and data management (using

WHONET and other software).

The main areas addressed in the antibiotic policy

• The analysis of antimicrobials use within the

SRH and by different wards (using the recommended WHO ATC/DDD methodology).
139

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

• Education of both microbiologists and clinicians

on clinical pharmacology of antimicrobials and

current issues on antimicrobial resistance.

• Development and implementation of antimicrobial drug formularies.

• Policy to restrict the prescription of III-IV

generation of cephalosporins, carbapenems,

amikacin, vancomycin, and so on.

• Improvements in the microbiological service

provided.

Level of policy enacted

This was a regional level policy that could be used

as an example for other hospitals wishing to implement a similar strategy.

Interim results of the antibiotic policy

In 1999, a total of 33 antimicrobials were used in

the SRH and 4 antibiotics were not given in comparison with 1997.

Over the same time period, hospital expenses

on antimicrobials decreased by 40%.

Interim analysis of intensive care unit (ICU) data

from 1997 was compared with data from 1997 (before and after implementing the above policy).

In general, the consumption of antimicrobials

decreased 1.3-fold in 1999 compared with 1997

(from 214.43 DDDs to 162.95 per 100 beds/days,

respectively). This was mainly due to a 1.2-fold

decrease in the use of penicillins (from 118.6 to

98.23 DDDs per 100 beds/days in 1997 and 1999,

respectively), a 1.8 times decrease in the use of all

cephalosporins (from 20.4 to 11.4 DDDs per 100

beds/days in 1997 and 1999, respectively) and a

1.4-fold decrease in the use of aminoglycosides,

especially gentamicin (from 48.9 to 34.0 DDDs

per 100 beds/days). There was also a decrease in

the consumption of imipenem and ciprofloxacin.

There was a decrease in resistance amongst nosocomial gram-negative bacteria: the resistance of

P. aeruginosa to gentamicin decreased from 75.0%

to 31.2% in 1997 and 1999, respectively and to

amikacin from 7.0% to 1.8%.

At the same time, no changes were noted in resistance profiles of E. coli, Klebsiella spp., Enterobacter spp. and Acinetobacter spp.

In conclusion, the interim analysis showed that

the establishment of an antibiotic policy in the SRH

(by means of education of health care providers,

antimicrobial resistance surveillance, and a formulary system) had financial advantages (a total 2.2-

fold decrease in hospital spending on

antimicrobials) and led to improvement in the resistance profiles of the most prevalent pathogen in

the ICU (P. aeruginosa). An analysis of the influence of the antibiotic policy on the development

of antimicrobial resistance in other hospital wards

is currently under investigation.

Lessons learned from the above policy applicable to

other countries

Education of health care providers, implementation of antimicrobial formulary and establishment

of close connections between microbiologists and

clinicians have proved to be the most crucial

issues. Such approaches could be successfully used

in both industrialized and developing countries.

Antibiotic Prophylaxis Policy: Optimization of

antibiotic prophylaxis in surgical wards of

Smolensk Regional Hospital (SRH)

Background

Antibiotic prophylaxis in surgery is an area where

the consumption of antimicrobials remains very

high. The analysis of indications, regimens and

duration of antibiotic prophylaxis in the hospital

indicated that optimization in this area is required,

due to:

• Non-evidence-based administration of antibiotic

prophylaxis.

• Irrational selection of antimicrobials for prophylaxis.

• Long duration of antibiotic prophylaxis.

All the above have led to the establishment of

the main objective of the study: to evaluate the practice of antibiotic prophylaxis, conduct economic

analysis of antibiotic prophylaxis in abdominal surgery in the SRH, and to evaluate the impact of

educational and administrative activities on antibiotic prophylaxis.

Description of the antibiotic prophylaxis policy

• Targeted teaching of surgeons about the modern concept of antibiotic prophylaxis. Special

attention was given to heads of departments.

• In collaboration with SRH authorities, the development and distribution of official recommendations on antibiotic prophylaxis within the

surgical wards of SRH.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

140

The main areas addressed in the antibiotic

prophylaxis policy

• The education of surgeons on rational antibiotic prophylaxis and the principles of evidencebased medicine.

• The development and implementation of practical recommendations on antibiotic prophylaxis

within the surgical wards of the SRH.

• Involvement of the authorities of the SRH in

the implementation of antibiotic prophylaxis.

Level of policy enacted

This was a regional level policy, which could be

used as an example for other hospitals wishing to

implement a similar strategy.

Results of the antibiotic prophylaxis policy impact

Analysis was based on patient data, gathered retrospectively in 1993 and 1998. Three hundred and

twenty-seven patients who underwent open cholecystectomy (OCE), appendectomy (AE) and

hernia repair (HR) were included in the analysis.

Antibiotic prophylaxis frequency and quality

(selection of antimicrobials, dosage regimens, route

of administration, post-operative duration) were

assessed. In 1993, none of the patients received

preoperative antibiotic prophylaxis, however, many

patients received antimicrobial treatment after their

operation for 5 to 8 days. In 1998, the following

preoperative antibiotic prophylaxis frequency was

registered: OCE–78%, AE–0%, HR–46%. In

1993, antibacterial administration without evidence

of postoperative infection was registered for OCE

in 82% cases compared to 31% cases in 1998.

Lessons learned from the antibiotic prophylaxis policy

applicable to other countries

• Educational and administrative activities have a

positive impact on antibiotic prophylaxis practice in surgery.

• The monitoring of antibiotic prophylaxis practice and feedback to surgeons needs to be

implemented in hospitals for the optimization

of antibiotic prophylaxis.

In our opinion, this policy can also be used in

developing countries.

■ Bulgaria: Hospital Case Studies and

National Antibiotic Policy

Emma E. Keuleyan, PhD, Assistant Professor,

Department of Microbiology, Head Antimicrobial

Resistance Laboratory, Medical University, Sofia,

Bulgaria; Coordinator APUA Bulgaria Chapter.

Contact: keuleyan@medfac.acad.bg

In Bulgaria, as in other countries, the emergence

and dissemination of antimicrobial resistance has

been recognized as a major obstacle in antimicrobial chemotherapy, as well as an event with wide

biologic significance. Several years after R - plasmids

have been discovered by Okhiai and Akiba in

Japan, the scientists started investigations on the

genetic mechanisms of resistance and its epidemiology.

Some publications from the 1960s are cited

below:

• Tyagunenko Y and Z Kyolean. 1967. Transmission of Multiple Antimicrobial Resistance in

Strains of Fam. Enterobacteriaceae. Epidemiol

Microbiol Infect Dis (Sofia). 4, 1, 26–31

• Tyagunenko Y and Z Kiolean. 1968. Studies on

some characteristics in the transmission and

manifestations of an episome with 5 R–markers. Proceedings of the Postgraduate Medical

Institute ISUL. 15, 1, 35–41 (English).

With time, new aspects, new methods, and new

approaches got more people interested in the antibiotic problem. The Department of Microbiology

at Medical University,Sofia and the National

Centre of Infectious and Parasitic Diseases have

played the leading role in this evolution of knowledge, research, and activities.

As shown by experience, antibiotic resistance

continues to increase and spread globally. Bulgaria

has had some success in decreasing the antibiotic

resistance problem, illustrated by the following

examples.

A. Institutional level

Some hospitals, primarily at universities, have initiated programmes for resistance surveillance and

control of infections, and established therapeutic

committees to optimize antibiotic use.

1. Alexander’s Hospital—Medical University, Sofia

(1, 2)

While third generation cephalosporins, tetracyclines

and aminopenicillins were widely used in 1993–
141

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

1994, the comparative analysis of 1997–1996 shows

some improvement (decrease in third generation

cephalosporins, tetracyclines, which need further

restriction, and aminopenicillins for Gramnegative infections).

Comment: The reported success in antibiotic usage

could be explained by: 1) introducing the

WHONET programme in 1993; 2) establishing a

Therapeutic Committee; 3) introducing the practice of a visiting microbiologist; 4) restricting some

broad-spectrum antibiotics; 5) cycling of antibiotics for empiric therapy; 6) and the personality of

the head of laboratory.

TABLE 1. ALEXANDER’S HOSPITAL

Antimicrobial resistance rate

Microorganism Resistance in %

1997 3/1993–3/1994

Penicillin – R S. pneumoniae 33 32

MRSA 23 31

HLGenR Enterococcus 21–46 42

Ampicillin – R E. coli 75 65

ESBLs Enterobacteriaceae 5–16 2–5

P. aeruginosa – R to Ciprofloxacin 55 22

R to Ceftazidime 28 17

R to Amikacin 45 9

A. baumannii – R to Ciprofloxacin 50 20

R to Ceftazidime 51

Emerging in 1997: VRE <5%, R to Imipenem in P. aeruginosa – 30%; in

A. baumanni – 5%

Antibiotic consumption (grams x 1000)

(DDD/100/day)

1996 1997 3/1993–3/1994

Aminopenicillins 10 17.5 3.2

Aminopenicillins/inhib Bla 11 9.5 0.3

Cephalosporins 1st gen 21.5 68.0 2.0

Cephalosporins 2nd gen 27.5 26.5 2.7–3.4

Cephalosporins 3rd gen 19.5 7.5 1.4–3.5

Aminoglycosides 7.0 8.5 0.7–2.5

Tetracyclines 2.1 4.0 3.3

Quinolones 10.45 4.5 3.3

Trimethoprim/

Sulfamethoxazole 6.8 10.3 0.8

2. Military Medical Academy

Antimicrobial resistance monitoring was performed

for a 20 year period. (3; and E. Savov–DSci thesis

“Contemporary approaches to study problematic

microorganisms for hospital pathology”, 1999)

Significant resistance to gentamicin was developed around the middle of the 1970s. Amikacin

was introduced in 1979. Like earlier experience in

the world, the decision was made to restrict

gentamicin and use amikacin as a first line

aminoglycoside.

As a result, by the end of the second period, a 2

to 3-fold decrease in resistance to gentamicin was

achieved in enterobacteria, without significant

dynamics in resistance to amikacin. There was also

some decrease in gentamicin resistance among

Gram-positive bacteria (S. aureus, S. epidermidis,

E. faecalis). Data from the Hospital Pharmacy about

antibiotic consumption showed that antibiotics

prescriptions had decreased in 1997 by 30% from

1996 and by 56% from 1995. The author’s opinion is that personal contact between microbiologists

and clinicians was more effective than written

guidelines and programmes.

3. Queen Ioanna Hospital–Medical University, Sofia

In 1993, a Therapeutic Committee was proposed

and a Hospital Antibiotic Policy was established

after wide discussions. This document suggests antibiotic prescribing to be at three levels: antibiotics

for common use (prescribed by every physician);

restricted antibiotics (to be discussed with the chief

of the unit, e.g., 3rd generation cephalosporins);

reserved antibiotics (for particularly resistant microorganisms, severe infections, or emergency; they

need permission from the department and repreTABLE 2. MILITARY MEDICAL ACADEMY

Resistance towards aminoglycosides in %

Microorganism First Period Second Period

Gentamicin Amikacin Gentamicin Amikacin

1975 94 75 94 1994 95 96 1994 95 96

E. coli 5 15 4 2 15 5 3 2 0 0

K.pneumoniae 13 60 3 8 60 63 25 8 12 5

E. cloacae 27 60 5 8 27 26 21 8 6 9

S. marcescens 13 55 9 11 55 30 22 11 4 3

P. aeruginosa 27 57 12 17 57 73 60 (data from thesis)
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

142

sentative of the Therapeutic Committee, e.g.,

imipenem, vancomycin). Because of the higher resistance rate to gentamicin, it was restricted and

amikacin suggested to be the first line amino-glycoside.

Her results show that the most common errors

in prescribing practice were:

• Antibiotics given without objective data about

bacterial infection

• Antibiotic prescribing not taking into account

the results from the Microbiology Laboratory

• Lack of strategy about the empirical choice of

antibiotic (misuse of broad-spectrum antibiotics)

• Frequent use of tetracyclin, tetracycline–oleandomycin and chloramphenicol

• Frequent use of ampicillin p.o. and subdosing

of azlocillin

• Late initiation and long lasting antimicrobial

prophylaxis in surgery

• Use of expensive and reserved antibiotics when

other possibilities are available

• Occasional long therapies for pneumonia and

pyelonephritis.

A survey about national antibiotic consumption

showed that the most frequently prescribed antibiotics were:

1. Tetracyclines

2. Broad-spectrum penicillins (ampicillin and

amoxicillin)

3. Sulfamethoxazole–Trimethoprim

4. Aminoglycosides (gentamicin)

5. Chloramphenicol

6. Narrow spectrum penicillins, macrolides,

cephalosporins, lincozamides, and quinolones.

This list, while similar to those from other Central and Eastern European countries (4, 5) does not

reflect contemporary principles of antibiotic usage.

The author explains this non-prudent antibiotic

policy by:

• Lack of systematic data about the dynamics of

resistant strains

• Lack of a regular drug supply and insufficient

budget

• Lack of basic, independent drug information

• Lack of an official strategy at most hospitals

• Lack of “sensitivity” in the society towards the

problems of antibiotic use

• Lack of a pharmacoeconomic approach.

TABLE 3. QUEEN IOANNA HOSPITAL–MEDICAL UNIVERSITY, SOFIA

Resistance to aminoglycosides in %

Microorganism Gentamicin Amikacin

1993 1995 1999 1993 1995 1999

E. coli 968 336

Klebsiella spp 41 34 26 7 5 17

Enterobacter spp 34 30 22 11 13 19

Serratia spp 62 53 24 9 35 22

Proteus spp 25 18 16 5 8 19

P. aeruginosa 24 60 59 5 37 50

Acnetobacter spp 51 77 66 36 70 69

A decrease in resistance rates to gentamicin was

achieved in Enterobacteriaceae, the most significant decrease occurring in Serratia. However, this

hospital had an increase of resistance to amikacin.

This may be due to the strains with ESBLs (genes

located on the same transposon).

Comment: It may be time to restrict amikacin.

The data cited above are from “Queen Ioanna

Hospital Antibiotic Policy”, 1993 and from

“Annual Analysis of Antibiotic Resistance Rate and

Antibiotic Use in QIUH”, 1994, 1995, 1996,

1997, 1998, 1999", N. Hadjieva; N. Hadjieva and

D. Ivanova. They have been presented at national

and international congresses.

B. National level of the efforts to fight

antimicrobial resistance

In her PhD thesis “Pharmacotherapeutic and

pharmacoeconomic aspects of treatment with antimicrobial drugs in Bulgaria”, 1997, M. Popova

evaluated the approaches for antibacterial treatment

of respiratory tract and urinary tract infections and

antibiotic prophylaxis in surgery. She conducted

the studies at two university hospitals, one general

hospital in Sofia, one general district hospital, one

specialized hospital, and several polyclinics. She also

analysed the national antibiotic consumption during the period from 1979 to 1994 by implementing DDD/1000/ day methodology.
143

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

To overcome these problems she suggested:

• Optimizing the contacts between clinicians and

microbiologists

• Establishing a hospital Therapeutic Committee

• Publishing guides for antimicrobial treatment

and prophylaxis

• Establishing a Society for rational antibiotic use

with wide participation of antibiotic prescribers, consumers, and providers.

This measure, according to M. Popova, would

be able to curb self-medication, irrational prescribing, free sales, and the unethical promotion of antibiotics.

Comment: It is also necessary to establish a National

Antibiotic Policy for both the hospital and ambulatory settings with strong legal and financial support of the Ministry of Healthcare, Government,

and Parliament.

Recent data about approaches in antimicrobial

treatment indicate significant improvement (6–9).

While some past examples of antibiotic prophylaxis in surgery sound anecdotal, today most institutions use antibiotic prophylaxis consistent with

international standards. Similarly, recent data about

national antibiotic consumption show some improvement (Bulgarian Drug Agency, M. Popova;

data have been sent to EURO DRUG):

Antibiotics DDD/1000/Day

1994 1995 1999

Tetracyclines J01A 7.38 7.09 4.24

Amphenicols J01B 0.29 0.20 0.18

Penicillins J01C 7.23 7.76 7.64

Broad-spectrum Penicillins J01CA 5.15 6.22 5.96

Comb.Penicillins/Bla inhibitor J01CR 0.54 0.14 0.27

Cephalosporins J01D1 1.21 1.95 1.37

Carbapenems J01DH 0.004

Sulfonamides & Trimetoprim J01E 1.35 1.03 1.08

Macrolides & Lincosamides J01F 0.85 0.61 0.42

Aminoglycosides J01G 2.42 1.70 0.87

Quinolones J01M 0.09 0.27 0.034

Glycopeptides J01XA 0.001

Imidazoles J01XD 0.41

Urinary antiseptics G04A 0.67

As it can be seen from the table, in 1999

pencillins and broad-spectrum penicillins were the

most commonly used antibiotics. From 1994 to

1999, use of aminoglycosides decreased nearly

three-fold and use of tetracyclines decreased nearly

two-fold.

Many factors have contributed to a better

understanding of the consequences of antimicrobial resistance and the necessity of prudent antibiotic use. Among them, special attention has to be

given to:

• The impact of scientists in research and education

• Political changes

• International collaboration and support.

Impact of scientists in research and education

Different aspects of epidemiology and mechanisms

of resistance in Bulgaria, and methods for their

detection have been studied (3, 10–42). A total of

seventeen fellowships on the problems of antibiotic policies, methods for detection of mechanisms

and epidemiology of antimicrobial resistance, and

susceptibility testing were performed in leading

world centres during the last 15 years. Eight research projects received grants from Bulgarian

(Ministry of Education and Sciences, Medical University–Sofia) and international (APUA) organizations. These issues have been the focus of 8 theses.

Pharmacodynamics, pharmacokinetics, and

pharmacoeconomics studies were performed and

several clinical trials were carried out.

Educational activities have been addressed to

practitioners, providers, and consumers of antibiotics. More working hours for studying antimicrobial chemotherapy and antimicrobial resistance

have been included in the education of students in

medicine, dentistry and pharmacy. Written materials on principles of rational antibiotic therapy have

become available for junior doctors. Post-graduate

education courses on strategies of antimicrobial

chemotherapy for different audiences (microbiologists, physicians, nurses) have been organized on

a regular basis by the Medical University of Sofia

and NCIPD. Popular articles were published in

mass media and television discussions took place

for the education of antibiotic consumers.

Political changes

Since 1989, when democratic changes started in

Bulgaria, new criteria and new standards of drug
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

144

use were developed. State laws about drugs and

pharmacies in human medicine were published and

updated. Significant changes were made in drug

regulation. As new antibiotics are licensed, each is

given a complete description of dosage regimen and

indications for all forms. The Ministry of Healthcare, National Drug Institute and Medical University’s Pharmacy Faculty elaborated “Indicators to

Follow up the National Drug Policy in Bulgaria”

(1994–1996)—P. Uzunov, T Benisheva, G Petrova,

Y Uzumov. A health care reform started on July 1,

2000, whose aim is to change the previously centralized state health care system to an insurancebased practice.

International cooperation and support

The progress during the last few years would not

have been possible without the support of different international organizations. The World Health

Organization (WHO) supported many different

projects and activities. Professor Thomas O’Brien

came personally to Bulgaria to speak on antimicrobial resistance and to introduce his WHONET

programme for resistance surveillance. This programme now performs most resistance monitoring

in Bulgaria. APUA supported the establishment of

the APUA Bulgaria Chapter in 1998. The APUA

has funded the current research project: “Survey of

Antimicrobial Resistance in Bulgaria—first step in

understanding the necessity of rational antibiotic

policy” (E. Keuleyan and E. Savov) and recently

supported another project: “Attempt to improve

antibiotic use in Bulgarian hospitals” (E. Keuleyan

and T. Sokolov). The European Community has

several programmes to support education (Tempus),

research, and other activities (PHARE). Due to a

PHARE project, many international journals became available to Bulgarian scientists. PHARE supported the edition, “Bulgarian Therapeutic School”,

in 1995.

The Open Society Foundation has supported

activities for Bulgarian scientists, including training courses, fellowships, participation at congresses,

and organizing of symposia. During 1998 it supported a conference in Sofia on anaerobic infections with participation of the American Society

for Microbiology. Bulgarian scientists participate

in different international programmes, projects and

organizations: WHO (Essential Drugs, EURO

DRUG, Emergency Diseases); APUA; National

Committee for Clinical and Laboratory Standards

(NCCLS); WHO/CDC External Quality Assurance Programme; European Study Group on Antibiotic Policy; European Study Group for Antimicrobial Resistance Surveillance; European Study

Group of Nosocomial Infections; European Society for Clinical Microbiology and Infectious

Diseases (ESCMID); European Antimicrobial Resistance Surveillance System (EARSS); etc. All these

forms of international collaboration are playing a

substantial role in developing different activities to

overcome the antimicrobial resistance problem.

Numerous additional organizations are taking

part in the improvement of antibiotic use in Bulgaria; they can not all be cited and acknowledged

in this brief review. It is also difficult to assess the

particular impact of all factors, events, activities,

and works that are dealing with developments in

this area. The author’s opinion is that fellowships

in the prestigious world centres play a very important role for the development of future leaders in

science, clinical work, and education. Among the

activities that have not been mentioned, some that

deserve to be noted are:

• In 1994 a National Society of Chemotherapy

was created, which became a member of the International Society of Chemotherapy (ISC), the

European Society of Chemotherapy (FESCI)

and the Mediterranean Society of Chemotherapy. The First National Conference on

Chemotherapy took place in Sofia in 1995.

• In 1998, the First National Conference on

Pharmacoeconomics was organized in Sofia.

• Materials about antibiotic resistance are being

discussed at the meetings of the National Societies of Clinical Microbiology and Medical

Microbiology,.

• Efforts have begun for standardization and quality assessment in Clinical Microbiology (43). A

specialized laboratory for these purposes was established at the National Center of Infectious

and Parasitic Diseases. In April 2000, a Conference on Standardization and Quality Control

was organized by Becton Dickinson—Bulgaria

and NCIPD in Borovetz.

• An Expert Committee on Antibiotic Policy

working with the Ministry of Healthcare was

created in August 2000, to work on developing

and establishing a national programme for a

rational antibiotic strategy.

In conclusion, these are some examples of what

has been done in recent years in Bulgaria to curb
145

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

antimicrobial resistance. This experience is on a

small scale. Many more people need to be engaged

to accomplish the goal. Many more people need to

be educated and convinced of the problem. The

perfection of antimicrobial chemotherapy will not

come with the efforts of a small group of people or

with fleeting interest. World experience shows that

this is a difficult and long process. Curbing antimicrobial resistance will take more knowledge,

work, education and funds.

References

1. Markova B. Analysis of resistance of bacterial pathogens in order to optimize antibacterial therapy. Informative bulletins of Department of Microbiology,

Medical University, Sofia and Clinical Microbiology Laboratory, Alexander’s University Hospital.

1993–1998;1–8.

2. Markova B, Bobtcheva S, Topalova S, Kolevsky A.

Approaches for the optimization of diagnosis and

antimicrobial therapy of infections at the

Alexandrovska State University Hospital. Proceedings of the Ninth Congress of the Bulgarian

microbiologists with foreign participation. 1998 V.

1. Clinical Microbiology, Sofia. 1998;1:324–329.

3. Savov E. Analysis of the structure of bacterial infections and antimicrobial resistance in order to

optimize antimicrobial chemotherapy. Department

of Military Epidemiology, Hygiene and Microbiology, Military Medical Academy, Sofia. 1996, 1997,

1998.

4. Kiivet RA, Biba V, Enache D, Fottau V, Guilbinovic

J, Oltvanyi N, Orazem A, Popova M, Stika L.

Changes in the use of antibacterial drugs in the countries of Central and Eastern Europe. Eur J Clin

Pharmacol 1995;48:299–304.

5. Popova M, Popova P, Guencheva G. Consumption

of anti-infective drugs in Bulgaria for the period from

1979 to 1994. Pharm World 1997;19(2):93–100.

6. Hadjiisky O. Antibacterial therapy in burns-pharmacokinetics, particularities and indications. J Emerg

Med 1999;7(2):5–12.

7. Pentcheva P. Strategy of antimicrobial chemotherapy

in emergency medicine. J Emerg Med 1993;1(2):6–

13.

8. Terziisky G. Programme for Antibiotic Policy of

Medical Institute of Transport. Sofia, 1993.

9. Vachkov P. Contemporary treatment of deep

mycoses. Infectious Diseases. Medical Review

2000;31(2):3–22.

10. Detcheva A, Chankova D, Kotcheva B, Savov E,

Dragijeva E, Genova V, Zamfirova E, Protich N,

Tomova I. Monitoring of the Antibiotic Susceptibility in Group A Streptococci 1994–1997. Proceedings of the Ninth Congress of the Bulgarian

microbiologists with foreign participation; 1998 V.

1. Clinical Microbiology, Sofia. 1998;1:380–382.

11. Grigorova V, Sredkova M, Popova V. Susceptibility

of S. pneumoniae strains towards different antibiotics. Ibidem. p.392–396.

12. Keuleyan E. Aminoglycoside-Aminocyclitols.

Mechanisms of action and antimicrobial resistance.

Medico-biologic information 1990;3:3–11 (English/

Russian).

13. Keuleyan E and R Avramova. Gentamicin-resistant

Enterobacteriaceae and the problem of their

polyresistance. Probl Infect Parasit Dis NCIPD,

Sofia 1994;21:19–20.

14. Keuleyan E, Avramova R, Barzashka S, Boyanova L,

Gergova R, Mitov I. Analysis of antibiotic susceptibility in orthopedics and trauma hospital. Probl

Infect Parasit Dis 1998;26(1):24–27.

15. Keuleyan E, Gergova R, Haralambieva I, Markovska

R, Sredkova M, Savov E, Dragijeva E, Genova V,

Gergova G, Toshkova K. Problematic MRSA/

MRSE-comparative susceptibility to antimicrobial

agents. Proceedings of the Ninth Congress of the

Bulgarian microbiologists with foreign participation.

1998 V. 1. Clinical Microbiology, Sofia. 1998;1:363–

367.

16. Keuleyan E, Markovska R, Savov E, Toshkova K,

Dragijeva E, Genova V, Borissova V, Sredkova M.

Susceptibility of clinically significant S. aureus

towards Macrolides, Lincosamides and Streptogramins. Ibidem. 358–362.

17. Keuleyan E, Savov E, Sabtcheva S, Balabanova M,

Gergova R, Haralambieva I, Guirgitzova B. Problematic Enterococcus: HLAR and Van-resistant:

Comparative study of strains from different hospitals. Ibidem. 401–405.

18. Nashev D and K Toshkova. Information on dissemination of methicillin-resistant Staphylococci during

1996. Informative Journal of National Center of

Infectious and Parasitic Diseases 1998;2:4–7.

19. Ribarova N and Y Mitova. Etiological characteristics of the nosocomial infection in different types of

high risk hospital departments. Infectology 2000;

37(1):27–32.

20. Sabtcheva S, Borissova V, Kantardjiev T. Occurrence

and fetection of β-lactamases in clinical isolates of

the family Enterobacteriaceae. Proceedings of the

Ninth Congress of the Bulgarian microbiologists

with foreign participation. 1998 V. 1. Clinical Microbiology, Sofia. 1998;1:333–342.

21. Savov E. Plasmids as epidemiological markers of

microorganisms in hospital infections. V Med Delo

1993;2:41–44.

22. Savov E. Clonal conception in epidemiology and

clinical microbiology. Military Medicine and Pharmacy 1997;1:41–43.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

146

23. Savov E, Toshkova K, van Belkum A, van Leenwen

W. Use of AP-RAPD polymerase chain reaction for

typing of Staphylococcus aureus strains. Infectology

1997;1:15–18.

24. Sotirova P, Tyagunenko Y. Plasmid Profile Analysis

of Clinical Isolates of A. baumannii. Proceedings of

the Ninth Congress of the Bulgarian microbiologists

with foreign participation. 1998 V. 1. Clinical Microbiology, Sofia. 1998;1:427–433.

25. Sredkova M. 1998. Resistance to penicillins,

aminoglycosides and vancomycin of clinical strains

of enterococci. Ibidem. 397–400.

26. Sredkova MP and SI Patchkova. Informative Bulletins: Resistance towards antimicrobial agents in clinical isolates. Department of Microbiology, Higher

Medical Institute–Pleven (1996, 1997; 1, 2).

27. Toshkova K. Methicillin-resistant Staphylococcus.

Sofia; 1995.

28. Vatcheva R, Savov E. Detection of clinical isolates

of Family Enterobacteriaceae producing broad spectrum β-lactamases. Proceedings of the Ninth Congress of the Bulgarian microbiologists with foreign

participation. 1998 V. 1. Clinical Microbiology,

Sofia. 1998;1:330–332.

29. Avramova R, Keuleyan E, Ekimova E. Resistance to

third generation cephalospoins in clinical strains of

Enterobacteriaceae. J Chemother 1993;Suppl 3:262–

264.

30. Boyanova L, Spassova Z, Kraslev Z, Petrov S,

Stancheva I, Docheva J, Mitov I, Koumanova R.

Characteristics and trends in macrolide resistance

among Helicobacter pylori strains isolated in Bulgaria

over four years. Diagn Microbiol Infect Dis 1999;

34(4):309–313.

31. Boyanova L, Stancheva I, Spassova Z, Katzarov N,

Mitov I, Koumanova R. Primary and combined resistance to four antimicrobial agents in Helicobacter

pylori in Sofia, Bulgaria. J Med Microbiol 2000;

49(5):415–418.

32. Keuleyan E. Biochemical determinants of aminoglycoside resistance in Gram-negative microorganisms, isolated from urocultures. J Hyg Epidemiol

Microbiol Immunol 1989;33(3):289–97(Czechoslovakia).

33. Keuleyan E. Aminoglycoside resistance among Gram

negative bacilli in Sofia, Bulgaria. APUA Newsletter

1992;10(4):1–2, 7.

34. Keuleyan E. Presence of acetyltransferases and adenylyltransferases in gentamicin-resistant transconjugants. Pathol Biol 1992;40(5):556–60 (France).

35. Keuleyan EE, Haralambieva YH, Gergova RT,

Markovska RD, Mitov IG. Antibiotic resistance in

two University Hospitals in Sofia, Bulgaria. APUA

Newsletter 1997;15(3):1, 4–5.

36. Keuleyan EE In: Schouten MA, Voss A, HookampKorstanje JAA and the European VRE Study Group.

Antimicrobial susceptibility patterns of Enterococci

causing infections in Europe. Antimicrob Agents

Chemother 1999;43(10):2542–2546.

37. Keuleyan E In: Jones RN, Hare RS, Sabatelli FJ and

the Ziracin Susceptibility Testing Group. In Vitro

Gram-positive antimicrobial activity of Evernimicin

(SCH 27899, Ziracin®), a new oligosaccharide compared with other antimicrobials: a multicenter international trial. J Antimicrob Chemother, in press.

38. Setchanova L, Tomasz A. Molecular characterization

of penicilln-resistant Streptococcus pneumoniae

isolated from Bulgaria. J Clin Microbiol 1999;

37(3):638–648.

39. Setchanova L In: Jacobs MR, Dagan R, Appelbaum

PC, Burch DJ. Prevalence of antimicrobial-resistant

pathogens in middle ear fluid: multinational study

of 917 children with acute otitis media. Antimicrob

Agents Chemother 1998;42(3):389–395.

40. Toshkova K, Savov E, Soedarmanto I, Lammler CU,

Chankova D, van Belkum A, Verbrugh HA, van

Leenwen W. Typing of Staphylococcus aureus isolated

from nasal carriers. Zbl Bact 1997;286:547–555.

41. Toshkova K In: Marples RR, Rosdohl VT and Members of the IUMS Subcommittee. International quality control of phage typing of Staphylococcus aureus.

J Med Microbiol 1997;46:511–516.

42. Von R Prager, Savov E, Tschape H. Nosokomiale

Verbreitung von Resistenzplasmiden durch die Praxis

der Kombinationstheraie mit Aminoglycosid- und

β-Lactam–Antibiotika. Bundesgesunbl 1994;1:24–30

(Germany).

43. Kantardjiev T, Batchvarova A, Velinov T, Kouzmanov

A. Development of external quality assessment for

microbiology in Bulgaria. Infectology 2000;37(1)27–

32.

■ Sweden: National Antibiotic Use and

Surveillance Projects

Major change in the use of antibiotics following a

national programme: Swedish Strategic Program for the

Rational Use of Antimicrobial Agents and Surveillance

of Resistance (STRAMA). Sigvard Molstad, Otto Cars.

Scand J Infect Dis 31:191–5, 1999. Report prepared by

Otto Cars, Swedish Institute of Infectious Disease

Control, Solna, Sweden; Chairman, STRAMA, Leader,

APUA Sweden, otto.cars@smi.ki.se

STRAMA

The increase in bacterial resistance in Europe, the

increasing sales of antibiotics in Sweden and the

spread of penicillin-resistant S. pneumoniae (PRSP)

in southern Sweden have alarmed both the medical profession and national health authorities.

Therefore a national project named STRAMA,
147

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Swedish Strategic Program for the Rational Use of

Antimicrobial Agents and Surveillance of Resistance, was initiated in 1994.

National STRAMA-group

A national STRAMA group (www.strama.org) was

appointed which was composed of specialists in

infectious diseases, microbiology, general practice,

ear, nose and throat (ENT), and pediatrics, from

the Swedish Reference Group for Antibiotics. In

addition, the national STRAMA-group included

members from the Swedish Institute for Infectious

Disease Control, the Swedish Medical Products

Agency, the National Board on Health and Welfare, the National Corporation of Pharmacies, the

Swedish Veterinary Agency, the Society of County

Medical Officers for Communicable Diseases, and

the Swedish Network for Pharmacoepidemiology

(NEPI). The primary goal of the National

STRAMA-group was to stimulate the formation

of STRAMA-groups in each county. Together with

these regional groups, the national STRAMA-group

mission was to increase knowledge and understanding of the relationship between antibiotic consumption and bacterial resistance by both the medical

profession and the public at large. The main objectives were to minimize the development and spread

of resistance, both in outpatients and in hospitals,

by a reduction of inappropriate antibiotic use,

especially of broad-spectrum antibiotics, and to

further develop and support resistance surveillance

programmes.

Regional STRAMA-groups

In each county at least one STRAMA-group has

been formed. The County Medical Officers for

Communicable Diseases are chairing these regional

groups, which include specialists from different

medical fields, e.g., infectious diseases, ENT,

pediatrics, microbiology, general practice and pharmacy. Some of the groups also include primary care

nurses. The groups’ main objective is to evaluate

the use of antibiotics in the area and the pattern of

resistance. After identifying problems in the area,

the group uses its knowledge to influence health

care workers to improve diagnostic procedures and

the prescribing pattern of antibiotics. In some counties with tertiary care hospitals, special groups are

formed to influence the use of antibiotics in hospitals. Since the immediate threat was the increasing

incidence of PRSP, in most counties the initial work

concentrated on the treatment of respiratory tract

infections and antibiotic usage in pre-school

children.

Antibiotic sales statistics

Apoteket AB (Corporation of Swedish pharmacies)

keeps records of sales of medicinal products from

the wholesalers to the pharmacies. From these

databases, raw data on sales of antibiotics are extracted. The Anatomical Therapeutic Chemical

classification system (ATC) is used for classification of drugs. The unit of measurement is defined

daily doses (DDD) for human medicine and for

veterinary medicine mostly in Kg of active substance. Dispensing of antinbiotics is monitored by

all pharmacies. This implies that data are broken

down according to hospital or community use. Prescriptions statistics are available for outpatients as

DDD as well as number of prescribed items/ 1000

inhabitants/ day. From 1980 to 1995 this has been

based on a sample of 1 out of 25 prescriptions,

after 1996 all prescriptions served have been registered. The statistics are produced at national, county

and since 1998 also at community level. It can be

broken down to individual drugs, sex and age

groups.

The Swedish Reference Group for Antibiotics

(SRGA) and the Swedish Institute for Infectious

Disease Control have developed a national recommendation for standardized antimicrobial susceptibility testing (www.srga.org). All 30 Swedish

microbiological laboratories use the SRGA standardized disc diffusion method. The species related

MIC and zone-diameter breakpoints from SRGA

have been uniformly adopted as well as SRGA recommendations for external and internal quality

assessment programmes. SRGA and the Swedish

Institute for Infectious Disease Control perform

yearly surveys of approximately 3000 strains (100

per laboratory) of each of S. pyogenes, H. influenzae,

S. pneumoniae and every second year of E. coli,

Klebsiella spp., Enterobacter spp, against a specified

number of commonly used antibiotics. Special surveys have been directed towards antibiotic resistance in Gram-negative hospital isolates, UTI

pathogens from primary care isolates and pathogens isolated from patients at Intensive Care Units.

Findings of methicillin-resistant pneumococci

(MIC>0.5 mg/l) and vancomycin-resistant enterococci (VRE) has been made notifiable.

In 2001, an Antibiotic Resistance Steering

Group was formed at the Swedish Institute for
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

148

Infectious Disease Control. The aim of this group

is to coordinate an extended national surveillance

of resistance built on existing networks of clinical

laboratories.

Activities and results

Between 1993 and 1997 the total antibiotic use

was reduced by 22%; the reduction was especially

evident for macrolides and broad-spectrum antibiotics. The reduction of antibiotic consumption has

been more prominent in Sweden than in the other

Nordic countries. Recommendations have been

produced for the use of macrolides, vancomycin,

fluoroquinolones and on the treatment of urinary

tract infections, chronic bronchitis and skin and

wound infections. A folder with information on

respiratory tract infections, antibiotics and resistance has been distributed to all Swedish medical

health care centres. Three symposia have been

arranged for the regional groups. Media interest for

the project has further increased the knowledge and

understanding of the problem in the general population. During the last year Sweden has been engaged in several European Union (EU) projects

concerning antibiotic resistance. The national

STRAMA-group will continue to regularly follow

the use of antibiotics and the incidence of resistance, coordinate necessary surveillance programmes

and other activities in the counties and, if needed,

make recommendations on identified problem areas.

The South Swedish Pneumococcal

Intervention Project

Role of communicable disease control measures in

affecting the spread of resistant pneumococci: the

Swedish model. Karl Ekdahl, Otto Cars. Clin Microbiol

Infect 1999; 5: 4S48-4S54.

During the last 20 years, the spread of penicillin

resistant and multiresistant Streptococcus pneumoniae has become an increasing international problem. In the early years of the 1990s, the incidence

figures in Malmöhus County in southern Sweden

increased to 8–15%, while the corresponding figures for the rest of Sweden have remained at lower

levels. Recommendations from a national expert

committee were issued in 1995, outlining possible

intervention measures against the spread of penicillin-resistant pneumococci (PRP) with minimal

inhibitory concentration (MIC) for penicillin G

(PcG) ≥0.5 mg/L among small children. The first

large-scale attempt to implement these recommendations was started in Malmöhus County, in March

1995. The project is still running and has been followed by similar initiatives in most other Swedish

counties.

Since March 1995, all PRP with MIC for PcG

≥0.5 mg/L have been directly reported from the

three microbiology laboratories in the county to

the Regional Center of Communicable Disease

Control (RCCDC) in Malmö. Comprehensive retrospective data are available from January 1995.

Whenever an individual with an infection due

to PRP is identified (“index case”), the RCCDC

contacts the local health care centre of that patient.

The local physician is then responsible for securing nasopharyngeal specimens from family members and other close contacts (e.g., day care group)

of the index case, in order to identify carriers in the

surrounding area (“contact cases”). All carriers

(index cases as well as contact cases) are followed

with weekly nasopharyngeal cultures, until two consecutive negative specimens have been obtained

(“PRP negative”). All control cultures, and other

health care contacts due to the project, are free of

charge for the individual patient. If an identified

carrier is a child participating in any form of child

day care, nasopharyngeal specimens are also obtained from the staff and other children in that day

care group. If more carriers are found, the screening procedures can be extended to the whole day

care centre. Repeated cultures are then obtained

every 1–2 weeks from the children and staff, until

no more carriers are identified. Pre-school children

who are identified as carriers stay away from group

day care until they are PRP negative. The parents

of these children are able to stay at home with full

reimbursement from the social security system, if

the day care cannot be arranged in any other way.

During the period from January 1, 1995 to June

30, 1998, 1545 PRP carriers (1492 individuals)

were identified in Malmöhus County. Of the 1545

episodes, 642 (41%) were in index cases and 903

(59%) in contact cases. The pattern of carriage has

shown a pronounced seasonal pattern, with most

cases occurring during the winter months. Altogether 170 of approximately 600 day care centres

in the county have been screened for PRP during

the period. The number of PRP carriers in each

day care centre has varied within great intervals

(median 2, interval 1–23), and in half of the day

care centres no further PRP carrier was identified.

Screening cultures were, on average, obtained twice

in each day care centre, before the day care centre

could be declared “PRP-free”.
149

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

The “Swedish intervention model” has applied

traditional communicable disease actions (contact

tracing and isolation) to a new phenomenon (antibiotic resistance). The measures are under continuing evaluation and the final conclusions have not

yet been drawn.

Audit project

Medical audit changes physicians’ prescribing of

antibiotics for respiratory tract infections. Eva Melander

et al. Scand J Prim Health Care 1999; 17:180–84.

In Sweden a prescription is needed to receive an

antibiotic, and 60% of all antibiotics are prescribed

for respiratory tract infections (RTIs). Several guidelines have been issued on a national level, giving

rather strict criteria for antibiotic prescribing for

RTIs. However, the actual sales of antibiotics do

not show compliance with given recommendations

in guidelines. Different methods have been tried

to change the prescribing of antibiotics for RTIs,

but the habits of physicians seem difficult to change.

A group studied the diagnostic procedure and prescribing of antibiotics in clinical practice by applying the special Audit Project Odense model (APO)

for quality development. The APO model has been

applied in Denmark and Sweden for some years,

and the method is based on a registration of consultations in a diagnostic area (e.g., hypertension,

diabetes), where each participating physician during a limited period of time should be able to register a considerable amount of consultations.

Participating physicians choose the registration

parameters before the registration. Statistics are collected from the registered parameters. Each participating physician receives his own personal result,

making a comparison between his own prescribing

and the general group possible. The aggregated data

of all consultations reflects clinical practice, which

in turn can be compared with guidelines, national

recommendations or other studies in the same field.

The same registration shall be performed after approximately one year. Most importantly, between

the two registrations a discussion should take place

and an educational programme based on the result

of the first registration be formulated.

The APO method was asked for in Orup, a

medical district in Malmöhus County, to see if a

change in the antibiotic prescribing habits of participating physicians could be obtained. Consultations for RTIs during the same periods among 25

doctors from a neighboring area who had not taken

part in any intervention or follow-up discussion

served as a control. The first registration took place

during 4 weeks in January–February and the

second during 4 weeks in November–December.

The physicians registered diagnosis, diagnostic

methods, C-reactive protein, bacterial culture,

X-ray, ultrasound, antibiotic prescribing (penicillin V, ampicillins, macrolides, tetracyclines,

cephalosporins, “other antibiotics” and “no antibiotic”).

In Orup, 33 physicians participated in the first

registration, 25 in the second. Twenty GPs who

participated in both registrations were included in

the study and registered 1124 consultations for

RTIs during the first period and 926 during the

second. In the control group the 25 GPs registered

1313 consultations for RTIs during the first period and 1309 during the second.

The proportion of patients not prescribed any

antibiotic increased in both groups—in the intervention group from 45 to 55% and in the control

group from 36 to 40%.

The APO model is a method for internal revision of medical practice. The method is based on

knowledge of recorded aspects of work and, through

discussion, the participants agree on what is better

and what is worse general practice and change their

care accordingly. The registrations are anonymous

and the individual physician’s result is known only

to himself. The APO model has been used on several occasions in Sweden but has not previously

been evaluated.

■ United Kingdom: Tackling antibiotic

resistance in the UK and Europe

A Personal Perspective by Ian M. Gould, Consultant

Microbiologist, Department of Medical Microbiology,

Aberdeen Royal Infirmary, Aberdeen Royal Hospital,

Aberdeen, Scotland. Contact: i.m.gould@abdn.ac.uk

In 1988, the British Society for Antimicrobial

Chemotherapy (BSAC) formed a working party

(WP), having been stimulated into action by the

Infectious Diseases Society of America (IDSA) Task

Force Reports. Up until then, there had been no

national initiatives concerning antibiotic prescribing, which historically was probably at a lower level

than in the United States.

In addition, because of the National Health Service, with free care for all, there was less of an issue

in the costs of antibiotics which, at least in hospitals, amounted to less than 20% of hospital drug

use.
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

150

With a nationwide survey the BSAC WP established which control measures were then operational in UK hospitals, amounts of consumption

in general practice, and educational practices for

medical students. Serious deficiencies were noted

in antibiotic policies and other control measures.

Recommendations were made for minimum

control measures to be implemented in hospitals.

Educational activities were established as sub-optimal and levels of consumption in general practice

were noted to be rising at 2–3% per year (past numbers). However, as measured by DDDs, consumption levels seemed moderate by comparison to many

other European countries (20 DDD/ 1000 patient

days).

These working party reports were published in

1993–4. In subsequent years little seems to have

happened except for local initiatives complicated

by reforms of the National Health Service and introduction of the purchase-provider split which may

have been counter-productive by reducing the use

of laboratory services by general practitioners who

then had to pay for these services. The same costconscious reforms in hospitals led to a marked

reduction in bed numbers with consequent overcrowding, bed shortages, and boarding possibly

leading to an upsurge in nosocomial spread of

multidrug-resistant bacterial clones. There was also

pressure to increase the emphasis on broad-spectrum empiric therapy and reduce the use of timely

laboratory investigations to discharge patients early.

At this time an increase in hospital cases of

C. difficile colitis was attributed to over-zealous interpretation of the British Thoracic Society guidelines for hospital treatment of community-acquired

pneumonia which recommended third generation

cephalosporin therapy for severe pneumonia but

which were commonly re-interpreted as recommending this treatment for any case of pneumonia

requiring hospital admission.

At the time of the House of Lords enquiry into

the problem (1997), which may have been initiated by the personal experiences of one or two of

their Lordships after they or their relatives acquired

a methicillin resistant Staphylococcus aureus (MRSA)

infection in a hospital, there had already been some

activity at a European level with the Commission

starting to give grants for Pan-European surveillance of resistance. Learned societies like the European Society for Biomodulation and Chemotherapy

(ESBIC) and The European Society for Clinical

Microbiology and Infectious Diseases (ESCMID)

formed study groups to study resistance surveillance, nosocomial infection, and antibiotic policies

such as ESGAP (www.escmid.org). Community

action groups such as SWAB (Holland) and

STRAMA (Sweden) were formed to educate both

the public and prescribers; the European Medicines

Evaluation Agency (EMEA) and the Office International des Epizooties (OIE) formed working

groups to address resistance and surveillance issues;

and the Copenhagen meeting brought all the

European Union (EU) countries together to address

the issues in 1998.

The most notable result of this meeting was the

ban on the use of antibiotic growth promoters in

1999, which is currently implemented but is being

debated in the courts by two pharmaceutical manufacturers. Nevertheless, it seems to have had a

major impact on the animal consumption of antibiotics in all European Union countries, if official

figures are to be believed. No doubt there is a large

black market which we know little about.

In light of the House of Lords Report (1998),

the UK government was stimulated into action with

its own expert Standing Medical Advisory Committee Report and its separate response to the House

of Lords Report (1999). The first result of this was

a public education campaign advising patients not

to pressure their doctors to give them antibiotics for

colds and flu and recommending 3 days treatment

for simple UTIs. There is some evidence now, from

this and similar local campaigns, of reduced expectations by patients, but no sudden downturn in community prescribing of antibiotics-there has been a

slow (3%) annual downturn since the mid 1990s.

Meanwhile, the Public Health Laboratory Service in England and Wales (PHLS), WMA (Welsh

Microbiological Association), SMA (Scottish

Microbiology Association) and a local Northern

Ireland initiative have been using computerized

laboratory facilities to organize national surveillance

systems both for nosocomial infection and antibiotic resistance, although all are still in their pilot

phases. The Scottish Government produced two

documents underlining the importance of infection control and nosocomial infection surveillance

and the PHLS published results of a large survey

on nosocomial infection. Combined with a report

from the National Audit Office (NAO) and

others, criticizing the levels of nosocomial infection and poor standards of hospital cleanliness, the

UK government (1999) (and latterly the Scottish

Government) have formed multi-disciplinary

expert advisory groups on antibiotic resistance

surveillance and nosocomial infection.
151

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

It is also the intention to monitor antibiotic consumption and quality of prescribing and there is a

commitment to computerized prescribing in hospitals by 2005 and computer links between laboratories and general practitioners by 2001. All general

practitioners should have had computerized prescribing facilities and links to the Internet by the

end of 2000. At the moment, all prescriptions in

general practice are monitored but there is little data

available on the indications for prescribing.

Approximately 80% of antibiotic consumption

takes place in the community. At the moment there

is no formal measurement of prescribing in hospitals but the little data in the public domain suggests a continued annual increase in cost and DDD,

although, as a percentage of hospital drug budgets,

it probably remains stable at 20%.

The little available comparative data suggests the

UK hospital antibiotic consumption compares

quite well with most European countries (40DDD

per 100 Patient Days). This area is also a priority

for the EU.

It is hoped that the latest round of reforms of

the National Health Service, with its drive to improve quality and ensure better education of and

performance by doctors, will improve antibiotic

prescribing. This includes the introduction of Clinical Governance which intends to make doctors

responsible for the quality of their antibiotic prescribing and empower their employers to ensure

that this quality is achieved. At the moment,

accreditation of doctors (and hospitals) is in its infancy but developing rapidly, and it is hoped that

CPD will have a large part devoted to antibiotic

resistance although legislatively. The matter of how

much can be done legislatively to force the issues

of Antibiotic Resistance and Nosocomial Infection

with hospitals is another matter.

The newly formed Clinical Standards Board

(Scotland) and Commission for Health Improvement (England, Wales & Northern Ireland) should

have the teeth to deal with this and consideration

is being given to benchmarking hospitals of similar types for infection and antibiotic resistance rates.

There are encouraging signs from the government

that they intend hospitals to carry the issue of antibiotic resistance forward as a Strategic Goal.

The drive towards evidence-based guidelines and

policies is slowly progressing with separate government, PHLS, BSAC, Royal College of Physicians,

and other institutions’ initiatives, and the PHLS

have published evidence-based guidance for primary care doctors on the Internet (www.phls.co.uk)

The BSAC has also reformed its Education Working Party and the National Prescribing Centre in

Liverpool has developed a computer self education

and assessment programme for changing doctors’

practices, which looks specifically at antibiotic

prescribing.

With the merger of many pharmaceutical companies, consequent movement out of the UK, and

the development of European Registration of new

antibiotics, there is a great concern in the UK at

the loss of a research base from which to develop

new antibiotics, so new initiatives in this field are

likely. While there are always counter rumors, there

does seem to be a genuine, continued desire both

at a UK and a European level to continue with these

initiatives, not withstanding the politics!

It is too early yet to evaluate the success of any

of this activity. With devolution and the establishment of the Scottish Parliament and the Welsh and

Northern Ireland General Assemblies there is even

more danger of duplication of activities than there

would have been otherwise, so one of the main

concerns will be to ensure coordination. To this end

there are a relatively small number of core opinion-leaders who seem to serve on most of the UK

central and devolved advisory committees and

working parties and it is hoped that they will ensure as little duplication as possible.

At a European level the commission in Luxembourg has an interest in many aspects of the issues

and has recently issued a draft resolution calling

for a publicity campaign with an annual Antibiotic Free Day. They are also interested in as much

harmonization of antibiotic use and control measures between member states as is possible and there

is some possibility of legislative control on measurement of antibiotic consumption, both in

animals and humans. On the issue of antibiotic resistance surveillance, Pan-European initiatives are

proving expensive and there is a move to improving the quality of routinely generated data from

diagnostic laboratories so that it can be used for

European surveillance purposes.

Unfortunately there are several systems of susceptibility testing in common use in Europe in

addition to National Committee for Clinical and

Laboratory Standards (NCCLS). These include

Swedish, French (CA-SFM), German (DIN) and

UK (British Society for Antimicrobial Chemotherapy, BSAC) methods, all with different interpretative criteria. There have been calls for a

European system, perhaps adopting NCCLS in all

countries, but we are nowhere near reaching agree-
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

152

ment. Many people consider the diversity of susceptibility testing methods a strength, especially

when discovering new resistance mechanisms, and

they suggest that establishing comparability

between different systems will be a satisfactory compromise. They have, though, been saying this for

30 years and we don’t seem to be any further forward. Scotland, which does not have a PHLS, has

decided to adopt NCCLS and also the NISS system for nosocomial infection surveillance and Wales

and Northern Ireland may well do the same. England (through the PHLS) looks as though it will

adopt the BSAC methodology for susceptibility

testing and the NINS (Nosocomial Infection

National Surveillance) system for nosocomial

infection surveillance. This latter system uses a different set of risk factors than NISS (Nosocomial

Infection Surveillance System)

■ Scotland: Antimicrobial Resistance

Strategy and Action Plan 2001

Ian M.Gould, Consultant Microbiologist, Department of

Medical Microbiology, Royal Infirmary, Aberdeen Royal

Hospital, Aberdeen, Scotland.

Contact: i.m.gould@abdn.ac.uk

The main causes of antibiotic resistance bacteria in

diseases of humans in the UK at present are:

1. Excess antibiotic use in primary care

2. Excess use in hospitals exacerbated by epidemics of antibiotic resistant bacteria in our hospitals.

The underlying reasons are prescriber ignorance

and lack of ownership of the problem.

Audits repeatedly show poor quality, often completely unnecessary antibiotic prescribing, poor

cleaning standards in hospitals, and poor compliance with infection control procedures. The action

plan concentrates on recommendations to address

these areas with detail on implementation.

In hospitals, audits repeatedly show unnecessary

antibiotic use in the absence of positive microbiology and in patients with no sepsis parameters.

Often unnecessary, expensive, broad spectrum,

toxic agents are administered by the IV route for

too long, in often inappropriate doses. There is both

inappropriate and under-utilization of laboratories.

There is a lack of understanding of how the laboratories can help in therapeutic decision-making,

such as deciding the need for empiric therapy, the

choice of antibiotic, or how to streamline or stop

the therapy. Finally, there is poor compliance with

antibiotic policies.

Poor compliance with policies for hospital cleaning, hand washing, standard precautions, barrier

nursing, and isolation of colonized or infected

patients also occurs due to ignorance, bad practice,

overcrowding, or lack of facilities.

The solutions are:

1. Via education, persuade all doctors, health administration and managers to accept ownership

of the problem.

2. Use incentives, penalties, or extensive, aggressive education to get doctors to change their ways

of practice (known to be very difficult). Implementation and audit should become priorities

for health boards, hospital trusts, etc.

3. Increase resources to allow better patient isolation, improved laboratory facilities, (including

access to them and communication by them),

improved hospital cleanliness, increased staffpatient ratios and reduced overcrowding/boarding of patients.

Animals and horticulture, surveillance and research are all important (but side) issues. We know

there is a major problem, albeit much greater in

most other countries than in the UK, and we

understand enough about the causes to address

them now.
153

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

APPENDIX C

About the authors

August of 1998 was President of the International

Society of Pharmaco-Epidemiology. Dr. Avorn is

the author of over 150 papers in the medical literature on medication use and its outcomes.

John F. Barrett, Ph.D.

Executive Director, Microbiology Department

Bristol-Myers Squibb Company

Pharmaceutical Research Institute

5 Research Parkway

Wallingford, CT 06492-7660

Phone: 203-677-6499

Fax: 203-677-6771

E-mail: john.barrett@bms.com

Currently Executive Director of Anti-Infectives

Research at Bristol-Myers Squibb, Wallingford, CT.

With 16 years experience in the pharmaceutical

industry, he has experience in a wide breadth of

antibacterial and antifungal discovery and development efforts at Pfizer and Johnson & Johnson’s

RW Johnson Pharmaceutical Research Institute. Dr.

Barrett received his B.S. in Biochemistry from Temple University in Philadelphia, PA, and his doctorate in Microbiology and Microbial Physiology from

Temple University School of Medicine, with the

late Gerry Shockman, Ph.D. He completed a

postdoctoral fellowship in genetic engineering with

Roy Curtiss III, Ph.D. (UAB and Washington

University), and joined Pfizer in 1985, RWJPRI in

1989, and BMS in 1997. His research efforts have

included β-lactams, penams, penems, β-lactamase

inhibitors, quinolones, novel gyrase inhibitors, HIV

gp120/CD4 antagonists, cephems, signal transduction inhibitors, virulence factors, and mammalian

topoisomerase II inhibitors. Dr. Barrett is a member of numerous editorial boards and author of over

160 publications, as well as the 1999–2000

Division A Chair of the American Society of Microbiology. He became a Fellow in the American

Academy of Microbiology in 2000. He leads a

group of research scientists seeking the identification and development of novel antimicrobials and

Alliance for the Prudent Use of Antibiotics

(APUA)

75 Kneeland Street

Boston, MA 02111-1901

Phone: 617-636-0966

Fax: 617-636-3999

E-mail: apua@opal.tufts.edu

Jerry L. Avorn, M.D.

Director, Program for the Analysis of Clinical

Strategies

Brigham and Women’s Hospital

Suite 341

221 Longwood Avenue

Boston, MA 02115-5822

Phone: 617-278-0930

E-mail: javorn@partners.org

Associate Professor of Medicine at Harvard Medical School and Chief of the Division of PharmacoEpidemiology and Pharmacoeconomics at Brigham

and Women’s Hospital. An internist, geriatrician,

and pharmaco-epidemiologist, his research centres

on medication use, with particular reference to elderly patients and chronic disease. Topics of particular interest include: scientific, policy, and social

determinants of physician prescribing practices;

efficacy and effectiveness of specific medications;

compliance by patients with prescribed regimens;

methods to improve the appropriateness of drug

prescribing and drug taking; quantification of risks

and benefits of drugs; and pharmaceutical costeffectiveness analysis. Dr. Avorn is also director of

the Program for the Analysis of Clinical Strategies,

a research unit with faculty and staff representing

the disciplines of epidemiology, internal medicine,

health services research, psychiatry, and biostatistics. He attended Columbia College and Harvard

Medical School, and completed a residency in

internal medicine at the Beth Israel Hospital in Boston. Dr. Avorn serves on several national and

international panels as an expert on the determinants and outcomes of medication use, and until
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10

154

antifungals through a combination of classical discovery strategies and techniques and a proprietary

genomics effort. Dr. Barrett has been involved with

the development of several antibacterials currently

on the market including ofloxacin, levofloxacin, and

gatifloxacin, and is currently working on the development of a novel MRSA-cephem (BMS247243) and the des-quinolone (BMS-284756/

T-3811) at Bristol-Myers Squibb.

Peter G. Davey, M.D.

Professor of Clinical Pharmacology

University of Dundee

Nethergate, Dundee DD1 4HN

Scotland, UK

Phone: +44 (0)1382 660111

E-mail: peter@memo.dundee.ac.uk

Has expertise in clinical pharmacology, infectious

diseases, and health economics. He has served as a

Professor of Pharmacoeconomics, Clinical Pharmacology and Infectious Diseases at the University of

Dundee, Scotland. Among his many teaching activities, he has developed new curricula focusing

on antimicrobials for a number of courses for medical and dental students. He has extensive research

experience, including clinical trials and evaluations

of antimicrobials, assessments of antimicrobial action in vitro and in experimental animals; clinical

pharmacokinetic studies of antimicrobials, and

studies of gentamicin treatment. Since 1996, Dr.

Davey has served as Head of Pharmacoeconomics

for the Medicines Monitoring Unit (MEMO),

where he focuses on economic evaluation and outcomes research of drug treatment, and on antibiotic policies and their influence on the development

of drug resistance in hospitals and the community.

He has helped develop treatment guidelines and

national policies on antibiotic use in Scotland,

served as an advisor to the House of Lords Commission on Antimicrobial Resistance, and has

spoken extensively on antimicrobial use at international symposia, conferences, and meetings.

Stuart B. Levy, M.D.

President, Alliance for the Prudent Use of Antibiotics

Room 704, South Cove

Tufts University School of Medicine

136 Harrison Avenue

Boston, MA 02111-1817

Phone: 617-636-6765

Fax: 617-636-0458

E-mail: stuart.levy@tufts.edu

President and founder of the Alliance for the Prudent Use of Antibiotics, and immediate past president of the American Society for Microbiology. A

microbiologist and physician, Dr. Levy discovered

the mechanism for tetracycline resistance (efflux)

and was among the first to document the transfer

of drug resistance among animals and humans. Dr.

Levy is the author of one of the most important

books on the subject, The Antibiotic Paradox: How

Miracle Drugs are Destroying the Miracle, which has

been widely cited in both the lay and scientific

media. He has also written more than 200 scientific and medical papers and special journal editions on the topic. A world-renowned leader in the

field of antibiotic use and resistance, he has chaired

and served on numerous national and international

advisory boards and committees, including: the

NIH Fogarty Center’s study on The Use of Antibiotics Worldwide (as Chairman); the advisory panel

for the USA Office of Technology Assessment report on the Impacts of Antibiotic Resistant Bacteria; the EPA Subcommittees on Health and

Antibiotic Resistance; and the WHO Scientific

Advisory Group on Antimicrobial Resistance. Dr.

Levy has also served as a consultant for the World

Health Organization, the USA FDA, the National

Institutes of Health, and other national and international organizations. He is currently Professor of

Medicine and of Molecular Biology/Microbiology,

the Director of the Center for Adaptation Genetics and Drug Resistance at Tufts University School

of Medicine, and a Staff Physician at the New England Medical Center.

Scott A. McEwen, D.V.M.

Professor, Department of Population Medicine

University of Guelph

Guelph, Ontario N1G 2W1

Canada

Phone: 519-824-4120, ext. 4751

E-mail: smcewen@uoguelph.ca

Professor in the Department of Population Medicine, Ontario Veterinary College, University of

Guelph. He is a veterinarian whose research focuses

on the epidemiology of food-borne infections in

food animal populations, particularly Salmonella,

E. coli and antibiotic resistant organisms. He has
155

WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

conducted extensive research on human health

impacts of antimicrobial use in animals, including

studies of antibiotic and chemical residues in milk

and meat, and the association between resistance

and antibiotic use on farms, and has published more

than 80 papers in peer review journals. Dr. McEwen

has served as a consultant for WHO on the human

health impact of antimicrobials in food animals,

and as panel member for the U.S. FDA on antimicrobial resistance risk assessment. He also chaired

the Health Canada Advisory Committee on Animal Uses of Antimicrobials and their Impact on

Resistance and Human Health. Dr. McEwen

teaches food safety to veterinary students and graduate students at the University of Guelph.

Thomas F. O’Brien, M.D.

Medical Director, Microbiology Lab

Brigham and Women’s Hospital

75 Francis Street

Boston, MA 02115-6110

Phone: 617-732-6803

E-mail: tobrien@rics.bwh.harvard.edu

Vice President of APUA, is a leading authority on

antibiotic resistance and AMR surveillance. An infectious disease specialist and microbiologist, Dr.

O’Brien helped develop the WHONET surveillance program. He also set up the WHO Collaborating Center for Surveillance of Resistance to

Antimicrobial Agents at Brigham and Women’s

Hospital in Boston in 1985, which has established

an international network of microbiology laboratories dealing with antimicrobial resistance surveillance. Dr. O’Brien has served as an advisor on

numerous national and international committees

dealing with antimicrobial resistance, including the

NIH Task Force on Antibiotic Resistance, which

he chaired from 1984 to 1986; the WHO Scientific Working Group on AMR (1981); the FDA’s

Veterinary Medicine Advisory Committee (since

1994); the Office of Technology Assessment

Advisory Panel on Impacts of Antibiotic-Resistant

Bacteria; the Inter-Agency (FDA, CDC, USDA)

Working Group on Antimicrobial Resistance; and

the CDC Working Group on Drug Resistant Streptococcus pneumoniae. He has also served as a consultant on antimicrobial resistance to WHO (in

Geneva and Manila), PAHO, the British House of

Lords, and the National Health Research Institute

of Taiwan, among others. Medical Director of the

Microbiology Laboratory at Brigham and Women’s Hospital for the past 20 years, Dr. O’Brien is a

pioneering researcher in the area of antimicrobial

resistance, having conducted microbiological studies on resistance since the mid-1960s.