WHO/CDS/CSR/DRS/2001.2DISTR: GENERALORIGINAL: ENGLISH

WHO GlobalStrategy forContainmentof AntimicrobialResistance

World Health Organization

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Copies can be obtained from the CDS Information Resource CentreWorld Health Organization, 1211 Geneva 27, Switzerland

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WHO/CDS/CSR/DRS/2001.2ORIGINAL: ENGLISHDISTRIBUTION: GENERAL

WHO GlobalStrategy forContainmentof AntimicrobialResistance

World Health Organization

Acknowledgements

The World Health Organization (WHO) wishes to acknowledge with gratitude the significant supportfrom the United States Agency for International Development (USAID) and additional assistance forthis work from the United Kingdom Department for International Development and the Ministry ofHealth, Labour and Welfare, Japan.

This strategy is the product of collaborative efforts across WHO, particularly in the clusters of Commu-nicable Diseases, Health Technology and Pharmaceuticals, and Family and Community Health, withsignificant input from the staff at WHO Regional Offices and from many partners working with WHOworldwide. In particular, WHO would like to acknowledge the important contributions made to thedrafting of the strategy by Professor W Stamm, Professor ML Grayson, Professor L Nicolle and Dr MPowell, and the generosity of their respective institutions—Infectious Diseases Department, HarborviewMedical Center, University of Washington, Seattle, USA; Infectious Diseases and Clinical Epidemiol-ogy Department, Monash Medical Centre, Monash University, Melbourne, Australia; Department ofInternal Medicine, University of Manitoba, Winnipeg, Canada; Medicines Control Agency, LondonUK—that enabled them to spend time at WHO.

WHO also wishes to thank all those who participated and contributed their expertise in the consulta-tions (see Annex B) and those individuals and organizations that provided valuable comments on draftsof this document.

© World Health Organization 2001

This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by theOrganization. The document may, however, be freely reviewed, abstracted, reproduced and translated, in part or in whole, butnot 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 theexpression of any opinion whatsoever on the part of the secretariat of the World Health Organization concerning the legal statusof any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dottedlines 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 recom-mended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the namesof proprietary products are distinguished by initial capital letters.

Designed by minimum graphicsPrinted in Switzerland

Contents

iii

Executive Summary 1

Summary of recommendations for intervention 3

Part A. Introduction and background 9

Introduction 11Antimicrobial resistance is a global problem that needs urgent action 11A global problem calls for a global response 12Implementation of the WHO Global Strategy 13

Background 15What is antimicrobial resistance? 15Appropriate use of antimicrobials 15Surveillance of antimicrobial resistance 15The prevalence of resistance 16Conclusion 16

Part B. Appropriate antimicrobial use and emerging resistance: issues and interventions 19

Chapter 1. Patients and the general community 21Chapter 2. Prescribers and dispensers 25Chapter 3. Hospitals 31Chapter 4. Use of antimicrobials in food-producing animals 37Chapter 5. National governments and health systems 41Chapter 6. Drug and vaccine development 47Chapter 7. Pharmaceutical promotion 51Chapter 8. International aspects of containing antimicrobial resistance 55

Part C. Implementation of the WHO Global Strategy 61

Introduction 63Prioritization and implementation 63Implementation guidelines 66Monitoring outcomes 66Summary 67Recommendations for intervention 68Tables 71Suggested model framework for implementation of core interventions 76

References 83

Annexes 93

Annex A. National Action Plans 95Annex B. Participation in WHO Consultations 96

1

Executive Summary

■ Resistance is only just beginning to be consid-ered as a societal issue and, in economic terms, asa negative externality in the health care context.Individual decisions to use antimicrobials (takenby the consumer alone or by the decision-makingcombination of health care worker and patient)often ignore the societal perspective and the per-spective of the health service.

■ The World Health Assembly (WHA) Resolu-tion of 1998 (1) urged Member States to developmeasures to encourage appropriate and cost-effective use of antimicrobials, to prohibit the dis-pensing of antimicrobials without the prescriptionof a qualified health care professional, to improvepractices to prevent the spread of infection andthereby the spread of resistant pathogens, tostrengthen legislation to prevent the manufacture,sale and distribution of counterfeit antimicrobialsand the sale of antimicrobials on the informalmarket, and to reduce the use of antimicrobials infood-animal production. Countries were also en-couraged to develop sustainable systems to detectresistant pathogens, to monitor volumes and pat-terns of use of antimicrobials and the impact ofcontrol measures.

■ Since the WHA Resolution, many countrieshave expressed growing concern about the prob-lem of antimicrobial resistance and some havedeveloped national action plans to address theproblem. Despite the mass of literature on anti-microbial resistance, there is depressingly little onthe true costs of resistance and the effectiveness ofinterventions. Given this lack of data in the faceof a growing realization that actions need to betaken now to avert future disaster, the challenge iswhat to do and how to do it.

■ The WHO Global Strategy for Containmentof Antimicrobial Resistance addresses this chal-lenge. It provides a framework of interventions toslow the emergence and reduce the spread of anti-microbial-resistant microorganisms through:

■ Deaths from acute respiratory infections,diarrhoeal diseases, measles, AIDS, malaria andtuberculosis account for more than 85% of themortality from infection worldwide. Resistance tofirst-line drugs in most of the pathogens causingthese diseases ranges from zero to almost 100%.In some instances resistance to second- and third-line agents is seriously compromising treatmentoutcome. Added to this is the significant globalburden of resistant hospital-acquired infections,the emerging problems of antiviral resistance andthe increasing problems of drug resistance in theneglected parasitic diseases of poor and mar-ginalized populations.

■ Resistance is not a new phenomenon; it wasrecognized early as a scientific curiosity and thenas a threat to effective treatment outcome. How-ever, the development of new families ofantimicrobials throughout the 1950s and 1960sand of modifications of these molecules throughthe 1970s and 1980s allowed us to believe that wecould always remain ahead of the pathogens. Bythe turn of the century this complacency had cometo haunt us. The pipeline of new drugs is runningdry and the incentives to develop new anti-microbials to address the global problems of drugresistance are weak.

■ Resistance costs money, livelihoods and livesand threatens to undermine the effectiveness ofhealth delivery programmes. It has recently beendescribed as a threat to global stability and na-tional security. A few studies have suggested thatresistant clones can be replaced by susceptible ones;in general, however, resistance is slow to reverseor is irreversible.

■ Antimicrobial use is the key driver of resistance.Paradoxically this selective pressure comes from acombination of overuse in many parts of the world,particularly for minor infections, misuse due tolack of access to appropriate treatment and under-use due to lack of financial support to completetreatment courses.

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— reducing the disease burden and the spreadof infection

— improving access to appropriate anti-microbials

— improving use of antimicrobials— strengthening health systems and their sur-

veillance capabilities— enforcing regulations and legislation— encouraging the development of appropri-

ate new drugs and vaccines.

■ The strategy highlights aspects of the contain-ment of resistance and the need for further researchdirected towards filling the existing gaps in knowl-edge.

■ The strategy is people-centred, with interven-tions directed towards the groups of people whoare involved in the problem and need to be partof the solution, i.e. prescribers and dispensers,veterinarians, consumers, policy-makers in hos-pitals, public health and agriculture, professionalsocieties and the pharmaceutical industry.

■ The strategy addresses antimicrobial resistancein general rather than through a disease-specificapproach, but is particularly focused on resistanceto antibacterial drugs.

■ Much of the responsibility for implementationof the strategy will fall on individual countries.Governments have a critical role to play in the

provision of public goods such as information, insurveillance, analysis of cost-effectiveness andcross-sectoral coordination.

■ Given the complex nature of antimicrobial re-sistance, the strategy necessarily contains a largenumber of recommendations for interventions.Prioritization of the implementation of these in-terventions needs to be customized to nationalrealities. To assist in this process an implementa-tion approach has been defined together withindicators for monitoring implementation andoutcomes.

■ Recognition that the problem of resistanceexists and the creation of effective national inter-sectoral task forces are considered critical to thesuccess of implementation and monitoring ofinterventions. International interdisciplinary co-operation will also be essential.

■ Improving antimicrobial use must be a keyaction in efforts to contain resistance. This requiresimproving access and changing behaviour; suchchanges take time.

■ Containment will require significant strength-ening of the health systems in many countries andthe costs of implementation will not be negligi-ble. However, such costs must be weighed againstfuture costs averted by the containment of wide-spread antimicrobial resistance.

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1.3 Educate patients on simple measures that

may reduce transmission of infection in the

household and community, such as

handwashing, food hygiene, etc.

1.4 Encourage appropriate and informed

health care seeking behaviour.

1.5 Educate patients on suitable alternatives to

antimicrobials for relief of symptoms and

discourage patient self-initiation of treat-

ment, except in specific circumstances.

2 PRESCRIBERS AND DISPENSERS

Education2.1 Educate all groups of prescribers and dis-

pensers (including drug sellers) on the im-

portance of appropriate antimicrobial use

and containment of antimicrobial resist-

ance.

2.2 Educate all groups of prescribers on dis-

ease prevention (including immunization)

and infection control issues.

2.3 Promote targeted undergraduate and

postgraduate educational programmes on

the accurate diagnosis and management

of common infections for all health care

workers, veterinarians, prescribers and dis-

pensers.

2.4 Encourage prescribers and dispensers to

educate patients on antimicrobial use and

the importance of adherence to prescribed

treatments.

2.5 Educate all groups of prescribers and dis-

pensers on factors that may strongly influ-

ence their prescribing habits, such as

economic incentives, promotional activi-

ties and inducements by the pharmaceu-

tical industry.

Management, guidelines and formularies2.6 Improve antimicrobial use by supervision

and support of clinical practices, especially

diagnostic and treatment strategies.

Patients and the general community &prescribers and dispensers

The emergence of antimicrobial resistance is acomplex problem driven by many interconnectedfactors, in particular the use and misuse ofantimicrobials. Antimicrobial use, in turn, is in-fluenced by an interplay of the knowledge, expec-tations and interactions of prescribers and patients,economic incentives, characteristics of the healthsystem(s) and the regulatory environment. In thelight of this complexity, coordinated interventionsare needed that simultaneously target the behav-iour of providers and patients and change impor-tant features of the environments in which theyinteract. These interventions are most likely to besuccessful if the following factors are understoodwithin each health setting:

• which infectious diseases and resistance prob-lems are important

• which antimicrobials are used and by whom• what factors determine patterns of antimi-

crobial use• what the relative costs and benefits are from

changing use• what barriers exist to changing use.

Although the interventions directed towardsproviders and patients are presented separately (1and 2) for clarity, they will require implementa-tion in an integrated fashion.

1 PATIENTS AND THE GENERALCOMMUNITY

Education1.1 Educate patients and the general commu-

nity on the appropriate use of antimicro-

bials.

1.2 Educate patients on the importance of

measures to prevent infection, such as im-

munization, vector control, use of bednets,

etc.

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2.7 Audit prescribing and dispensing practices

and utilize peer group or external stand-

ard comparisons to provide feedback and

endorsement of appropriate antimicrobial

prescribing.

2.8 Encourage development and use of guide-

lines and treatment algorithms to foster

appropriate use of antimicrobials.

2.9 Empower formulary managers to limit

antimicrobial use to the prescription of an

appropriate range of selected anti-

microbials.

Regulation2.10 Link professional registration requirements

for prescribers and dispensers to require-

ments for training and continuing educa-

tion.

Hospitals

Although most antimicrobial use occurs in thecommunity, the intensity of use in hospitals is farhigher; hospitals are therefore particularly impor-tant in the containment of antimicrobial resist-ance. In hospitals it is crucial to develop integratedapproaches to improving the use of antimicrobials,reducing the incidence and spread of hospital-ac-quired (nosocomial) infections, and linking thera-peutic and drug supply decision-making. This willrequire training of key individuals and the alloca-tion of resources to effective surveillance, infec-tion control and therapeutic support.

3 HOSPITALS

Management3.1 Establish infection control programmes,

based on current best practice, with the

responsibility for effective management of

antimicrobial resistance in hospitals and

ensure that all hospitals have access to

such a programme.

3.2 Establish effective hospital therapeutics

committees with the responsibility for

overseeing antimicrobial use in hospitals.

3.3 Develop and regularly update guidelines

for antimicrobial treatment and prophy-

laxis, and hospital antimicrobial formular-

ies.

3.4 Monitor antimicrobial usage, including the

quantity and patterns of use, and feedback

results to prescribers.

Diagnostic laboratories3.5 Ensure access to microbiology laboratory

services that match the level of the hospi-

tal, e.g. secondary, tertiary.

3.6 Ensure performance and quality assurance

of appropriate diagnostic tests, microbial

identification, antimicrobial susceptibility

tests of key pathogens, and timely and rel-

evant reporting of results.

3.7 Ensure that laboratory data are recorded,

preferably on a database, and are used to

produce clinically- and epidemiologically-

useful surveillance reports of resistance

patterns among common pathogens and

infections in a timely manner with feed-

back to prescribers and to the infection

control programme.

Interactions with the pharmaceuticalindustry3.8 Control and monitor pharmaceutical com-

pany promotional activities within the hos-

pital environment and ensure that such

activities have educational benefit.

Use of antimicrobials in food-producinganimals

A growing body of evidence establishes a linkbetween the use of antimicrobials in food-produc-ing animals and the emergence of resistance amongcommon pathogens. Such resistance has an im-pact on animal health and on human health ifthese pathogens enter the food chain. The factorsaffecting such antimicrobial use, whether for thera-peutic, prophylactic or growth promotion pur-poses, are complex and the required interventionsneed coordinated implementation. The underly-ing principles of appropriate antimicrobial use andcontainment of resistance are similar to thoseapplicable to humans. The WHO global princi-ples for the containment of antimicrobial resist-ance in animals intended for food (2) were adoptedat a WHO consultation in June 2000 in Geneva.They provide a framework of recommendationsto reduce the overuse and misuse of antimicrobialsin food animals for the protection of humanhealth. Antimicrobials are widely used in a vari-ety of other settings outside human medicine, e.g.horticulture and aquaculture, but the risks tohuman health from such uses are less well under-stood and they have not been included in thisdocument.

5

4 USE OF ANTIMICROBIALS IN FOOD-PRODUCING ANIMALS

This topic has been the subject of specific con-

sultations which resulted in “WHO global prin-

ciples for the containment of antimicrobial

resistance in animals intended for food”*. A

complete description of all recommendations

is contained in that document and only a sum-

mary is reproduced here.

Summary4.1 Require obligatory prescriptions for all

antimicrobials used for disease control in

food animals.

4.2 In the absence of a public health safety

evaluation, terminate or rapidly phase out

the use of antimicrobials for growth pro-

motion if they are also used for treatment

of humans.

4.3 Create national systems to monitor antimi-

crobial usage in food animals.

4.4 Introduce pre-licensing safety evaluation

of antimicrobials with consideration of

potential resistance to human drugs.

4.5 Monitor resistance to identify emerging

health problems and take timely corrective

actions to protect human health.

4.6 Develop guidelines for veterinarians to re-

duce overuse and misuse of antimicrobials

in food animals.

* http:// www.who.int/emc/diseases/zoo/

who_global_principles.html

National governments and health systems

Government health policies and the health caresystems in which they are implemented play a cru-cial role in determining the efficacy of interven-tions to contain antimicrobial resistance. Nationalcommitment to understand and address the prob-lem and the designation of authority and respon-sibility are prerequisites. Effective action requiresthe introduction and enforcement of appropriateregulations and allocation of appropriate resourcesfor education and surveillance. Constructive in-teractions with the pharmaceutical industry arecritical, both for ensuring appropriate licensure,promotion and marketing of existingantimicrobials and for encouraging the develop-ment of new drugs and vaccines. For clarity, in-terventions relating to these interactions with theindustry are shown in separate recommendationgroups (6 and 7).

5 NATIONAL GOVERNMENTS ANDHEALTH SYSTEMS

Advocacy and intersectoral action5.1 Make the containment of antimicrobial

resistance a national priority.

— Create a national intersectoral task

force (membership to include health

care professionals, veterinarians,

agriculturalists, pharmaceutical manu-

facturers, government, media repre-

sentatives, consumers and other

interested parties) to raise awareness

about antimicrobial resistance, organ-

ize data collection and oversee local

task forces. For practical purposes such

a task force may need to be a govern-

ment task force which receives input

from multiple sectors.

— Allocate resources to promote the

implementation of interventions to

contain resistance. These interventions

should include the appropriate utiliza-

tion of antimicrobial drugs, the control

and prevention of infection, and re-

search activities.

— Develop indicators to monitor and

evaluate the impact of the antimicro-

bial resistance containment strategy.

Regulations5.2 Establish an effective registration scheme

for dispensing outlets.

5.3 Limit the availability of antimicrobials to

prescription-only status, except in special

circumstances when they may be dis-

pensed on the advice of a trained health

care professional.

5.4 Link prescription-only status to regulations

regarding the sale, supply, dispensing and

allowable promotional activities of antimi-

crobial agents; institute mechanisms to

facilitate compliance by practitioners and

systems to monitor compliance.

5.5 Ensure that only antimicrobials meeting

international standards of quality, safety

and efficacy are granted marketing

authorization.

5.6 Introduce legal requirements for manufac-

turers to collect and report data on anti-

microbial distribution (including import/

export).

5.7 Create economic incentives for the appro-

priate use of antimicrobials.

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Policies and guidelines5.8 Establish and maintain updated national

Standard Treatment Guidelines (STGs) and

encourage their implementation.

5.9 Establish an Essential Drugs List (EDL) con-

sistent with the national STGs and ensure

the accessibility and quality of these drugs.

5.10 Enhance immunization coverage and other

disease preventive measures, thereby re-

ducing the need for antimicrobials.

Education5.11 Maximize and maintain the effectiveness

of the EDL and STGs by conducting appro-

priate undergraduate and postgraduate

education programmes of health care

professionals on the importance of appro-

priate antimicrobial use and containment

of antimicrobial resistance.

5.12 Ensure that prescribers have access to ap-

proved prescribing literature on individual

drugs.

Surveillance of resistance, antimicrobialusage and disease burden5.13 Designate or develop reference microbiol-

ogy laboratory facilities to coordinate

effective epidemiologically sound surveil-

lance of antimicrobial resistance among

common pathogens in the community,

hospitals and other health care facilities.

The standard of these laboratory facilities

should be at least at the level of recom-

mendation 3.6.

5.14 Adapt and apply WHO model systems

for antimicrobial resistance surveillance

and ensure data flow to the national inter-

sectoral task force, to authorities responsi-

ble for the national STGs and drug policy,

and to prescribers.

5.15 Establish systems for monitoring antimi-

crobial use in hospitals and the community,

and link these findings to resistance and

disease surveillance data.

5.16 Establish surveillance for key infectious

diseases and syndromes according to

country priorities, and link this information

to other surveillance data.

6 DRUG AND VACCINE DEVELOPMENT6.1 Encourage cooperation between industry,

government bodies and academic institu-

tions in the search for new drugs and

vaccines.

6.2 Encourage drug development pro-

grammes which seek to optimize treat-

ment regimens with regard to safety,

efficacy and the risk of selecting resistant

organisms.

6.3 Provide incentives for industry to invest in

the research and development of new

antimicrobials.

6.4 Consider establishing or utilizing fast-track

marketing authorization for safe new

agents.

6.5 Consider using an orphan drug scheme

where available and applicable.

6.6 Make available time-limited exclusivity for

new formulations and/or indications for

use of antimicrobials.

6.7 Align intellectual property rights to pro-

vide suitable patent protection for new

antimicrobial agents and vaccines.

6.8 Seek innovative partnerships with the

pharmaceutical industry to improve access

to newer essential drugs.

7 PHARMACEUTICAL PROMOTION7.1 Introduce requirements for pharmaceuti-

cal companies to comply with national or

international codes of practice on promo-

tional activities.

7.2 Ensure that national or international codes

of practice cover direct-to-consumer

advertising, including advertising on the

Internet.

7.3 Institute systems for monitoring compli-

ance with legislation on promotional

activities.

7.4 Identify and eliminate economic incentives

that encourage inappropriate antimicro-

bial use.

7.5 Make prescribers aware that promotion in

accordance with the datasheet may not

necessarily constitute appropriate antimi-

crobial use.

7

8 INTERNATIONAL ASPECTS OFCONTAINING ANTIMICROBIALRESISTANCE

8.1 Encourage collaboration between govern-

ments, non-governmental organizations,

professional societies and international

agencies to recognize the importance of

antimicrobial resistance, to present consist-

ent, simple and accurate messages regard-

ing the importance of antimicrobial use,

antimicrobial resistance and its contain-

ment, and to implement strategies to con-

tain resistance.

8.2 Consider the information derived from the

surveillance of antimicrobial use and anti-

microbial resistance, including the contain-

ment thereof, as global public goods for

health to which all governments should

contribute.

8.3 Encourage governments, non-governmen-

tal organizations, professional societies and

international agencies to support the es-

tablishment of networks, with trained staff

and adequate infrastructures, which can

undertake epidemiologically valid surveil-

lance of antimicrobial resistance and anti-

microbial use to provide information for

the optimal containment of resistance.

8.4 Support drug donations in line with the UN

interagency guidelines*.

8.5 Encourage the establishment of interna-

tional inspection teams qualified to con-

duct valid assessments of pharmaceutical

manufacturing plants.

8.6 Support an international approach to the

control of counterfeit antimicrobials in line

with the WHO guidelines**.

8.7 Encourage innovative approaches to

incentives for the development of new

pharmaceutical products and vaccines for

neglected diseases.

8.8 Establish an international database of

potential research funding agencies with

an interest in antimicrobial resistance.

8.9 Establish new, and reinforce existing, pro-

grammes for researchers to improve the

design, preparation and conduct of re-

search to contain antimicrobial resistance.

* Interagency Guidelines. Guidelines for Drug

Donations, revised 1999. Geneva, World

Health Organization, 1999. WHO/EDM/PAR/

99.4.

** Counterfeit drugs. Guidelines for the develop-

ment of measures to combat counterfeit drugs.

Geneva, World Health Organization, 1999.

WHO/EDM/QSM/99.1.

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PART A

Introduction andbackground

Introduction

expensive drugs to treat a fraction of thepopulation needing treatment, or to increasehealth care expenditure.

• Ineffective therapy leads to increased costsassociated with prolonged illness, morefrequent hospital admissions and longerperiods of hospitalization. In addition,resistant pathogens in the hospital environ-ment result in hospital-acquired infectionswhich are expensive to control and extremelydifficult to eradicate.

• The use of antimicrobials outside the fieldof human medicine also has an impact onhuman health. Resistant microorganisms infood-producing animals may have majorfinancial implications for both farmers andconsumers. Resistant animal pathogens insome food products, especially meat, maycause infections in humans that are difficultto treat. In addition, loss of public confi-dence in the safety of food affects the de-mand for products, with potentially seriouseconomic effects on the farming sector.

Risk management and national security

Antimicrobial resistance threatens other healthcare gains. For example, co-infection with HIVand antimicrobial-resistant pathogens, e.g. tuber-culosis, salmonellosis, other sexually transmittedinfections, may result in rapid disease progressionin the infected individual and has a potentialmultiplier effect on the dissemination of resistantpathogens to the rest of the population—therebyplacing more demands on health care resources.The emergence of antimicrobial resistance isregarded as a major future threat to the securityand political stability of some regions (5).

Antimicrobial resistance is frequently irreversible

Although a few studies (6,7) have suggested thatresistant clones can be replaced by susceptible ones,

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Antimicrobial resistance is a globalproblem that needs urgent action

Deaths from acute respiratory infections, diar-rhoeal diseases, measles, AIDS, malaria andtuberculosis account for more than 85% of themortality from infection worldwide (3). Resist-ance to first-line drugs in the pathogens causingthese diseases ranges from zero to almost 100%.In some instances resistance to second- and third-line agents is seriously compromising treatmentoutcome. Added to these major killers is thesignificant global burden of hospital-acquired(nosocomial) infections usually caused by resist-ant pathogens, the emerging problems of antivi-ral resistance and the increasing threats of drugresistance in parasitic diseases such as Africantrypanosomiasis and leishmaniasis.

The massive increases in trade and humanmobility brought about by globalization haveenabled the rapid spread of infectious agents, in-cluding those that are drug resistant. While richercountries, to a large extent, are still able to rely onthe latest antimicrobials to treat resistant infec-tions, access to these life-saving drugs is often lim-ited or totally absent in many parts of the world.Urgent global action is needed, as outlined below.

Costs of resistance

The relentless emergence of antimicrobial resist-ance has an impact on the cost of health careworldwide. Ineffective therapy due to antimicro-bial resistance is associated with increased humansuffering, lost productivity and often death. De-spite a dearth of data on the costs of resistance(4), there is growing consensus about the follow-ing points.

• In many regions the prevalence of resistanceamong common pathogens to readily avail-able cheap antimicrobials is so high thatthese agents are now of limited clinicaleffectiveness. Increasingly, this results in dif-ficult choices: to spend money on cheapuseless drugs, to use more effective but more

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resistance is generally slow to reverse or is irre-versible. This suggests that interventions to stopthe development of resistance should be imple-mented early, before resistance becomes a prob-lem. The earlier interventions are implemented,the slower will be the development of resistance(4). However, this implies taking action before theprevalence of resistant infections climbs, based ondecisions made whilst the number of people suf-fering resistant infections is low. Antimicrobialresistance is only just beginning to be consideredas a societal issue and, in economic terms, as anegative externality (8,9). Individual decisions touse antimicrobials (taken by the consumer aloneor by the decision-making combination of pre-scriber and patient) often ignore the societal per-spective and the perspective of the health service.

A dwindling supply of new antimicrobials

The development of new antimicrobial agentseffective against resistant pathogens and of alter-native approaches such as vaccines is crucial to re-duce the future impact of resistance. However, newagents are expensive and time-consuming todevelop. Interest in antimicrobial research and de-velopment among the research-based pharmaceu-tical industry has declined as infectious diseasesin richer country populations appear to have beenconquered and as priorities have shifted to thedevelopment of lifestyle drugs. Unless the currentrate of emerging resistance is controlled and slowedto preserve the life of existing drugs, this declinein new antimicrobial development, even if reversednow, is likely to result in the absence of effectivetherapies for some pathogens within the next tenyears.

A global problem calls for a global response

There can be no doubt that antimicrobial resist-ance poses a global challenge. No single nation,however effective it is at containing resistancewithin its boundaries, can protect itself from theimportation of resistant pathogens through traveland trade. The global nature of resistance calls fora global response, not only in the geographic sense,i.e. across national boundaries, but also across thewhole range of sectors involved. Nobody is ex-empt from the problem, nor from playing a rolein the solution.

The response of the World Health Organiza-tion is to:

• raise awareness of the problems posed byantimicrobial resistance

• promote the sharing of information aboutand understanding of resistance

• provide strategic and technical guidance oninterventions to contain resistance

• assist Member States to implement theseinterventions

• stimulate research to address the knowledgegaps and improve understanding of antimi-crobial resistance and to encourage researchand development of new antimicrobialagents.

Development of the WHO Global Strategy

Following the Resolution on Antimicrobial Re-sistance in 1998 (1), WHO has worked with manypartners to develop the WHO Global Strategy forContainment of Antimicrobial Resistance (referredto as the WHO Global Strategy hereafter). Theaim of this strategy is to provide, for all MemberStates, a framework of interventions to stimulatethe prevention of infection, to slow the emergenceof resistance and to reduce the spread of resistantmicroorganisms, in order to reduce the impact ofresistance on health and health care costs, whileimproving access to existing agents and encour-aging the development of new agents. The strat-egy has been formulated on the basis of expertopinion, published evidence, commissioned re-views and the deliberations of international andnational bodies (see Annex B) on the key factorscontributing to antimicrobial resistance and theinterventions needed for its containment. Basedon these inputs, a series of recommendations isproposed, directed towards the aims stated above.Part B of this document provides a summary ofthe evidence on which the recommendations arebased.

It is important to recognize that much remainsto be learnt about the interplay between the fac-tors responsible for the emergence and spread ofresistance and the optimization and cost-effective-ness of appropriate interventions. However, theurgency of the situation requires that implemen-tation of the WHO Global Strategy moves for-ward on the evidence currently available.

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Implementation of theWHO Global Strategy

The approach to implementation is crucial to itsefficacy and success. Much of the responsibilityfor implementing interventions will fall on indi-vidual Member States. There are certain actionsthat only governments can assure, including theprovision of public goods such as information,surveillance and analysis of cost-effectiveness ofinterventions, and the cross-sectoral coordinationcritical for an effective response (10). Given thelarge number of recommendations for the con-

tainment of antimicrobial resistance presentedhere, there is a practical need for prioritization andcustomization to the individual national setting.To assist in the implementation of the WHO Glo-bal Strategy, an approach to defining a smaller coreset of recommendations is presented (Part C).Furthermore, since antimicrobial resistance is aclearly a global issue, international interdiscipli-nary cooperation is critical and the areas in whichthis can be most effective are outlined (Part B,Chapter 8).

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Background

Appropriate use of antimicrobials

The WHO Global Strategy defines the appropri-ate use of antimicrobials as the cost-effective use ofantimicrobials which maximizes clinical therapeu-tic effect while minimizing both drug-related toxic-ity and the development of antimicrobial resistance.

The general principles of appropriate antimi-crobial use (11) are the same as those for all othermedicinal products. An additional dimension forantimicrobials is that therapy for the individualmay affect the health of society as a result of theselective pressure exerted by all use of antimicro-bial agents. In addition, therapeutic failures dueto drug-resistant pathogens or superinfections leadto an increased potential for the spread of theseorganisms throughout hospitals and the commu-nity. Although these risks occur even whenantimicrobials are used appropriately, inappropri-ate use increases the overall selective pressure infavour of drug-resistant microorganisms.

The choice of an appropriate antimicrobialagent may be straightforward when the causativepathogen(s) is/are known or can be presumed withsome certainty from the patient’s clinical presen-tation. However, in the absence of reliable micro-biological diagnosis or when several pathogens maybe responsible for the same clinical presentation,empiric treatment, often with broad-spectrumantimicrobials, is common. Ideally, the choice ofantimicrobial should be guided by local or nationalresistance surveillance data and treatment guide-lines. The reality is often far removed from thisideal.

Surveillance of antimicrobial resistance

Surveillance of antimicrobial resistance is essen-tial for providing information on the magnitudeand trends in resistance and for monitoring theeffect of interventions. The actions taken on thebasis of surveillance data will depend on the levelat which the data are being collected and analysed.For example, local surveillance data should be usedto guide clinical management and to update treat-

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What is antimicrobial resistance?

Resistance to antimicrobials is a natural biologi-cal phenomenon. The introduction of every anti-microbial agent into clinical practice has beenfollowed by the detection in the laboratory ofstrains of microorganisms that are resistant, i.e.able to multiply in the presence of drug concen-trations higher than the concentrations in humansreceiving therapeutic doses. Such resistance mayeither be a characteristic associated with the en-tire species or emerge in strains of a normally sus-ceptible species through mutation or gene transfer.Resistance genes encode various mechanismswhich allow microorganisms to resist the inhibi-tory effects of specific antimicrobials. These mech-anisms offer resistance to other antimicrobials ofthe same class and sometimes to several differentantimicrobial classes.

All antimicrobial agents have the potential toselect drug-resistant subpopulations of microor-ganisms. With the widespread use of antimi-crobials, the prevalence of resistance to each newdrug has increased. The prevalence of resistancevaries between geographical regions and over time,but sooner or later resistance emerges to everyantimicrobial.

While much evidence supports the view thatthe total consumption of antimicrobials is the criti-cal factor in selecting resistance, the relationshipbetween use and resistance is not a simple correla-tion. In particular, the relative contribution ofmode of use (dose, duration of therapy, route ofadministration, dosage interval) as opposed to to-tal consumption is poorly understood. Paradoxi-cally, underuse through lack of access, inadequatedosing, poor adherence and sub-standardantimicrobials may play as important a role asoveruse. There is consensus, however, that the in-appropriate use of antimicrobial agents does notachieve the desired therapeutic outcomes and isassociated with the emergence of resistance. Forthis reason, improving use is a priority if the emer-gence and spread of resistance is to be controlled.

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ment guidelines, educate prescribers and guideinfection control policies. The frequency at whichsurveillance information is updated is alsoimportant given that the rise in prevalence of aresistance phenotype may be rapid and the imple-mentation of policy changes is often slow.

Nationally collected surveillance data may beused to inform policy decisions, update nationalformularies or lists of essential drugs and stand-ard treatment guidelines and evaluate the cost-effectiveness of interventions. Since resistance is aglobal problem, international collation of resist-ance data may also have a useful role (see Chapter8).

National surveillance systems

WHO and its partners have been successful insupporting the surveillance of drug-resistanttuberculosis in many countries (12,13). Despitethe many ongoing activities worldwide in moni-toring resistance among other bacteria, few coun-tries have well-established national networks thatregularly collect and report relevant data. In manydeveloping countries and countries whose econo-mies are in transition, microbiology laboratoryfacilities and information networks will requireconsiderable strengthening before reliable surveil-lance of resistance is a reality.

Standardization of methods to detect resistance

Current methods for monitoring antimicrobialresistance can be classified as in vivo, in vitro andmolecular methods. The extent to which each ofthese is used depends on the pathogen/disease andthe facilities available. In vivo methods or thera-peutic efficacy tests are the gold standard for moni-toring resistance to antimalarial drugs (14) but arenot used routinely to monitor resistance in otherpathogens. However, linking clinical outcome oftreatment with in vitro detection of resistance isof critical importance to understand the predic-tive value of in vitro tests.

In vitro methods are the techniques of choicefor monitoring resistance in the vast majority ofbacterial pathogens, including Mycobacterium tu-berculosis. However, there is no single internationalstandard method. Different methods have gainedpopularity in different parts of the world—at leastten different methods for antimicrobial suscepti-bility tests are used in Europe and more than twelveworldwide. International quality assurance stand-ards can help to overcome the potential difficul-ties arising from the use of different methods.

Modern techniques have enabled the develop-ment and application of molecular methods todetermine the presence of specific resistance genesin microbes. They are most widely used to detectgenotypic resistance in viruses such as HIV andHBV and, in the future, may form the basis ofsystems to monitor antiviral resistance. Howeverthese molecular methods rely on sophisticatedtechnology that is not available in many settings.

Epidemiologically valid patient selection

Currently, epidemiological methods are not ap-plied in most resistance surveillance studies. Theterms incidence and prevalence tend to be used in-terchangeably and usually refer to the number ofresistant isolates among the total number of iso-lates surveyed. In contrast, from a public healthstandpoint, one of the goals of surveillance is todetect the incidence of resistant infections amongthe total number of infections in a population (15).Further bias arises since tests to detect resistanceare performed on a subset of patients presentingfor treatment who may be more likely to havefailed empiric therapy previously or to have othercomplications. Much greater epidemiologic rig-our and more active surveillance approaches areneeded to better understand the impact of resist-ance. In this respect, surveillance of drug resist-ance in tuberculosis is more advanced than thatof other bacteria (12).

Surveillance of antimicrobial resistance is fun-damental to understanding trends in resistance,to developing treatment guidelines accurately andto assessing the effectiveness of interventions ap-propriately. Without adequate surveillance, themajority of efforts to contain emerging antimi-crobial resistance will be difficult.

The prevalence of resistance

The prevalence of resistance varies widely betweenand within countries, and over time.

Data on the prevalence of resistance in acuterespiratory infections, diarrhoeal diseases, malaria,tuberculosis and gonorrhoea can be found in re-cent reviews (16,17,18,19,20,21).

Conclusion

While it is difficult to quantify the total impact ofresistance on health, published data clearly indi-cate that morbidity and mortality are increasedby delays in administering effective treatment forinfections caused by resistant pathogens. The pro-

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longed illness and hospitalization of patients withresistant infections and the additional proceduresand drugs that they may require carry financialimplications. There may also be economic impli-cations for the patient in terms of lost productiv-ity. Antimicrobial-resistant infections infood-producing animals may have major finan-cial implications for both farmers and consumers.

In addition, antimicrobial resistance diverts

financial resources that could otherwise be usedfor improving health and threatens the success ofglobal efforts to combat the major infectious dis-eases of poverty. In this light, implementation ofthe WHO Global Strategy can be consideredappropriate risk management to protect currenthealth care initiatives and the availability of treat-ment for future generations.

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PART B

Appropriateantimicrobial use

and emergingresistance:issues and

interventions

CHAPTER 1

Patients and the general community

Patients’ misperceptions

Many patients believe that most infections, regard-less of etiology, respond to antimicrobials and thusexpect to receive a prescription from their physi-cian for any perceived infection. In a study byMacfarlane et al., 85% of patients thought theirrespiratory symptoms were caused by infection and87% believed that antimicrobials would help.One-fifth of these patients specifically asked theirphysician to prescribe an antimicrobial (22).Another study showed that patients’ expectationsfor a prescription were met 75% of the time byprescribers (23). In a survey of 3610 patients con-ducted by Branthwaite and Pechère (24), over 50%of interviewees believed that antimicrobials shouldbe prescribed for all respiratory tract infectionswith the exception of the common cold. It wasnoted that 81% of patients expected to see a defi-nite improvement in their respiratory symptomsafter three days and that 87% believed that feel-ing better was a good reason for cessation of anti-microbial therapy. Most of these patients alsobelieved that any remaining antimicrobials couldbe saved for use at a later time. Physicians’perceptions of patient expectations are clearly alsocrucial (see Chapter 2).

Many patients believe that new and expensivemedications are more efficacious than older agents;this belief is shared by some prescribers and dis-pensers and often results in the unnecessary useof the newer agents. In addition to causing un-necessary health care expenditure, this practiceencourages the selection of resistance to thesenewer agents as well as to older agents in theirclass.

Patients commonly misunderstand the phar-macological actions of antimicrobial agents.Experience suggests that many people do not knowthe difference between antimicrobials and otherclasses of drugs and thus will not understand theissues of resistance uniquely related to antimi-crobials. In the Philippines, isoniazid is viewed asa “vitamin for the lungs” and mothers purchaseisoniazid syrup for children with “weak lungs” in

Recommendations for intervention

Education

1.1 Educate patients and the general communityon the appropriate use of antimicrobials.

1.2 Educate patients on the importance of meas-ures to prevent infection, such as immuniza-tion, vector control, use of bednets, etc.

1.3 Educate patients on simple measures that mayreduce transmission of infection in the house-hold and community, such as handwashing,food hygiene, etc.

1.4 Encourage appropriate and informed healthcare seeking behaviour.

1.5 Educate patients on suitable alternatives toantimicrobials for relief of symptoms and dis-courage patient self-initiation of treatment,except in specific circumstances.

Introduction

Patient-related factors are major drivers of inap-propriate antimicrobial use and therefore contrib-ute to the increasing prevalence of antimicrobialresistance. In particular, the perception of patientsthat most episodes of suspected infection requireantimicrobial therapy notably influences theprescribing practices of providers. The direct-to-consumer marketing by the pharmaceutical indus-try increasingly influences patient expectations andbehaviour.

Patient-related factors that are thought to con-tribute to the problem of antimicrobial resistanceinclude the following:

• patients’ misperceptions

• self-medication

• advertising and promotion

• poor adherence to dosage regimens.

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the absence of documented tuberculosis (25).Patients also fail to recognize that many brandnames may actually be the same antimicrobial—resulting in the unnecessary overstocking of someagents. For example, specific patient demandcaused one pharmacy in South India to stock morethan 25 of the 100 or so brands of co-trimoxazoleavailable (26).

A greater interaction between health providersand consumers for health and drug (antimicro-bial)-related education has been proposed (27).The WHO Action Programme on Essential Drugsconvened a consultation to address the need forpublic education in rational drug use (28) and hassince produced a document “Rational Drug Use:Consumer Education and Information” (29). Thisdocument discusses the practical issues and dilem-mas related to the need for rational drug use edu-cation, its priority and content, underlyingprinciples and target population. In a study car-ried out in Peru, a multifaceted educational inter-vention directed at the community using media,face-to-face meetings and training on the use ofmedicines was successful in decreasing the inap-propriate use of antidiarrhoeals and antimicrobialsfor simple diarrhoea (30).

Self-medication

Self-medication with antimicrobials is often citedas a major factor contributing to drug resistance(31). In a Brazilian study, it was determined thatthe three most common types of medication usedby villagers were antimicrobials, analgesics andvitamins. The majority of antimicrobials were pre-scribed by a pharmacy attendant or were purchasedby the patient without prescription (32) despitehaving prescription-only legal status. In additionto obvious uncertainty as to whether the patienthas an illness that will benefit from antimicrobialtreatment, self-medicated antimicrobials are ofteninadequately dosed (33) or may not containadequate amounts of active drug, especially if theyare counterfeit drugs (34). This is especiallyimportant in the treatment of diseases such astuberculosis.

Advertising and promotion

Direct-to-consumer advertising allows pharmaceu-tical manufacturers to market medicines directlyto the public via television, radio, print media andthe Internet. Where permitted, this practice has“the potential to stimulate demand by playing on

the consumer’s relative lack of sophistication aboutthe evidence supporting the use of one treatmentover another” (35). These advertising methods areapparently quite effective, since pharmacists arefrequently able to guess the feature advertisementsof the previous day’s television programmes basedupon daily customer requests for specific medica-tions (31). A survey of physicians in the USA dem-onstrated that, on average, each had encounteredseven patients within the previous six months whohad specifically requested prescription-only drugsas a result of direct-to-consumer advertising (36).Over 70% of the physicians reported that requestsfrom patients as a result of direct-to-consumeradvertisements had led them to prescribe a phar-maceutical agent that they might not have other-wise chosen.

In a telephone survey of consumers regardingdirect advertising, 66% believed that advertise-ments for medications would provide usefulinformation but 88% said that they would seekout more information about a drug that they sawadvertised on television or in print before purchas-ing it. On the other hand, only one-third of inter-viewees agreed with the statement that most peoplewould know if they were being misled by the ad-vertisements (37).

Recently, the United States Food and DrugAdministration proposed new guidelines that liftprevious restrictions on direct-to-consumer adver-tising and allow pharmaceutical manufacturersgreater freedom on advertised health claims. Atwo-year evaluation period was proposed to assessthe impacts and implications of these guidelines(27).

Advertising and promotion can also be used toimprove the appropriate use of antibiotics. Publiceducation campaigns in India, which include theuse of mass media such as television, appear tohave effectively educated even illiterate popula-tions about antimicrobial resistance in someregions (Bhatia, personal communication).

Interventions to address the effects of advertis-ing and promotion are discussed in Chapter 7.

Poor adherence to dosage regimens

In a 1988 literature search, over 4000 Englishlanguage articles were available on the topic ofpatient adherence to dosing instructions, morethan 75% of which had been published withinthe previous ten years (38). In the majority of stud-ies, it was reported that a lack of patient under-standing and provider communication led to most

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instances of non-adherence (39,40). Patients whofail to complete therapy have a higher likelihoodof relapse, development of resistance and need forre-treatment; this applies especially to thosepatients requiring prolonged treatment, e.g. thosewith tuberculosis or HIV infection. Previousantimicrobial treatment and excessive duration oftreatment are considered two of the most impor-tant factors in the selection of resistant microor-ganisms (41,42).

Many methods have been used to ensure ad-herence to antimicrobial therapy. These includethe use of fixed dose combinations to minimizethe number of tablets or capsules, special calen-dars, blister packing, DOT (directly observedtherapy) for tuberculosis (12,13,43,44), othercourse-of-therapy packaging using symbols inlabelling, and more simplified therapy (45,46).Directly observed therapy, short-course (DOTS)is the WHO strategy for TB control that has beenshown to significantly decrease acquired resistancein tuberculosis (47,48). Education of patients onthe name, dosage, description and common

adverse effects of their medication(s) has been usedto increase adherence (49) (see also Chapter 5,Recommendations).

Price is a powerful factor in determining howconsumers use antimicrobials—economic hard-ship can lead to early cessation of therapy. Forexample, antimicrobials are purchased in singledoses in many developing countries and are takenfor only a fraction of the recommended effectiveduration, until the patient feels better. This prac-tice has the potential for fostering the selection ofresistant microorganisms and therefore has ahigher likelihood of treatment failure (50,51). Thisis especially important for diseases such as tuber-culosis and endocarditis (43,52). Governmentschemes which subsidize the cost of certain pre-ferred antimicrobials are one economic means ofimproving the appropriateness of antimicrobialuse. Where insurance systems exist, charging dif-ferential co-payments to patients, with lower pay-ments for the more desirable drugs, may encourageappropriate use.

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CHAPTER 2

Prescribers and dispensers

Regulation

2.10 Link professional registration requirementsfor prescribers and dispensers to require-ments for training and continuing educa-tion.

Introduction

Prevention of infection should be the primary goalto improve health and reduce the need for anti-microbial therapy. Where appropriate, vaccineuptake should be improved to achieve this. Boththe emergence and maintenance of resistantmicroorganisms are promoted by antimicrobialuse. Furthermore, once they are widespread, re-sistant strains are difficult to replace by their sus-ceptible counterparts. Early action to optimizeprescribing patterns and to reduce inappropriateuse is thus crucial. The difficulty is that multiplefactors influence prescribers and dispensers in de-ciding when to use antimicrobials. These factorsappear to vary in importance depending on geo-graphical region, social circumstances and theprevailing health care system. Often, the most im-portant factors are interlinked. Many traditionalapproaches to improving antimicrobial use rely onproviding correct information about drugs or dis-eases, with the implicit assumption that prescrib-ers and dispensers will incorporate the newknowledge and make appropriate adjustments intheir practice. However, experience and reviewsof well-designed research studies (53,54,55) haveshown that this is rarely the case. Effective inter-ventions to improve antimicrobial use mustaddress the underlying causes of current practiceand barriers to change (56).

Lack of knowledge and training

Lack of knowledge about differential diagnoses,infectious diseases and microbiology and about theappropriate choice of antimicrobials for variousinfections all play a role in inappropriate prescrib-ing practices (34). Even in developed countries,

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Recommendations for intervention

Education

2.1 Educate all groups of prescribers and dispens-ers (including drug sellers) on the importanceof appropriate antimicrobial use and contain-ment of antimicrobial resistance.

2.2 Educate all groups of prescribers on diseaseprevention (including immunization) andinfection control issues.

2.3 Promote targeted undergraduate and post-graduate educational programmes on the ac-curate diagnosis and management of commoninfections for all health care workers,veterinarians, prescribers and dispensers.

2.4 Encourage prescribers and dispensers to edu-cate patients on antimicrobial use and theimportance of adherence to prescribed treat-ments.

2.5 Educate all groups of prescribers and dispens-ers on factors that may strongly influence theirprescribing habits, such as economic incen-tives, promotional activities and inducementsby the pharmaceutical industry.

Management, guidelines and formularies

2.6 Improve antimicrobial use by supervision andsupport of clinical practices, especially diag-nostic and treatment strategies.

2.7 Audit prescribing and dispensing practicesand utilize peer group or external standardcomparisons to provide feedback and endorse-ment of appropriate antimicrobial prescrib-ing.

2.8 Encourage development and use of guidelinesand treatment algorithms to foster appropri-ate use of antimicrobials.

2.9 Empower formulary managers to limit anti-microbial use to the prescription of an appro-priate range of selected antimicrobials.

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the pharmacology of antimicrobial agents, theirmodes of action and spectrum of activity andissues relating to resistance receive limited cover-age in medical school curricula, resulting in poorlyinformed prescribers (57). It is not uncommonfor drug company sales representatives and thecommercially oriented publications they provideto be the main sources of information for prescrib-ers (58).

Lack of knowledge is a major factor responsi-ble for inappropriate antimicrobial use globally.In one study in China, 63% of antimicrobialsselected to treat proven bacterial infections werefound to be inappropriate (59). In a retrospectivestudy in Viet Nam, more than 70% of patientswere prescribed inadequate dosages (60). Gumo-doka et al. (61) reported that one in four patientsin their medical districts received antimicrobialsby injection and that approximately 70% of theseinjections were unnecessary. Studies in manyEuropean countries and in the USA demonstratewidespread unnecessary use of antimicrobials inpatients with viral upper respiratory tract infec-tions (62).

Printed materials are the most common andleast expensive educational interventions but in-appropriate prescribing is rarely due to a lack ofknowledge alone. Many studies have found thatthe use of printed material only, without otherforms of supporting interventions, is ineffectivein altering prescribing behaviours (63,64,65).Continuing education and in-service trainingprogrammes have traditionally involved lecture-and seminar-style presentations oriented to thepresentation of factual information. A large bodyof research has shown that these approaches arenot necessarily the most effective for improvingpractice (66). Academic detailing, or unadvertise-ments, and educational programmes directed tophysicians have been shown to decrease antimi-crobial use/misuse (67,68,69,70). One consist-ently successful method has been educationaloutreach, which consists of brief, targeted, face-to-face educational visits to clinicians by speciallytrained staff (67,71,72). In developing countrieswhere individual educational outreach visits maynot be practical or cost-effective, interactive prob-lem-oriented educational sessions with smallgroups of physicians, paramedics, or pharmacycounter attendants have demonstrated similar suc-cess, especially when sessions are repeated over timeor reinforced with improved clinical supervision(53). Another promising approach involves engag-ing local opinion leaders in the process of dissemi-

nating targeted educational messages to their peergroup (73,74). Unfortunately, none of these stud-ies looked at resistance as an outcome or impactindicator. Increasing problem-based pharmaco-therapy training for medical and paramedical stu-dents can have a positive impact on long-termgood prescribing habits. The use of a WHOmanual (75) designed to support problem-basedlearning for medical students has been demon-strated to have a positive impact on prescribingskills of students in seven medical schools (76).

In countries with limited resources, the dispens-ing of antimicrobials by unauthorized personslacking appropriate knowledge is common. In astudy of 40 randomly selected health facilities inGhana, only 8.3% of dispensers had received for-mal training (77). Bruneton et al. (78) found thatdrug sellers in seven sub-Saharan African coun-tries frequently recommended antimicrobials notpresent on the regions’ Essential Drugs List andrarely suggested that the patient should consult aphysician.

Improving the drug education of non-physi-cian prescribers and dispensers is another recom-mended step in improving drug use. A study inGhana showed that educational interventionsaimed at dispensers significantly improved druguse by increasing the percentage of appropriatelylabelled containers and by increasing patientknowledge of their medications (77). Interventionstargeted at local drug sellers in the Philippines sig-nificantly improved their quality of practice (79).

Lack of access to information

Even relatively well-trained prescribers often lackthe up-to-date information required to makeappropriate prescribing decisions. This tends toresult in the excessive use of newer antimicrobialagents, often with a broader spectrum of action.Conversely, lack of surveillance data and updatedtreatment guidelines may lead to the inappropri-ate prescription of older antimicrobials which areeither no longer effective due to the emergence ofresistance or should have been replaced by neweragents with improved cost-effectiveness or reducedtoxicity.

Use of clinical practice guidelines is a coremanagerial strategy in every health system forimproving diagnosis and therapy. Despite theabundance of guidelines, research has shown thatthey have little effect on clinical practice unlessthey are actively disseminated (80). Factors thatincrease the likelihood of guidelines being adopted

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include local involvement of end-users in the proc-ess of development, the presentation of key ele-ments in a simple algorithm or protocol, anddissemination in a multi-component programmethat includes interactive education, monitoring ofadherence and reinforcement of positive changes.A combination of national prescribing guidelinesand educational campaigns on the appropriate useof antimicrobials targeted at prescribers has hadsome success in reducing the prevalence of spe-cific antimicrobial resistance (7). There has alsobeen some success in the use of educational cam-paigns targeted at prescribers and patients torecognize that not all infections require the use ofantimicrobials. Included in one such campaign wasa message to parents discouraging them fromsending their sick children to day care in order toreduce the opportunities for transmission of in-fection (81).

Lack of diagnostic support

Lack of access to or use of appropriate diagnosticfacilities and slow or inaccurate diagnostic resultsencourage prescribers to cover the possibility thatinfection may be responsible for a patient’s illness,even when this is not the case (58). In particular,the lack of accurate tests at point-of-care to achievea rapid diagnosis is a significant problem for manydiseases and is an area in which future researchcould be very beneficial. Empiric treatment of in-fections with a reasonably well-defined clinicalpresentation is more likely to be appropriate thanthat of infections with an undifferentiated pres-entation e.g. malaria presenting as fever alone. Inthis latter situation the differential diagnosis maybe wide and therefore empiric treatment protocolswill necessarily need to be broad—leading to ahigher likelihood of unnecessary antimicrobialtherapy. A careful history and access to adequatediagnostic facilities allow the differential diagno-sis to be narrowed and therapy more targeted. Astudy of barefoot doctors in a district of Bangla-desh found that antimicrobials were prescribed for60% of all patients seen in areas without diagnos-tic services—a higher rate than noted in otherdistricts (82). Other studies have had similar find-ings (83,84). In developed countries, empiricantimicrobial therapy is sometimes considered tobe more cost-effective than awaiting laboratoryproof of infection before commencing treatment.

For conditions such as acute respiratory infec-tions, diarrhoea and malaria in children, andsexually transmitted disease in adults, treatment

algorithms have been developed (55,85,86). Thesediagnostic and treatment algorithms are based ondetailed research studies, generally in resource-poor regions, in which the patients’ clinical pres-entations have been correlated with subsequentmicrobiological confirmation of disease. Thissyndromic approach is particularly useful in healthcare settings where diagnostic capabilities are lim-ited, since it allows a rational approach to deter-mining the need for antimicrobial therapy and themost appropriate agents.

Fear of bad clinical outcomes

Prescribers may overuse antimicrobials becausethey fear that their patients may suffer poor out-comes in the absence of such therapy. Prescribingjust to be safe increases when there is diagnosticuncertainty, lack of prescriber knowledge regard-ing optimal diagnostic approaches, lack of oppor-tunity for patient follow-up, or fear of possiblelitigation (87,88).

Perception of patient demands andpreferences

Prescribers’ perceptions regarding patient expec-tations and demands substantially influence pre-scribing practices (22,23,58,87,89). Althoughthese perceptions may be incorrect, they can leadto a perpetual cycle whereby patients who repeat-edly receive unnecessary antimicrobials develop themisconception that antimicrobials are frequentlynecessary for most ailments and therefore requestthem excessively (22,90). Prescribers and dispens-ers may also respond to patient demand for par-ticular formulations of antimicrobials, e.g. capsulesrather than tablets. In some cultural settings,antimicrobials given by injection are consideredmore efficacious than oral formulations. This tendsto be associated with the overprescribing of broad-spectrum injectable agents when a narrow-spectrum oral agent would be more appropriate(61).

In an effort to reduce re-consultation ofpatients, Macfarlane et al. (23) utilized a patientinformation leaflet regarding coughs. Amongpatients not prescribed antimicrobials, those giventhe educational leaflet appeared less likely tore-consult; this result, however, was not statisti-cally significant. The use of delayed prescribingtechniques has been proposed when physicians feelpressured by their patients into prescribingantimicrobials (45,87). Some physicians say that

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they promise a free return visit if the patient feelsthat a re-consultation is necessary because they didnot receive antimicrobials (87).

Economic incentives

Many health providers practise in environmentswith financial incentives to prescribe or dispensegreater numbers of drugs overall or of specifictypes. Prescribers may fear the potential loss offuture patient custom and revenue if they do notrespond to perceived demands for antimicrobials(91). Furthermore, in some countries, prescribersprofit from both prescribing and dispensingantimicrobials, such that it is in their financialinterest to prescribe antimicrobials even when theyare not clinically indicated. Additional profit issometimes gained by recommending newer moreexpensive antimicrobials in preference to oldercheaper agents. In countries where physicians arepoorly paid, pharmaceutical companies have beenknown to pay commissions to prescribers who usetheir products (92). Other less direct incentivessuch as financial support for attendance at meet-ings, entertainment, or payment for enrollingpatients in marketing research studies may alsoinfluence prescribing practices. Even in healthsystems where there is no overt incentive toprescribe, there is usually no incentive not toprescribe (8).

It is desirable to minimize financial conflictsof interest in therapeutic decision-making byhealth providers, such as allowing physicians toprofit from dispensing drugs that they prescribeor allowing pharmacists who sell drugs to prescribethem as well. Coast et al. (9) and Smith and Coast(93) explored economic perspectives of policiesused to decrease antimicrobial resistance. Theydiscuss techniques such as regulation (controllingprescription practices by means of policies andguidelines or by enforcing a global limit to theprescription of antimicrobials), permits (allowingphysicians to prescribe up to a certain quantity ofantimicrobials per permit) and charges (levyingtaxes on antimicrobials). In their model, they sug-gest that the use of permits may offer a methodfor reducing antimicrobial resistance.

Several countries have introduced health pro-vider reimbursement strategies that are designedto encourage physicians to limit overall use ofmedicines and often to share in the resultingfinancial savings. Examples of these strategies arecapitation payments that include pharmaceuticalcosts, general practice fundholding (94) and

bonuses tied to practice pharmaceutical budgets.While these strategies may reduce inappropriateuse of antimicrobials, they may also reduceappropriate use. Nevertheless, a number ofScandinavian studies have suggested that nationalantibiotic policies together with changes in reim-bursement policy can be safe and effective(95,96,97).

Peer pressure and social norms

In focus group studies, prescribers expressed con-cern that, if they did not prescribe antimicrobials,patients would seek other sources of care wherethey could obtain antimicrobials (91). In addition,the physician offering the latest and often the mostexpensive and broad-spectrum antibiotic may beperceived to be the most informed and desirablesource of care.

Understanding prescribing patterns is crucialto identifying areas for potential intervention toimprove use (58). Drug use patterns and prescrib-ing behaviour, including the influence of varioussocial and patient pressures, can be described us-ing the indicators and methods in the WHOmanual “How to investigate drug use in healthfacilities” (98). After undertaking interventions toimprove drug use, these same indicators can beused to measure impact.

Factors associated with the prescriber’sworking environment

In busy clinical practices, health care providers maynot have time to explain to patients why they havechosen to prescribe or not prescribe antimicrobialtherapy (99). Some clinicians in this situation maybelieve it is simply most time-effective to prescribean antimicrobial. Lack of privacy in consultationfacilities may also impact on prescribing behav-iour since some conditions, such as urinary tractsepsis and sexually transmitted diseases, requirediagnostic specimens and/or physical examinationthat are difficult to undertake in public. The lackof opportunity for health care workers to followup their patients to assess progress after treatmentand poor continuity of care in general negativelyinfluence communication and the developmentof trust between the patient and health care pro-vider. It is thus often easier for both prescriberand patient if an antimicrobial agent is prescribedon first contact.

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Lack of appropriate legislation orenforcement of legislation

Absence of appropriate legislation or its enforce-ment may result in the proliferation of locationswhere untrained or poorly trained persons dispenseantimicrobials, leading to overuse and inappro-priate use (see Chapter 5).

Inadequate drug supply infrastructure

In many parts of the world, the ability of prescrib-ers and dispensers to provide appropriate antimi-crobial therapy is limited by the lack of availabilityof the necessary drugs (100).

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Hospitals

Introduction

Hospitals are a critical component of the antimi-crobial resistance problem worldwide. The com-bination of highly susceptible patients, intensiveand prolonged antimicrobial use, and cross-infection has resulted in nosocomial infectionswith highly resistant bacterial pathogens such asmulti-resistant Gram-negative rods, vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) as well asresistant fungal infections. Some of these resist-ant strains have now spread outside the hospitalcausing infections in the community. Hospitalsare also the eventual site of treatment for manypatients with severe infections due to resistantpathogens acquired in the community, includingpenicillin-resistant Streptococcus pneumoniae,multi-resistant salmonellae and multi-resistantMycobacterium tuberculosis. In the wake of theAIDS epidemic, the prevalence of such infectionscan be expected to increase, both in the commu-nity and in hospitals. Hospitals can thus serve bothas a point of origin of and as a reservoir for highlyresistant pathogens which may later enter the com-munity or chronic care facilities.

Infection control

Transmission of highly resistant bacteria frompatient to patient within the hospital environment(nosocomial transmission) amplifies the problemof antimicrobial resistance and may result in theinfection of patients who are not receiving anti-microbials. Transmission of antimicrobial-resist-ant strains from hospital personnel to patients orvice versa may also occur. The key element in mini-mizing such horizontal transmission of infectionwithin hospitals is careful attention to infectioncontrol practices (101).

Failure to implement simple infection controlpractices such as handwashing and changing glovesbefore and after contact with patients is common(102,103,104,105). In some cases, especially inresource-poor regions, this may be due to the ab-

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Recommendations for intervention

Management

3.1 Establish infection control programmes, basedon current best practice, with the responsi-bility for effective management of antimicro-bial resistance in hospitals and ensure that allhospitals have access to such a programme.

3.2 Establish effective hospital therapeutics com-mittees with the responsibility for overseeingantimicrobial use in hospitals.

3.3 Develop and regularly update guidelines forantimicrobial treatment and prophylaxis, andhospital antimicrobial formularies.

3.4 Monitor antimicrobial usage, including thequantity and patterns of use, and feedbackresults to prescribers.

Diagnostic laboratories

3.5 Ensure access to microbiology laboratoryservices that match the level of the hospital,e.g. secondary, tertiary.

3.6 Ensure performance and quality assurance ofappropriate diagnostic tests, microbial iden-tification, antimicrobial susceptibility tests ofkey pathogens, and timely and relevantreporting of results.

3.7 Ensure that laboratory data are recorded, pref-erably on a database, and are used to produceclinically- and epidemiologically-usefulsurveillance reports of resistance patternsamong common pathogens and infections ina timely manner with feedback to prescribersand to the infection control programme.

Interactions with the pharmaceutical industry

3.8 Control and monitor pharmaceuticalcompany promotional activities within thehospital environment and ensure that suchactivities have educational benefit.

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sence of suitable handwashing facilities. However,inadequate handwashing is generally due to lackof recognition of its importance in maintaininggood infection control, understaffing or health careworker forgetfulness. Regardless of the reasons,poor infection control practices result in theincreased dissemination of resistant bacterialstrains in hospital and health care facilities. Thespread of resistance appears to be widening aspatients move more rapidly from intensive carewards to general wards and then to the commu-nity or between hospitals and nursing homes(51,106,107).

Infections can also be transmitted via non-sterile injection and surgical equipment. In a studyof health facilities in Tanzania, 40% of suppos-edly sterilized needles and syringes were bacteri-ally contaminated (61). Poor decontamination orfailures in sterilization of equipment can have anenormous impact on the spread of viral infectionssuch as HIV (108), hepatitis B and C. Re-use ofsingle-use needles and syringes has played a majorrole in the spread of viral hepatitis following im-munization programmes in some countries andamong intravenous drug users (109,110,111,112).Any practice that permits the spread of infectionpermits the spread of resistant infections.

Infection control activities are best coordinatedby an active and effective infection control pro-gramme. The SENIC study, conducted by theCenters for Disease Control (CDC) and whichincluded a large sample of hospitals in the USA,demonstrated that hospitals having infection con-trol programmes with both active surveillance andcontrol elements were effective in reducing ratesof nosocomial infection (113,114,115). In par-ticular, interventions such as education and moti-vation programmes, improvement of equipment,and performance feedback can increase adherenceto improved handwashing (104). Barrier precau-tions have been shown to be effective in reducinginfection transmission rates and thereby the spreadof resistance. Mayer et al. (116) showed that im-proved handwashing and the use of gloves andgowns decreased infection rates.

With respect to the control of antimicrobialresistance within the hospital setting, the majorevidence of effectiveness stems from the manage-ment of outbreaks or clusters of resistant infec-tions. In these situations, a variety of techniquesincluding targeted cohorting of infected patients,enhanced surveillance, isolation or rigorousbarrier precautions, early discharge and alterationin antimicrobial usage have been effective.

The key elements of an effective infection con-trol programme include:

— development and implementation of appro-priate barrier precautions (handwashing,wearing of gloves and gowns) and isolationprocedures

— adequate sterilization and disinfection ofsupplies and equipment

— the use of aseptic techniques for medicaland nursing procedures

— training of health care personnel in appro-priate sterile techniques and infection con-trol procedures

— maintenance of appropriate disinfectionand sanitary control of the hospital envi-ronment, including air

— active surveillance of infections and anti-microbial resistance, with data analysis andfeedback to prescribers and other staff

— recognition and investigation of outbreaksor clusters of infections.

The programme should have a qualified chair-person and staff and adequate resources to accom-plish these goals. The most effective infectioncontrol team consists of a physician (preferablytrained in infectious diseases), a microbiologist,infection control nurses, pharmacist(s) andhospital management representatives, with theresponsibility for the day-to-day management ofresistance issues. Increased efficiency may beachieved by an overlap in the membership of theinfection control team and the hospital therapeu-tics committee.

Appropriate facilities for optimal infectioncontrol practices, including sufficient basins andclean towels to regularly wash hands betweenpatient contacts, may be difficult to achieve insome countries. Nevertheless, such facilities arevital if nosocomial transmission of infections is tobe controlled. Handwashing, isolation practices,sufficient beds (and space between them), as wellas clean ventilation are needed in hospitals to pre-vent the spread of bacteria, including resistantstrains.

Control of antimicrobial use in hospitals

Hospitals provide an important training groundfor students to learn about prescribing practices.Unfortunately, antimicrobial prescribing in hos-pitals is often irrational. In an analysis of prescrib-

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ing practices in ten studies from teaching hospi-tals worldwide, 41% to 91% of all antimicrobialsprescribed were considered inappropriate (117).Patterns of prescribing become entrenched and, ifthey are not consistent with appropriate antimi-crobial treatment guidelines, they may have anenormous effect on the emergence of resistantpathogens and on the pharmacy budget of a hos-pital if the drugs are expensive. For many clini-cians, a common source of information regardinghospital antimicrobial use is the literature providedby pharmaceutical representatives. Such informa-tion is less likely to be objective than national orregional treatment guidelines (see Chapter 7).

Antimicrobial prophylaxis for surgical proce-dures is a common reason for excessive prescrib-ing in many hospitals. Numerous studies haveoutlined those procedures in which patientsbenefit from such prophylaxis and those in whichthey do not (118,119,120,121,122,123,124), butinappropriate prophylaxis is still widely used. Afurther problem is the continuation of anti-microbials, initially administered as prophylaxis,well beyond the required 12 to 24 hour post-surgical period without clear medical indicationother than the opinion of the surgeon. Such pre-scribing patterns result in high rates of antimicro-bial exposure among hospitalized patients,potentially leading to high colonization rates ofresistant nosocomial pathogens and antibiotic-associated diarrhoea. For these reasons a varietyof approaches have been utilized to modify anti-microbial prescribing practices within the hospi-tal setting. These have the overall goal of reducingthe total consumption of antimicrobials and ofaltering the type of usage in favour of regimensless likely to foster the emergence of resistantstrains.

Hospital therapeutics committees

An active and effective hospital therapeutics com-mittee is considered a key element for the controlof antimicrobial usage in hospitals, although thereare only limited published data to support thisview and there are few data regarding the impactof hospital therapeutics committees in develop-ing countries. However, their beneficial role in thepromotion of rational prescribing habits, moni-toring of drug usage and cost containment is wellestablished in developed countries (125,126). Forthis reason, the establishment of such a commit-tee is considered important. The premise that anyclinician should be allowed to use any antimicro-

bial considered necessary without any peer-reviewprocess is generally inconsistent with optimizingantimicrobial use. All clinicians should be preparedto justify their antimicrobial usage patterns.

The following activities represent some of thekey roles of an effective therapeutics committee.

• Development of written policies and guide-lines for appropriate antimicrobial usage inthe hospital, based on local resistance sur-veillance data. Policies should be developedlocally, with broad input and consensus fromhealth care providers and microbiologists.

• Selection and provision of appropriate anti-microbials in the pharmacy after considera-tion of local clinical needs.

• Establishment of formal links with aninfection control committee, preferably withsome overlap in membership.

• Definition of an antimicrobial utilizationreview programme, with audit and feedbackon a regular basis to providers, and promo-tion of active surveillance of the natureand amount of antimicrobial use in thehospital.

• Overseeing antimicrobial use through asystem of monitoring the quantity used andthe indications for use.

With regard to the last point, it is important torecognize that such seemingly basic data collec-tion can be difficult to undertake accurately, evenin the best medical centres. Nevertheless, accu-rate antimicrobial usage information is crucial torational decision-making and the interpretationof antimicrobial resistance data. In systems whereprescribing data are collected routinely, utilizationreview (or audit) combined with feedback of per-formance data to prescribers has become a com-mon strategy to influence patterns of prescribingpractice. The success of audit and feedbackprogrammes is mixed (127). Audit and feedbackprogrammes using manually collected samples ofprescribing data and simple performance indica-tors have been successful at improving antibioticprescribing in some developing country settings(53). Although a decrease in resistance prevalencecan be achieved with the use of controlprogrammes, once monitoring is relaxed, theprevalence of drug-resistant organisms may quicklyincrease again (128).

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Formularies

Hospital formularies, or lists of drugs routinelystocked by the hospital pharmacy for inpatient andoutpatient use, guide the parallel processes of an-timicrobial selection, procurement and supply, andrepresent a means for decreasing inappropriateantimicrobial prescribing and reducing expendi-tures. In conjunction with clinical guidelines,formularies encourage the proper use of preferreddrugs within each category of antimicrobial.Antimicrobial formularies should relate to localor regional treatment guidelines and should ide-ally be based on relative efficacy, cost-effectivenessdata and local patterns of resistance (129). This,however, is difficult in many hospitals. In a USAsurvey in which a great majority of hospitalshad implemented formularies as a method ofdecreasing antimicrobial costs, many noted thatexpenditures actually increased—this was usuallyconsidered to be due to drug resistance (130).Although some authors have suggested that arestrictive hospital formulary may actually con-tribute to the selection of resistant bacteria by nar-rowing and focusing selective pressures, there arefew data to support this view (131). Thus, formu-laries are useful in avoiding the unnecessary keep-ing in stock of a range of antimicrobials thatduplicate their spectrum and in reinforcing theimportance for clinicians to understand an appro-priate range of antimicrobials well. However, thespecific effectiveness of a formulary in reducingthe emergence of antimicrobial resistance is un-clear.

Cycling of antibiotics

The cycling of antimicrobials within a health careinstitution has been suggested as a possible inter-vention to decrease drug resistance. This techniquealternates formulary antimicrobials between drugclasses every couple of months and theoreticallyreduces the selective pressure of one antimicro-bial class (132). However, in a recent review ofthe topic, there was no evidence that cyclingreduced antimicrobial resistance (133). Cyclingmay have only a temporary effect on resistancepatterns and ultimately may simply replace oneresistance problem with another (134).

Use of clinical practice or treatment guidelines

Clinical practice guidelines (80) can improvedecision-making and therefore improve patientcare. They should be developed locally or

regionally with wide input and consensus andshould utilize information from local surveillancedata whenever possible. Programmes that utilizeclinical practice guidelines supported by other in-terventions such as education and peer review aremore effective than those without such support(135). In an observational study of one hospitalwith a computerized prescribing guideline systemthat encouraged appropriate use of antimicrobials,trend analysis showed that resistance patterns inselected hospital-acquired infections stabilized overa seven-year period (136). Another study noted areduction in one type of resistance when controlson selected agents were applied, but an increasein resistance to other antimicrobials which werenot controlled—the so-called “squeezing the bal-loon” effect (137). Nevertheless, treatment guide-lines are particularly useful in resource-poorcountries where they can be used to streamlinetreatment protocols and limit the range ofantimicrobials stocked in pharmacies. However,such treatment guidelines need to be developedcarefully and their implementation reviewed regu-larly. Their appropriateness is dependent onaccurate and updated resistance surveillance andclinical outcome data.

Other techniques to control or modifyantimicrobial use in hospitals

Several types of innovative tools to guide antimi-crobial prescribing and dispensing have beentested; some have been shown to be effective inchanging antimicrobial use in hospital settings.Antimicrobial order forms have been used withmixed success, showing improvement in antimi-crobial prescribing in some hospitals but not inothers (138,139,140). Automatic review of the useof selected antimicrobials by a consultant orautomatic cessation of antimicrobial administra-tion after a defined period may also reduceunnecessary use (46). However, these controlmeasures are either labour-intensive or requirereasonably sophisticated computerized pharmacyrecords—both of which are not generally avail-able.

Integrated interventions

Multi-disciplinary and integrated approaches toreduce antimicrobial use in hospitals have beenproposed as a solution (105,141,142,143). Hos-pital administrators, clinicians, infectious diseasesspecialists, infection control practitioners,microbiologists, clinical epidemiologists and

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hospital pharmacists all have a role—but coordi-nation of their activities is vital. Such activitiesinclude the selection of formulary drugs, thedevelopment of formulary-based guidelines, moni-toring and evaluating drug use, surveillance andreporting of bacterial resistance patterns, detec-tion and appropriate care of patients with resist-ant organisms, and promotion and monitoring ofbasic infection control practices (143). Interactionswith the pharmaceutical industry must also be con-sidered, including appropriate control of theaccess of sales representatives to clinical staff andmonitoring industry-sponsored educational pro-grammes for providers. Targeted antimicrobialcontrol policies in combination with improvedhygiene and education have reduced antimicro-bial resistance in some settings (144,145). How-ever, in one study, prescriber education combinedwith hospital antimicrobial control policies led todecreased antimicrobial costs and improved pre-scribing, but only limited change in resistance(146).

The microbiology laboratory andantimicrobial resistance

Delayed or incorrect laboratory diagnostic datafrequently result in prolonged empiric antimicro-bial therapy (see also Chapters 2 and 5). The hos-pital microbiology laboratory plays an importantrole in the recognition and surveillance of antimi-crobial resistance, both within the hospital and inthe community. The laboratory must provide highquality diagnostic testing to correctly identify in-fection and accurate antimicrobial susceptibilitytesting to guide appropriate treatment. Appropri-ately trained personnel, adequate supplies, mate-

rials and equipment, and internal quality controland external quality assurance procedures, areessential. The laboratory should produce and dis-seminate meaningful local surveillance data bothwith respect to the predominant pathogens/syn-dromes and their antimicrobial resistance patterns.The laboratory should work closely with hospitalinfection control personnel, with the hospitaltherapeutics committee and with providers toensure that appropriate antimicrobials are testedand reported in order to recognize outbreaks orunusual infections and identify trends in antimi-crobial resistance. Software tools such asWHONET are available to facilitate analysis anddata sharing (147). Depending on resources, thelaboratory should also provide specialized testing,e.g. molecular typing of bacterial strains, to assistepidemiological investigations.

Interactions between the hospitaland the community

Following discharge from hospital, patients maystill be colonized or infected with resistant bacte-ria acquired in hospital. In general, little action isnecessary in such circumstances if the patient ishealthy and discharged home. However, this is thelikely mechanism through which highly resistanthospital-acquired pathogens eventually becomewidespread in the community. Of greater concernis the transfer of such patients to chronic carefacilities where they have been shown to be thesource of strains that subsequently spread through-out the facility. Patients known to be colonized orinfected with resistant pathogens upon dischargeto a care facility should generally be identified sothat appropriate precautions can be taken.

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CHAPTER 4

Use of antimicrobials infood-producing animals

— an increased risk for resistant pathogens tobe transferred to humans by direct contactwith animals or through the consumptionof contaminated food or water

— the transfer of resistance genes from ani-mal to human bacterial flora.

Increasingly, data suggest that inappropriateantimicrobial use poses an emerging public healthrisk (148,149,150,151).

Factors associated with the emergence of anti-microbial resistance in food-producing animalsand the farming industry appear to be similar tothose responsible for such resistance in humans.Inadequate understanding about and training onappropriate usage guidelines and the effects of in-appropriate antimicrobial use on resistance arecommon among farmers, veterinary prescribersand dispensers.

There are three modes of antimicrobial use inanimals—prophylaxis, treatment and growthpromotion. Overall, the largest quantities of anti-microbials are used as regular supplements forprophylaxis or growth promotion in the feed ofanimal herds and poultry flocks. This results inthe exposure of a large number of animals, irre-spective of their health, to frequently subthera-peutic concentrations of antimicrobials (152).Furthermore, a lack of diagnostic services and theirperceived high cost means that most therapeuticantimicrobial use in animals is empiric, rather thanbeing based on laboratory-proven disease. Foranimals and birds that are farmed in large herdsor flocks, the identification of a few ill individualsgenerally results in the entire herd or flock beingtreated to avoid rapid dissemination and stocklosses. Clearly this is a different situation to mosthuman diseases where decisions are generally madeabout the need for individual therapy, rather thanthe empiric treatment of an entire population. Inaddition to these issues, veterinarians in somecountries earn as much as 40% or more of theirincome by the sale of drugs, so there is a disincen-tive to limit antimicrobial use (153,154).

This topic has been the subject of specific consul-tations which resulted in “WHO global princi-ples for the containment of antimicrobialresistance in animals intended for food”*. A com-plete description of all recommendations is con-tained in that document and only a summary isreproduced here.

Recommendations for intervention

Summary

4.1 Require obligatory prescriptions for allantimicrobials used for disease control in foodanimals.

4.2 In the absence of a public health safety evalu-ation, terminate or rapidly phase out the useof antimicrobials for growth promotion if theyare also used for treatment of humans.

4.3 Create national systems to monitor antimi-crobial usage in food animals.

4.4 Introduce pre-licensing safety evaluation ofantimicrobials with consideration of poten-tial resistance to human drugs.

4.5 Monitor resistance to identify emerging healthproblems and take timely corrective actionsto protect human health.

4.6 Develop guidelines for veterinarians to reduceoveruse and misuse of antimicrobials in foodanimals.

Introduction

Antimicrobial use in food-producing animals mayaffect human health by the presence of drugresidues in foods and particularly by the selectionof resistant bacteria in animals. The consequencesof such selection include:

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* http:// www.who.int/emc/diseases/zoo/who_global_principles.html

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As in human medicine, inefficient and inad-equately enforced regulatory mechanisms regard-ing antimicrobial supply contribute to excessiveand inappropriate drug use. Discrepancies betweenregulatory requirements and prescribing/dispens-ing realities for animal antimicrobial use are oftenworse than in human medicine (155). In addi-tion, antimicrobials that are used as growth pro-moters are generally not even considered as drugsand are either not licensed or licensed solely asfeed additives. Poor manufacturing quality assur-ance in some settings results in the supply ofsub-standard drugs. Marketing practices ofantimicrobials for therapeutic, prophylactic orgrowth promoter purposes in animals by privateindustry influence the prescribing patterns andbehaviour of veterinarians, feed producers andfarmers.

In North America and Europe it is estimatedthat about 50% in tonnage of all antimicrobialproduction is used in food-producing animals andpoultry (156). The increased intensity of meatproduction under crowded industrialized condi-tions contributes to the increased use of anti-microbials since they are used in subtherapeuticdoses as growth promoters, given as prophylaxisfor disease prevention and used therapeutically forthe treatment of infected animals. In addition, theimpact of antimicrobial metabolites and non-metabolized drug in animal sewage that is releasedinto the environment is not clear.

Use of antimicrobials as growth promoters

Some antimicrobials, particularly those thattarget Gram-positive bacteria, are associated withan increase in the rate of animal growth when theyare provided in subtherapeutic quantities in stockfeed to food-producing animals. The mechanismof this effect is uncertain. However, these drugsalso alter the gut flora of exposed animals suchthat they frequently contain bacteria that are re-sistant to the antimicrobial used. When suchantimicrobial growth promoters belong to a classsimilar to that of antimicrobials used in humanmedicine, these resistant animal bacteria areoften also resistant, i.e. cross-resistant, to impor-tant human use antimicrobials (157). Five growthpromoters (bacitracin, tylosin, spiramycin,virginiamycin and avoparcin [a similar agent tovancomycin]) have recently been banned by theEuropean Union due to fears of such cross-resist-ance (158,159).

Scientific data strongly suggest that avoparcin

use in animals contributes to an increased pool ofvancomycin-resistant enterococci (VRE) (160,161). However, the extent to which the microbialgene pool in animals contributes to the prevalenceof VRE colonization and infection in humans isless well defined. VRE cause serious infections,mainly in hospitalized immunocompromisedpatients. Such infections are difficult to cure dueto the limited number of effective treatmentoptions and are thus associated with increasedmorbidity and mortality. There are also concernsthat the genes that cause resistance to vancomy-cin may spread from enterococci to other bacte-ria, such as Staphylococcus aureus, for whichvancomycin is one of the drugs of last resort.

Studies in Denmark have shown that the banof avoparcin in animals has led to a reduction inthe prevalence of VRE in poultry and pigs(162,163). Similarly, studies in Germany and theNetherlands suggest that banning avoparcin hasled to a reduction in the prevalence of VRE inhealthy individuals in the community (164,165).Sweden banned the use of growth promoters inlivestock and poultry in 1987 and focused on theimplementation of disease prevention methodsthat did not involve antimicrobials and on theprudent use of antimicrobials for therapeutic pur-poses. The subsequent national antimicrobial con-sumption has reduced by approximately 50%(166,167). Furthermore, the prevalence of anti-microbial resistance in pathogenic bacteria isolatedfrom animals in Sweden has been maintained at alow prevalence since 1985 (168).

Use of antimicrobials that affect food-borne pathogens such as Salmonella andCampylobacter spp.

Non-typhoidal Salmonella spp. and Campylobacterjejuni are among the most commonly identifiedcauses of bacterial diarrhoea in humans. Suchspecies are generally transmitted to humans viafood or direct contact with animals (169). Datademonstrate that antimicrobial use in animalsselects for resistance among non-typhoidal Salmo-nella spp., thus limiting the effective available treat-ment options (170,171,172). A recent example isa clone of Salmonella typhimurium DT104 thathas become prevalent in many countries includ-ing the UK, Germany and the USA—it is resist-ant to commonly used agents including ampicillin,tetracycline, streptomycin, chloramphenicol andsulphonamides (171,173,174). Multi-drug resist-ance has likewise been noted in other Salmonellaspp. (175).

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Following the introduction of fluoroquinolonesfor use in food-producing animals, the emergenceof Salmonella serotypes with reduced susceptibil-ity to fluoroquinolones has been observed incountries such as France, Germany, Ireland, theNetherlands, the Russian Federation, Spain andthe UK (176,177,178). Little has been docu-mented about the impact of this resistance onhuman health to date, but there is concern aboutthe potential human health consequences. Thishas been substantiated by a recent outbreak ofquinolone-resistant S. typhimurium DT104 result-ing in treatment failures in hospitalized patientsin Denmark (179).

The introduction of fluoroquinolone use inpoultry has been associated with a dramatic rise

in the prevalence of fluoroquinolone-resistantCampylobacter jejuni isolated in live poultry,poultry meat and from infected humans (180,181,182). Prior to fluoroquinolone use in poultry, noresistant strains were reported in individuals with-out previous exposure to these agents (178,183).Because of their broad antibacterial spectrum,fluoroquinolones are often used for empiric treat-ment of gastrointestinal infections in severely illor immunocompromised patients. Fluoro-quinolone resistance among Campylobacter spp.is associated with a higher rate of clinical treat-ment failure than for susceptible strains whenfluoroquinolones are used for treatment of disease(184,185,186). A recent review by APUA (187)provides further material on this topic.

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CHAPTER 5

National governments and health systems

5.5 Ensure that only antimicrobials meeting in-ternational standards of quality, safety andefficacy are granted marketing authorization.

5.6 Introduce legal requirements for manufactur-ers to collect and report data on antimicro-bial distribution (including import/export).

5.7 Create economic incentives for the appropri-ate use of antimicrobials.

Policies and guidelines

5.8 Establish and maintain updated nationalStandard Treatment Guidelines (STGs) andencourage their implementation.

5.9 Establish an Essential Drugs List (EDL) con-sistent with the national STGs and ensurethe accessibility and quality of these drugs.

5.10 Enhance immunization coverage and otherdisease preventive measures, thereby reduc-ing the need for antimicrobials.

Education

5.11 Maximize and maintain the effectiveness ofthe EDL and STGs by conducting appro-priate undergraduate and postgraduateeducation programmes of health care pro-fessionals on the importance of appropriateantimicrobial use and containment of anti-microbial resistance.

5.12 Ensure that prescribers have access to approvedprescribing literature on individual drugs.

Surveillance of resistance, antimicrobial usageand disease burden

5.13 Designate or develop reference microbiol-ogy laboratory facilities to coordinate effec-tive epidemiologically sound surveillance ofantimicrobial resistance among commonpathogens in the community, hospitals andother health care facilities. The standard ofthese laboratory facilities should be at leastat the level of recommendation 3.6.

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Advocacy and intersectoral action

5.1 Make the containment of antimicrobialresistance a national priority.

— Create a national intersectoral task force(membership to include health care pro-fessionals, veterinarians, agriculturalists,pharmaceutical manufacturers, govern-ment, media representatives, consumersand other interested parties) to raiseawareness about antimicrobial resistance,organize data collection and overseelocal task forces. For practical purposessuch a task force may need to be a gov-ernment task force which receives inputfrom multiple sectors.

— Allocate resources to promote the imple-mentation of interventions to containresistance. These interventions shouldinclude the appropriate utilization ofantimicrobial drugs, the control andprevention of infection, and researchactivities.

— Develop indicators to monitor and evalu-ate the impact of the antimicrobialresistance containment strategy.

Regulations

5.2 Establish an effective registration scheme fordispensing outlets.

5.3 Limit the availability of antimicrobials toprescription-only status, except in special cir-cumstances when they may be dispensed onthe advice of a trained health care professional.

5.4 Link prescription-only status to regulationsregarding the sale, supply, dispensing andallowable promotional activities of antimicro-bial agents; institute mechanisms to facilitatecompliance by practitioners and systems tomonitor compliance.

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5.14 Adapt and apply WHO model systems forantimicrobial resistance surveillance andensure data flow to the national intersectoraltask force, to authorities responsible for thenational STGs and drug policy, and to pre-scribers.

5.15 Establish systems for monitoring antimicro-bial use in hospitals and the community, andlink these findings to resistance and diseasesurveillance data.

5.16 Establish surveillance for key infectious dis-eases and syndromes according to countrypriorities, and link this information to othersurveillance data.

Introduction

Placing antimicrobial resistance high on the na-tional agenda should be a priority in tackling theproblem of resistance. National governments andhealth care systems can have considerable impacton limiting the emergence and development ofantimicrobial resistance through the introductionof legislation and policies concerning the devel-opment, licensing, distribution and sale of anti-microbial agents. Health and pharmaceuticalregulations shape the way antimicrobials are used.Key regulatory frameworks include professionallicensing, the ability to prescribe and dispensemedicines, drug registration, product quality, pric-ing and movement of drugs in the supply system.Although pharmaceutical regulations represent apowerful tool, implementing them to influencepatterns of antimicrobial use can be a two-edgedsword, achieving both intended and unintendedeffects. For example, active enforcement of regu-lations regarding the sale of antimicrobials with-out prescription in pharmacies and drug shops mayreduce unnecessary use while at the same timelimiting access to appropriate therapy, especiallyamong the poor. The unintended effects of pro-posed regulations should be carefully consideredbefore and monitored during their implementa-tion.

National governments also have the responsi-bility for coordinating surveillance networks andfor directing educational efforts to improveunderstanding about appropriate antimicrobialuse.

Government legislation—drug licensing

Marketing authorization

Many countries have legislation that requires allmedicinal products to undergo licensure beforebeing placed on the market. Marketing authori-zation usually follows a detailed assessment of dataprovided by the applicant, generally by a desig-nated government department and sometimeswith input from an expert advisory group(s). Somecountries are willing to license new medicinesbased on their prior approval in other countries,such as the USA or EU. Whatever the process,the fundamental requirement is that the datashould support the quality, safety and efficacy ofthe product (188,189). The use of antimicrobialsthat do not meet appropriate standards in each ofthese three areas has implications for human healthand for antimicrobial resistance.

Quality

As with all medicinal products, control of thequality of antimicrobial agents is vital for the de-livery of accurate dosage units to patients—dosesthat have been shown to be safe and effective inclinical trials (188,189,190). Antimicrobial agentscontaining less than the stated dose may producesuboptimal levels of circulating drug, which mayresult in both therapeutic failure and selection ofdrug-resistant strains. Similar problems may ariseas a result of counterfeit products, which com-monly contain little or none of the active substancestated on the label and may even contain entirelydifferent active ingredients. The CounterfeitIntelligence Bureau estimated that, in 1991, 5%of all the world’s trade was in counterfeit goods,with this percentage likely to be higher for phar-maceuticals since they are easily transportable(191). Excessive drug content may lead to con-centrations in the body associated with certainadverse events. Unnecessarily high concentrationsmay also lead to a marked disruption of the nor-mal flora and an increased risk of superinfectionssuch as fungal disease and C. difficile enterocolitis.

Government-initiated inspection of drugmanufacturing plants for adherence to GoodManufacturing Practice (GMP) with certificationfor defined time periods, adherence to the prod-uct specifications agreed upon at the time oflicensure, and the elimination of unauthorizedmedicines from the market are essential. Strictcontrols limiting drug importation and exporta-tion to those products and manufacturers that havebeen inspected and approved can serve to reduce

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the risks posed by substandard and counterfeitmedicines. Countries that carry out spot checksand drug analyses are able to make a major con-tribution to reducing the production of poorquality and counterfeit products.

Safety and efficacy

The scope and quality of data presented to sup-port the safety and efficacy of new drugs aredetermined mainly by the requirements of the USFood and Drug Administration (FDA), the Euro-pean Commission, and the Japanese Ministry ofHealth, Labour and Welfare (MHLW) (188,189,192). The individual regulations issued by thesebodies, together with the activities of the Interna-tional Conference on Harmonisation (193), havegreatly influenced the content and conduct of pre-clinical and clinical development programmes forpharmaceuticals. Dossiers meeting these inter-national standards are generally acceptable world-wide, although there may be additional localstipulations. In this way, all countries may benefitfrom high quality development programmes thatbetter identify the safety and efficacy of new drugs.In one sense, the emergence of resistance associ-ated with the use of a particular antimicrobialcould be viewed as an adverse event. However,current regulatory and licensure bodies do notregard the emergence of resistance in this man-ner.

Countries that do not have systems for theadequate assessment of safety and efficacy beforeand after drug licensure face an increased risk ofexposure to drugs of inferior efficacy and unac-ceptable toxicity, as well as a potentially highermarket penetration of counterfeit drugs. Theestablishment of Assessment Report SharingSchemes has facilitated assessment of the safetyand efficacy of antimicrobial agents by resource-poor countries. Participating countries are able torequest detailed reports of pharmaceutical, pre-clinical and clinical data that have been preparedby drug regulatory authorities in other countries.The Product Evaluation Report (PER) networkand the arrangements made by the EuropeanAgency for the Evaluation of Medicinal Products(EMEA) are examples of schemes which allowcountries access to information to assist in mak-ing licensing decisions. In addition, regional as-sociations of regulatory bodies, e.g. AFDRAN inAfrica, have contributed to the application of simi-lar standards and requirements for drug approvalsin many countries.

Prescribing information

Wherever there are formal procedures for druglicensure, the content of the prescribing informa-tion is subject to approval by the licensing authori-ties. Requirements for international alignment onthe essential content of the prescribing informa-tion and on the reporting of safety data have ledto the development of core datasheets by manypharmaceutical companies (194,195). Thesedescribe the minimal prescribing information,including contraindications, warnings and poten-tial adverse reactions, which should be availableto users in all countries where the product is mar-keted. However, it may not be feasible for allcompanies, especially those that are large and mul-tinational, to regularly audit compliance with theuse of core datasheets in all regions or to requirethat national or regional offices fully adopt statedcorporate standards. Also, in countries where thereare inadequate regulations to ensure the availabil-ity of prescribing information to prescribers andusers, health care professionals may have little orno access to independently-assessed material re-garding antimicrobial agents (see also Chapters 2and 7).

Failure to specify precisely in the prescribinginformation the types of infections for which safetyand efficacy have been demonstrated in clinicaltrials may serve to encourage antimicrobial use forconditions that have not been studied. An exam-ple is the use of the term “lower respiratory infec-tions” instead of specifying the types of pneumoniaor bronchitis that were studied. Thus, withoutcareful attention to detail and to translation, eventhe approved prescribing information may inad-vertently encourage inappropriate antimicrobialuse.

The product literature usually reflects the dos-age regimens shown to be efficacious in clinicaltrials for each indication. Identification of opti-mal antimicrobial treatment regimens for variousdiseases is important to ensure that the drug isgiven in an appropriate dose and for an appropri-ate duration to maximize the likelihood of cure,while minimizing the risk of toxicity. Low doseregimens may be associated with less toxicity, butmay result in insufficient drug concentrations atthe site of infection to effect bacterial eradicationand may therefore encourage the development ofresistance among target pathogens. In contrast,higher dose regimens may result in greater effectson the host’s normal flora increasing the likeli-hood of superinfections, including those causedby highly resistant nosocomial pathogens. How-

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ever, clinical trials to support antimicrobial drugapproval are almost always designed to showequivalence to a licensed comparative agent.Therefore there is a tendency to use perhapsunnecessarily high dose or long duration regimensso as to avoid any risk of treatment failure (196,197,198). Companies are often reluctant to ex-plore a variety of dosage and treatment regimensin clinical trials with a new drug because of thestudy costs involved and the risk of failing to meetthe specified regulatory requirement (199). Doseregimens in clinical trials are often chosen by com-paring the pharmacokinetics of the drug in manwith the in vitro susceptibilities of the main targetpathogens. Increasingly, the pharmacokinetic andpharmacodynamic characteristics of new antimi-crobial agents are being used in pre-clinicalstudies to better predict the optimal clinical dos-ing regimens in man (200,201,202). While thisapproach does not replace clinical trials, the phar-maceutical industry and regulatory authoritieshave both recognized that this may also havebenefits in terms of reducing the risk of selectingfor drug-resistant organisms.

Government legislation—control of drugsupply, distribution and sales

Some countries are unable to control the supply,distribution and sale of medicines. In many re-gions there is minimal control over public accessto antimicrobials and these can be purchased overthe counter without prescription (34,203). Thereare also marked international differences in thetypes of retail outlets that provide access to pre-scription-only and non-prescription drugs, as wellas whether these outlets require government reg-istration. Where there is adequate legislationregarding the licensure of medicinal products, alegal classification system generally determines themode of sale, supply and dispensing. In such coun-tries, antimicrobial agents are almost uniformlyprescription-only medicines (POM), with dispens-ing restricted to registered outlets and by suitablyqualified personnel (204). In reality, however, thedegree of drug law enforcement and the penaltiesimposed for infringements vary enormouslybetween countries. For example, all systemicantibacterial agents are legally subject to prescrip-tion control in the EU, yet they can be purchasedover the counter in pharmacies in several EU mem-ber states (205). Antimicrobials can be purchasedwithout prescription in many resource-poor coun-tries (59,129,206). In a study of chemist shops in

Nairobi, it was noted that 64% of chemists soldantimicrobials without physicians’ prescriptionsand most sold incomplete treatment courses at therequest of the patient (207). In a study of a ruralvillage in Bangladesh, 95% of all medications con-sumed were obtained from pharmacies with only8% having been prescribed by graduate physicians;one-third of these medications were antimicrobials(208). Poor enforcement of prescription-only regu-lations is almost universally associated with inap-propriate antimicrobial usage.

Although the cost of antimicrobial agents with-out prescription is generally carried by the patient,in some regions this may actually be less expen-sive than the combined costs of a time-consum-ing visit to a distant and/or very busy health carefacility and the physician’s consulting fee. There-fore, depending on the structure and funding ofthe national health care system, restricting anti-microbial agents to prescription-only mayactually limit the access of many patients to thesedrugs, even when they are really needed. On theother hand, requiring a prescription for access toantimicrobial agents provides an opportunity todissuade patients from unnecessary antimicrobialtherapy and hopefully results in a trained healthcare worker selecting the drug and the treatmentregimen. This potential point of interventionshould help reduce inappropriate antimicrobialusage, especially if accompanied by an educationprogramme on the appropriate use of antimicro-bial agents (see Chapter 2).

With or without implementation of prescrip-tion-only access to antimicrobial agents, legisla-tion that restricts the sale of antimicrobials toregistered outlets would allow local policing andprevention of over-the-counter non-prescriptionsales. Ideally, such registered outlets should bestaffed by personnel with at least a basic knowl-edge of antimicrobials. Legislation that compelsregistered outlets to keep records of the sources ofdrugs purchased and quantities sold would allowthe auditing of antimicrobial sales and possibly ofusage data. Such surveillance may result in greaterrestriction of the sales of counterfeit and substand-ard medicines. However, in regions where prescrib-ers earn a considerable portion of their incomeeither by directly dispensing antimicrobials or viasubsequent pharmacy sales, such legislation islikely to be less effective. These circumstancesprovide a disincentive to appropriate antimicro-bial prescribing and prescribers are more likely torecommend antimicrobial use, particularly themore expensive agents, regardless of whether

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cheaper drugs may be just as appropriate (see alsoChapter 2).

Government legislation—inspectionand enforcement

The existence of appropriate legislation regardingthe manufacture, licensure, sale, supply and dis-pensing of antimicrobial agents cannot improvethe quality and appropriate use of these drugsunless it is enforced. Individual countries may nothave the financial or human resources needed tosupport policing activities by suitably qualifiedpersonnel. There may be reluctance on the part ofgovernments to take action because the introduc-tion of restrictions could prove unpopular withpatients, physicians and the pharmaceutical indus-try. Increasing international recognition of inspec-tions of manufacturing plants by teams from othercountries has relieved the burden on some gov-ernments and facilitated the quality control ofmedicines and adherence to Good Manufactur-ing Practice (GMP), Good Laboratory Practice(GLP) and Good Clinical Practice (GCP). Thepossibility of expanding these international coop-erative efforts by using suitably qualified staff fromnon-governmental organizations (NGOs) to aidpolicing efforts in other areas of drug law compli-ance may be worthy of serious consideration bysome countries (see also Chapter 8).

Health care systems and drug policies

Health care systems

The organization and funding of health care sys-tems varies between countries, with a mixture ofpublic- and privately-funded health care facilitiesand diagnostic laboratories being common. Thestructure and organization of these systems canbe an important factor in determining the reli-ability and practicality of data collection regard-ing antimicrobial use, surveillance of antimicrobialresistance and the impact of resistance on clinicaloutcomes. In addition, the system may have a di-rect influence on undergraduate medical curricula,on the existence and maintenance of registrationsystems for all health care professionals, and onthe attention paid to their continuing professionaleducation and accreditation. Whether or notantimicrobials are prescription-only, undergradu-ate and postgraduate medical and pharmacist edu-cation concerning appropriate antimicrobial useis vital (see Chapter 2), as is the need for evidence-based prescribing information.

Surveillance of resistance and antimicrobial use

Surveillance of both antimicrobial resistance andantimicrobial use are fundamental to the effectiveimplementation of any strategy for the contain-ment of antimicrobial resistance, as a means tomonitor the efficacy of various interventions.However, designing and implementing compre-hensive surveillance systems that are practical, cost-effective and interlink with the national healthcaresystem is a challenge. It is likely that in manyresource-poor countries, laboratory facilities andinformation networks will require considerablestrengthening before reliable surveillance of resist-ance can be undertaken.

Epidemiologically sound surveillance of resist-ance in key pathogens, using standardized micro-biological methods, may be developed on the basisof an existing laboratory surveillance system forantimicrobial resistance and routine diagnosticmicrobiology (see Part A, Background). To assistin this aim, WHO is developing “Surveillancestandards for antimicrobial resistance” which pro-pose practical epidemiological methods forseveral infections and key pathogens (209). Wherepossible, such surveillance should be integratedwith other national and hospital laboratory serv-ices to maximize efficiency and ensure surveillanceof clinically relevant isolates (see Chapter 3).

Measurement of antimicrobial usage could beapproached through the registration of outlets thatdispense antimicrobials, requiring them to main-tain accurate records of antimicrobial supply andsales. Incomplete patient adherence to treatmentprotocols means that antimicrobial dispensing datawill not necessarily be the same as antimicrobialconsumption, but it is likely to be the mostaccurate achievable surrogate available. Targetedresearch to measure the correlation between thequantity of antimicrobials dispensed and the quan-tity consumed could be used to adjust nationaldispensing data, providing a more accurate assess-ment of antimicrobial consumption. Establishingsurveillance systems of antimicrobial usage andcontrol of drug supply and dispensing outlets willrequire a major commitment from national gov-ernments in countries which do not currently haveeffective prescription-only regulations for anti-microbials. Implementation of an integrated sur-veillance system for antimicrobial resistance andantimicrobial usage will require national govern-ments to re-assess many regulatory aspects of theirhealth care system, including legislation relatedto drug licensure (including quality, safety andefficacy) and drug supply, distribution and sales.

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Essential Drugs Lists and policies

In 1977 the first WHO Model List of EssentialDrugs was developed to promote the availabilityof a selected number of drugs, including anti-microbials, and their rational use. The Model Listhas been revised regularly and serves as a guide forcountries in determining their national drug poli-cies. At present over 120 countries have imple-mented an Essential Drugs List. A retrospectivestudy of prescribing practices in Ethiopia found asignificant decrease in the prescribing of non-essential drugs after the introduction of an Essen-tial Drugs List (210). Studies have demonstratedthat in those areas in which an Essential DrugsProgramme is in operation, significantly moreessential drugs are available, significantly fewerinjections and antimicrobials are utilized, and drugstocks last about three times longer than in

regions without such a programme. Thus, suchprogrammes appear to improve access to essentialdrugs, especially when they are supported by edu-cational programmes and follow-up (83,117).

Establishing national treatment guidelines

Evidence-based national treatment guidelines en-courage appropriate antimicrobial prescribing.Using local laboratory and clinical surveillancedata on antimicrobial resistance, these guidelinescan be appropriately modified for community andhospital use in various regions, but should be up-dated regularly. The use of such guidelines is mosteffective when combined with supportive inter-ventions such as educational training and super-vision programmes (83,211).

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CHAPTER 6

Drug and vaccine development

drug and vaccine research is now a crucial issuefor all nations given the emergence of antimicro-bial resistance among human pathogens.

New drug and vaccine development

The fact that there are currently several novelantimicrobial agents and vaccines in clinical trialsreflects the awareness of the industry of the prob-lems of antimicrobial resistance and the enormousinvestment by some companies in anti-infectivedrug development. At the same time, however,there are concerns within the industry that effortsto encourage the more appropriate use of anti-microbials may have a negative impact on sales.This concern may potentially discourage compa-nies from either initiating or maintaining invest-ment in antimicrobial research and development.An overall drop in the antimicrobial-generatedrevenues of pharmaceutical companies may alsoinfluence the quantity of antimicrobial agents andvaccines that they donate, or provide at reducedcost, to some regions of the world.

Schemes that encourage investment in antimi-crobial and vaccine research must thereforerecognize the need for companies to recoup theirdevelopment costs as well as make a profit frompost-licensing sales. A range of incentives to theindustry, including both push and pull mecha-nisms, are currently under discussion (212). Somecountries, such as Australia, have devised provi-sions by which companies which conduct researchaimed at identifying new therapies and whichperform some sections of the development pro-gramme in the home country can benefit fromtax reductions and incentive payments. Thisapproach also attracts some companies to estab-lish research facilities in supportive countries,which may have employment and other benefits.

Drug discovery may also be stimulated by co-operative research agreements between companiesand academic institutions. These agreements canstimulate basic science research and the sharing ofknowledge which may speed up the identification

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Recommendations for intervention

6.1 Encourage cooperation between industry,government bodies and academic institutionsin the search for new drugs and vaccines.

6.2 Encourage drug development programmeswhich seek to optimize treatment regimenswith regard to safety, efficacy and the risk ofselecting resistant organisms.

6.3 Provide incentives for industry to invest inthe research and development of newantimicrobials.

6.4 Consider establishing or utilizing fast-trackmarketing authorization for safe new agents.

6.5 Consider using an orphan drug scheme whereavailable and applicable.

6.6 Make available time-limited exclusivity fornew formulations and/or indications for useof antimicrobials.

6.7 Align intellectual property rights to providesuitable patent protection for new antimicro-bial agents and vaccines.

6.8 Seek innovative partnerships with the phar-maceutical industry to improve access tonewer essential drugs.

Introduction

The pharmaceutical industry is the predominantsource of new antimicrobial agents and new dis-ease prevention modalities, including novelvaccines and immunomodulating therapies. It isvital that there are incentives for companies toinvest resources into research and development inthese areas even though the development of othertypes of medicinal products may ultimately bemore profitable. Encouraging research intovaccines and antimicrobial agents that will pre-dominantly be used in low-resource countriesposes particular challenges given the need for phar-maceutical companies to make a profit. However,the continuation and expansion of anti-infective

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of promising compounds or vaccines. Thisapproach may potentially reduce overall costs byreducing the duplication of research activities (seeChapter 8). Public-private partnerships are increas-ingly being exploited for speeding up drugdiscovery and development and addressing unmetmedical needs where the market opportunities areless attractive (213).

Vaccines

Vaccines potentially provide a major means of lim-iting the clinical impact of emerging antimicro-bial resistance. Pneumococcal and Haemophilusinfluenzae type b (Hib) vaccines have had adramatic effect in reducing the incidence of clini-cal disease in some age groups and regions (214,215,216,217). Recent studies of a nonavalentpneumococcal conjugate vaccine demonstrated asignificant reduction in the carriage of penicillin-resistant and cotrimoxazole-resistant strains ofS. pneumoniae in children nine months aftervaccination, compared to controls (214). Thus,by reducing the incidence of disease and carriageof resistant strains, pneumococcal vaccination maylimit the impact of antimicrobial resistance. Whenthe information is available, knowledge of apatient’s vaccination status for pneumococcal, Hiband other diseases may aid the differential diag-nosis if the patient presents with an acute illnessand thereby allow narrower-spectrum agents to beemployed for empiric therapy.

Vaccines have also proven effective for somediarrhoeal diseases and enteric fever. A number oftyphoid vaccine preparations are now available,but their use has previously been limited mainlyto travellers to endemic areas. With the new oralpreparations, wider use may now be more feasibleonce they can be produced at reasonable cost.Given recent outbreaks of ciprofloxacin-resistanttyphoid fever, vaccination has been suggested asan adjunct to sanitation measures in some regions(218,219,220,221). Vaccines for other diarrhoealdiseases such as shigellosis, cholera, E. coli ETECand rotavirus are also under trial (218).

As the medical treatment of HIV, hepatitis Band C becomes more widespread, antiviral resist-ance will become a major limiting factor. Child-hood vaccination against hepatitis B, eitheruniversal or targeted to high risk groups depend-ing on the prevalence of hepatitis B in the popu-lation, is a very cost-effective means of controllingthe disease and avoiding the problems of resist-ance (109,222,223). Effective vaccines against

hepatitis C and HIV could likewise have enor-mous clinical impact.

Licensure and patent protection

To hasten the licensure of some new products, fast-track evaluation of innovative medicines is offeredby some licensing authorities (188,224), allowingtruly innovative products to reach the publicdomain as early as possible. Such schemes benefitboth the companies and the community—although careful post-licensure surveillance ofadverse effects is vital. Some products may beconsidered clinically useful but of limited com-mercial value due to infrequent disease occur-rence—for these, some countries provide speciallicensure under an orphan drug scheme which hasvariable eligibility requirements.

The safeguarding of intellectual property rightsis a major concern to the pharmaceutical indus-try. There may be opportunities to encourageresearch by furthering international agreementsand cooperation on innovative new approaches topatents and time-limited exclusivity arrangements.Time-limited exclusivities on new clinically use-ful formulations and/or additional indications foruse on some current agents might serve to stimu-late the additional pharmaceutical and clinicalstudies which are needed to support licensure forthese additional indications.

Clinical development programmes

Clinical development programmes are designedto undertake trials which will support drug regis-tration. These programmes offer possibilities toinvestigate not only the most effective treatmentregimens but also those which are least likely toresult in the emergence of antimicrobial resistance.However, these pre-registration clinical trials rarelyassess the degree to which in vitro susceptibilitydata correlate with the in vivo clinical outcomesof infected patients receiving treatment. Althoughthese correlations are of vital clinical importance,such trials can be difficult to perform. In mostpre-registration clinical antimicrobial trials, thenumber of treatment failures is generally too fewto allow such assessments and, in any case, theprimary goal of these studies is to assess equiva-lence of efficacy or drug toxicity, not the correla-tion between in vitro and in vivo outcomes. Inaddition, a number of design features of licensurestudies make such correlations even more diffi-cult. Firstly, some protocols require that enrolledpatients found to be infected with pathogens that

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are resistant in vitro to one of the trial drugs shouldbe withdrawn from the study. However, othersallow such patients to continue receiving trialtherapy if they are doing well, despite in vitroresistance. Such design issues have an importantimpact on the ability to accurately analyse corre-lation data. Furthermore, the site of infection mayinfluence the level of antimicrobial penetrationand therefore the likely concentrations of activedrug available under routine dosing conditions,e.g. drug concentrations in cerebrospinal fluid aregenerally lower than those achievable in serum.Therefore, in vitro definitions of resistance willdepend on potentially achievable drug concentra-tions in vivo, meaning that the MIC breakpointsfor individual pathogens may need to vary depend-ing on the site of infection.

Since clinical trials with antimicrobials arealmost exclusively designed to demonstrate equiva-lence to an approved comparative agent, thismeans that results cannot be used as a basis forrecommending one treatment over another. Thus,these studies generally do not provide clear evi-dence on which to base guidelines for the bestchoice of antimicrobial or the optimal mode ofmanagement of a particular infection. In addition,clinical drug trials have not been designed todetermine the most appropriate duration of anti-microbial therapy. Many scientists and cliniciansbelieve that shorter treatment courses for manyinfections may be as effective as longer courses(225). Potential benefits of shorter course thera-pies are to decrease disruption of the normal floraand the selective pressure of antimicrobials favour-ing drug-resistant microorganisms. Shorterdurations of therapy are also likely to encouragepatient adherence (see Chapter 1). It should benoted that, at the present time, relatively few clini-cal antimicrobial studies are conducted on paedi-atric populations and that this may be an area forgreater attention in the future.

Microbiological and pharmacological issues

A number of important microbiological and phar-macological features of antimicrobials appear toinfluence their likelihood of selecting and promot-ing resistant strains (51,226). Pharmacodynamicand pharmacokinetic parameters can be used tohelp identify the optimal dose and dosing inter-vals for each antimicrobial (202). The parametersmost appropriate in terms of encouraging theemergence of resistance have been investigated anddebated extensively (132,227,228). In addition,the use of antimicrobials in combinations has beensuggested for some infections, since a reducedincidence of resistance has been noted with com-bination therapy (229,230).

Cost-effectiveness

Cost-effectiveness studies are increasingly becom-ing a major component of clinical developmentprogrammes. While these are not required forlicensure, they may be needed in some countriesfor negotiations on drug supply contracts. Whilecompanies may have some cost-effectiveness dataavailable, few release such data to the public. Manypublished cost-effectiveness studies are at risk ofbias in favour of the new agent, since few studiesof older agents, that are often no longer patent-protected, are undertaken due to insufficientresearch funding support. Furthermore, studiesfocus neither on the cost of resistance nor on theclinical impact of resistance and there is a needfor new approaches to incorporate such evalua-tions into cost-effectiveness studies (8). Thus,current clinical development programmes rarelysupport decision-making regarding the cost-effec-tiveness or optimal dose of various antimicrobials.However, such programmes may provide someunique opportunities to gain more useful infor-mation in future if innovative modifications aremade to current trial designs.

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CHAPTER 7

Pharmaceutical promotion

macists, dentists, nurses and the general commu-nity. The close relationships between drug pro-motion, prescribing habits and drug sales havebeen demonstrated in several studies (34,231).Since drug promotion increases usage, it may beassumed that it can contribute to the prevalenceof antimicrobial resistance, particularly if it resultsin increased inappropriate use of antimicrobialagents.

Promotional literature and prescribing information

A number of studies have shown that advertise-ments and other promotional literature distrib-uted by companies at conferences and symposiaare major influential sources of information forhealth professionals (231,232). Indeed, the con-tent of advertisements and literature provided bycompanies may be the only readily accessiblesources of information on antimicrobial agents insome countries. In the absence of legislation or itsenforcement for promotional materials to reflectapproved prescribing information, companies maypresent to potential prescribers, suppliers andusers a very selective and biased view of the effi-cacy and safety of a drug. It has been suggestedthat physicians may not even be aware of theseinfluences. Avorn et al. (232) found that most pre-scribers believed that drug advertisements andpharmaceutical representatives played a role ofminimal importance in influencing prescribingpatterns whereas academic sources of informationwere very important yet the opposite appeared tobe true. This finding was supported by a study ofprescribing habits of physicians in Peru (231). Thestudy concluded that advertising materials distrib-uted by pharmaceutical companies appeared to bea key source of information for prescribers,despite claims by more than two-thirds of the phy-sicians surveyed that their primary source of druginformation came from medical literature. A re-view of the literature on the interactions betweenphysicians and the pharmaceutical industry con-cluded that there was strong evidence that these

Recommendations for intervention

7.1 Introduce requirements for pharmaceuticalcompanies to comply with national or inter-national codes of practice on promotionalactivities.

7.2 Ensure that national or international codesof practice cover direct-to-consumer advertis-ing, including advertising on the Internet.

7.3 Institute systems for monitoring compliancewith legislation on promotional activities.

7.4 Identify and eliminate economic incentivesthat encourage inappropriate antimicrobialuse.

7.5 Make prescribers aware that promotion inaccordance with the datasheet may not nec-essarily constitute appropriate antimicrobialuse.

Introduction

National governments have an important legisla-tive role in ensuring the appropriate manufacture,licensure and sale of antimicrobials (see Chapter5) and also an important responsibility in ensur-ing that these drugs are promoted in a fair andaccurate manner. Government controls on drugpromotional activities and compliance of the phar-maceutical industry with both legislation andagreed codes of practice are important factors ifappropriate antimicrobial use is to be encouraged.

The power of promotional activities

Promotional activites include drug advertisementsin the media and over the Internet, personal con-tacts during visits from company representatives,sponsored symposia and guest lectures or lecturetours funded by companies, and other induce-ments to prescribe a particular product or brand.The target audience for promotional activitiesdepends on the product and the local regulatoryenvironment, but generally includes doctors, phar-

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interactions influence prescribing behaviour (233).Thus, pharmaceutical promotional material thatcontains misinformation may ultimately encour-age inappropriate antimicrobial use and theemergence of resistance.

Promotional materials must not only reflectapproved prescribing information correctly butmust also be accurate, comprehensive and up todate. Particular difficulties may be encounteredwith older antimicrobials for which the initiallylicensed indications may now be consideredexcessively broad or vague, e.g. upper respiratoryinfections, and may no longer reflect current think-ing on the optimal evidence-based managementof certain infections. Although pharmaceuticalcompanies may apply to update sections of theprescribing information, they are unlikely to doso voluntarily if there is a risk of a negative impacton sales. Licensing authorities may require thatthe prescribing information be updated or modi-fied but are unlikely to do so without strong evi-dence to support the changes, due to the possibilityof a legal challenge from companies. Furthermore,the fact that many older agents are no longer pat-ent-protected means that license holders may notconsider that the drug’s market value warrants suchapplications and effort.

Prescribers

Promotion of products to health professionals in-forms prescribers about the range of drugs avail-able and alerts them to the availability of newagents. Inherently, pharmaceutical marketing re-sults in the highlighting of potential benefits andadvantages of new agents over existing agents tothe extent allowable. Under these circumstancesit is often difficult for prescribers to identify themost appropriate role of the new agents withinthe context of existing protocols. Promotionalmaterials often emphasize simple messages in pref-erence to more complex ones, not infrequentlyresulting in over-prescribing.

It is also difficult to regulate the provision ofinducements such as meals, event tickets, andtravel to conferences. These perks may serve asrewards for using a company’s products and asenticements to prescribe newly-introduced drugs(234,235). This may also encourage prescribersto prescribe using brand names rather thangeneric names, which may markedly increasespecific company sales in those countries whichdo not allow pharmacists to substitute betweenbrands of the same active substance when dispens-ing prescriptions (see Chapter 2).

Patients

Health care professionals in all countries, includ-ing those subject to prescription control, often feelpressured by patients to prescribe antimicrobialsfor minor infections which do not need specifictherapy (see Chapter 2). Direct-to-public adver-tisements in countries with prescription-onlyrestrictions on antimicrobial agents may enhancethe pressures on health care professionals to pre-scribe when their clinical judgement suggests thatspecific therapy is unnecessary. In addition,advertising on the Internet is gaining market pen-etration yet is difficult to control with legislationdue to poor enforceability. To counter this prob-lem, education campaigns directed at health careprofessionals and the general public are underwayin some countries where antimicrobial agents areavailable by prescription only. The aim of such acampaign in the UK, ongoing in 2000, was toinform all parties about those infections least likelyto require antimicrobial treatment—therebyreducing patient expectation of the need for anantimicrobial agent. Data on the effects of suchefforts are awaited.

The effects of direct-to-public promotion ontotal and specific antimicrobial usage are likely tobe much greater in countries where these agentsare available without prescription. In these circum-stances, even promotion in accordance with theprescribing information is likely to result in un-necessary antimicrobial use as purchasers are lessable to fully appreciate the information providedand to weigh the possible risks and benefits.Inappropriate antimicrobial use as a result of over-the-counter availability may therefore be greatlyexacerbated by direct-to-public advertising.

Sales

Pharmaceutical promotion directed towards healthcare professionals who sell antimicrobials may re-sult in a conflict of interest. The desire to profitfrom making the sale and/or to favour a particu-lar company’s product in expectation of rewardsmay override clinical judgement. In this manner,the decision regarding the necessity for treatmentand the choice of the most suitable agent are lesslikely to reflect appropriate clinical management.Sales of antimicrobial drugs through outlets notstaffed by health care professionals are likely to bedriven predominantly by profit margins with onlylimited potential for control of antimicrobialusage.

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Control of drug promotion

Legislation and enforcement

Where licensing, supply and sales legislation arein place, the regulation of promotional activitiesis frequently linked to the legal classification ofmedicines (236,237,238). In such countries, e.g.the European Union, it is common to restrict thepromotion of prescription-only products to healthprofessionals, whereas over-the-counter medicinesmay be promoted to the general public. Certaincountries, e.g. the USA, adopt a middle course byallowing direct promotion to the public whileenforcing restricted access to prescription-onlyproducts. Promotional activities that are consid-ered acceptable, and the regulations regardingthem, vary by country. Any legislation applicableto promotional activities may be supplemented byvoluntary codes that have been agreed nationallybetween companies, or internationally betweenfederations of pharmaceutical companies.

Advertisements in peer-reviewed journals,magazines and newspapers and broadcast viaradio or television can be reviewed and made sub-ject to controls. However, the advent of advertis-ing on the Internet has provided a means by whichcompanies can circumvent regulations, reachingwide audiences and global markets with unre-strained messages about their products.

Codes of practice

In addition to legislative control mechanisms,there are various codes of practice regarding

appropriate promotional activities that have beendrawn up by national and international associa-tions of pharmaceutical companies (239,240,241).Unfortunately, these codes vary between countriesand in the manner in which they are executed(235), such that there are many pharmaceuticalcompanies that have not agreed to any such codeof practice. When these companies market prod-ucts in countries in which there is little or nogovernmental control on promotional activities,there is no way of monitoring the situation andpreventing misinformation to health care profes-sionals and to the public.

Some pharmaceutical associations carry outinspections of the promotional activities of theirmembers in order to monitor compliance. Com-panies may also complain to these associationsabout the activities of rivals when these seem togo beyond the agreed codes of practice. Severalnon-governmental organizations undertake auditsand investigate complaints regarding some formsof promotion (234). Whereas none of thesebodies has legal empowerment, they may exertconsiderable pressure to improve compliance withvoluntary codes of practice and internationallyaccepted standards. Nevertheless, despite thesecodes and monitoring activities, there is clearly aneed for greater effort to ensure that health pro-fessionals receive accurate information regardingthe efficacy and safety of antimicrobial agents(117) and of the problems of antimicrobial resist-ance.

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International aspects of containingantimicrobial resistance

8.7 Encourage innovative approaches to incen-tives for the development of new pharma-ceutical products and vaccines for neglecteddiseases.

8.8 Establish an international database of poten-tial research funding agencies with an inter-est in antimicrobial resistance.

8.9 Establish new, and reinforce existing,programmes for researchers to improve thedesign, preparation and conduct of researchto contain antimicrobial resistance.

Background—the changing globalcontext of public health

Multiple global factors are influencing the epide-miology of infectious diseases, the contexts inwhich they need to be managed, and thus thedemands on health care systems. Increasingurbanization, with its associated overcrowding andinadequate housing, poor sanitation and lack ofclean water supplies, has a major influence on theburden of infectious disease. Pollution and envi-ronmental change, including deforestation, chang-ing weather patterns and desertification, may alsoaffect the incidence and distribution of infectiousdiseases. Demographic changes resulting in agrowing proportion of elderly people and the ex-panding use of modern medical interventions areincreasing the risks of acquiring infections,especially those caused by multi-resistant hospitalpathogens. The AIDS epidemic has greatly en-larged the population of immunocompromisedpatients at risk of infections. Changing patternsof lifestyle also have an effect, e.g. the increase incigarette smoking in many societies and the con-sequent increase in associated respiratory diseases,including pneumonia.

An increased incidence of infections leads tomore antimicrobial use and consequently a greaterselection pressure in favour of resistant microor-ganisms. Furthermore, the increased food require-ments of expanding populations may promote an

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Recommendations for intervention

8.1 Encourage collaboration between govern-ments, non-governmental organizations, pro-fessional societies and international agenciesto recognize the importance of antimicrobialresistance, to present consistent, simple andaccurate messages regarding the importanceof antimicrobial use, antimicrobial resistanceand its containment, and to implement strat-egies to contain resistance.

8.2 Consider the information derived from thesurveillance of antimicrobial use and antimi-crobial resistance, including the containmentthereof, as global public goods for health towhich all governments should contribute.

8.3 Encourage governments, non-governmentalorganizations, professional societies andinternational agencies to support the estab-lishment of networks, with trained staff andadequate infrastructures, which can undertakeepidemiologically valid surveillance of anti-microbial resistance and antimicrobial use toprovide information for the optimal contain-ment of resistance.

8.4 Support drug donations in line with the UNinteragency guidelines*.

8.5 Encourage the establishment of internationalinspection teams qualified to conduct validassessments of pharmaceutical manufacturingplants.

8.6 Support an international approach to the con-trol of counterfeit antimicrobials in line withthe WHO guidelines**.

* Interagency guidelines. Guidelines for Drug Donations, revised1999. Geneva, World Health Organization, 1999. WHO/EDM/PAR/99.4.

**Counterfeit drugs. Guidelines for the development of measuresto combat counterfeit drugs. Geneva, World Health Organi-zation, 1999. WHO/EDM/QSM/99.1.

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increased use of antimicrobial agents in agricul-ture, in turn contributing to the emergence ofantimicrobial resistance in zoonotic pathogens.Increases in global trade and travel have increasedthe speed with which both infectious diseases andresistant microorganisms can spread betweencontinents.

A call for international cooperative action

Containing antimicrobial resistance must involveconcerted international action. While the major-ity of the interventions recommended in earlierchapters of this document are directed at thenational level, interventions also need to be un-dertaken at an international level. It is no longerjustifiable for countries to exempt themselves fromtaking action to contain resistance, since inactionwill have both national and international conse-quences.

At the same time it is important to recognizethe barriers to action and work to remove them.Antimicrobial resistance is a multi-faceted prob-lem which calls for a multi-sectoral response, butit is a challenge to get all the sectors on board whenthe magnitude of the problem is unknown. Thereis a lack of coordination between different groupsand disciplines working in this field and even alack of knowledge that the different groups exist.Thus messages concerning antimicrobial use andresistance are often confusing and conflicting.Many countries lack the money, the skilled pro-fessionals and sufficient laboratory capacity totackle even the definition of the size of the prob-lem of resistance.

Closer cooperation between national govern-ments and agencies, professional societies,non-governmental organizations (NGOs) and in-ternational agencies would raise the importanceof antimicrobial resistance and its threat to healthand development up the political agenda and pro-vide additional resources for the implementationof the containment strategy. The development ofconsistent messages is critical. Internationalorganizations and NGOs can be particularlyeffective in raising the awareness of their mem-bers and the public about the importance of anti-microbial resistance and in lobbying governmentsabout the issue so that antimicrobial resistance isseen by governments as being important. Byincluding the containment of antimicrobial resist-ance in their aims and objectives, relevant NGOsand professional societies can educate their mem-bers. Furthermore, such international organiza-

tions can encourage both the health and educa-tion sectors of national governments to ensure thatsufficient education on infectious disease, antimi-crobial use and infection control is provided to allstudents in health care professions.

Experience of the successful implementation ofinterventions to contain resistance is a resourcethat should not be wasted; sharing informationbetween nations should be given high priority tomaximize the success of national strategies. Theseare areas in which organizations such as WHOcan and should play a leading role. A summary ofcurrently available national programmes and strat-egies to contain antimicrobial resistance is shownin Annex A; some of these have been analysed inmore detail (187).

Legal issues associated withantimicrobial resistance

Existing laws at international level require report-ing of a limited number of infectious diseases (242)but do not extend to any systematic reporting ofantimicrobial resistance. In the revision of the In-ternational Health Regulations (IHR) currentlyunder evaluation, potential international threatsposed by resistant infections could be recognized.Some countries have now made certain multi-resistant pathogens, e.g. MRSA, notifiable at thenational level. However, the global nature of theantimicrobial resistance problem means thatnational legal measures alone are insufficient. Atthe same time, the creation of new internationalduties would be undermined if not incorporatedinto national law (88).

Antimicrobial resistance as aGlobal Public Good for Health

The concept of Global Public Goods for Health(GPGH) and their development to assist in theprevention and containment of communicablediseases is growing in importance (243,244). Inthe context of the current review by the Commis-sion for Macroeconomics and Health, epidemi-ologically sound surveillance of antimicrobial use,resistance and the overall burden of infectious dis-eases is an important component of GPGH. Theseare public goods which have quasi-universal healthbenefits in terms of countries, populations andgenerations, both current and future, or at leastmeet the needs of current generations withoutforeclosing development options for future gen-erations (243). Given the increasing ease of trans-

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mission of infectious diseases between populationsand across national boundaries, and the impor-tance to future generations of the current devel-opment of resistance, antimicrobial resistance isclearly a global public “bad” for health, with theinverse, i.e. the containment of resistance, thusbeing a global public “good” for health.

Given that there is no global government asfinal arbiter, the challenge is to determine howthe containment of antimicrobial resistance as aGPGH can be implemented so as to benefit theworld’s people. The large number of participants,e.g. governments, private sector, NGOs and citi-zens, complicates coordination of effort, especiallyin an area such as this where there is significanttechnical uncertainty. The potential for freeriding (nations benefiting from the action ofothers without reciprocation) and prisoners’dilemma (lack of communication resulting in asuboptimal decision for all parties compared tothe decision which could have occurred with im-proved communication) are significant considera-tions. Thus, identifying who will define the globalpolitical agenda, the priorities for resource alloca-tion and the enforcement of penalties if needed,are important international issues if the contain-ment of antimicrobial resistance is to successfullybecome a GPGH.

There are also practical problems in seeking toimplement global initiatives under the banner ofthe GPGH concept. For example, there may befinancial and technological barriers to accessinginformation about containing antimicrobialresistance. Some countries may not be able tocollaborate on certain global initiatives, such assurveillance or adhering to certain treatmentprotocols, due to deficiencies in their health careinfrastructure—in this context, strengthenedhealth systems may themselves become a GPGH.

Nevertheless, GPGH aspects of containmentcould be of great benefit. For instance, surveil-lance systems could include mechanisms for alert-ing governments about the emergence of newresistant strains. The maintenance of a globaldatabase regarding antimicrobial resistance couldbe valuable to individual nations, although the dif-ferences worldwide in interpretation of laboratorysusceptibility tests currently pose a challenge tothis idea. The availability of a database on the dis-tribution of antimicrobials could assist countries,especially those with limited resources, to under-take such data collection independently. Datagathering is likely to be most effective if coordi-nated, or at least facilitated, internationally.

International surveillance

Surveillance of antimicrobial resistance and anti-microbial use should be performed at local andnational levels to guide clinical management andinfection control, to monitor treatment guidelinesand to update lists of essential drugs. Surveillanceis also a critical tool to monitor the effectivenessof interventions to contain resistance. Interna-tional collaboration on surveillance may also beof value, to share information as an early warningof new or unusual resistance events. At presentthere are no formal mechanisms or internationallegal instruments that require reporting (seeabove); such resistance events are detected throughresearch studies published in scientific journals.Furthermore, surveillance for rare events such asa new resistance phenotype has different require-ments in terms of populations to test and samplesize, etc. from those required for routine surveil-lance. Given the lack of standardization of meth-ods and the worldwide lack of national surveillancesystems generating epidemiologically valid data onantimicrobial resistance, the first priority shouldbe at the national level. International organiza-tions and donors should contribute to the streng-thening of laboratory capacity in developingcountries such that diagnostic services and resist-ance surveillance can be provided effectively. Thedevelopment of international surveillance stand-ards is needed—for example, WHO antimicro-bial resistance surveillance standards (209), WHOguidelines for the management of drug-resistanttuberculosis (245) and WHO protocols fordetection of antimalarial drug resistance (14).

International agencies, professional societiesand the pharmaceutical industry could play a rolein defining the mechanisms for the establishmentand maintenance of an international resistancealert. In addition, assurance should be sought fromthe editorial boards of international scientific jour-nals that public notification of an internationalalert does not jeopardise subsequent publication.

International cooperation should also be soughtto extend the availability of External QualityAssurance Schemes to resource-poor nations toassist in improving the quality of surveillance datafrom microbiology laboratories.

Antimicrobial quality and availability

Drug donations

Generous drug donations by pharmaceutical com-panies, either in the form of actual drug or by re-lease of patent, have had a dramatic effect on the

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availability of treatment in complex emergenciesand in elimination and eradication programmesfor certain disabling diseases in resource-poorsettings e.g. leprosy, onchocerciasis (river blind-ness) and lymphatic filariasis. Such donationsshould be strongly encouraged, but in certain situ-ations may need to be better coordinated tooptimize the selection of drugs provided and theirdistribution and accessibility to avoid duplicationand wastage.

Donors may inadvertently promote inappro-priate use of antimicrobials, thereby contributingto the resistance problem, through supportingdonations that are inappropriate in terms of thetype and quantity of drug, or because a lack oflocal infrastructure and capacity prevents theappropriate use of the donated drugs. Thus,donor agencies should ensure that the advice theygive to governments in drawing up their nationalhealth plans takes into account antimicrobial re-sistance issues. International action should betaken to ensure that all donations follow theinteragency guidelines (246). Alternatively, finan-cial donations to countries to ensure the purchaseof the most effective antimicrobials for their needstogether with strategies for distribution and usemay be more appropriate. International pro-grammes concerned with drug donations shouldhave capacity-building, training and supervisioncomponents, and should be evaluated using indi-cators that are relevant at the community level,i.e. at household and primary health care facility,where most antimicrobial use takes place.

International inspections of pharmaceuticalmanufacturing

National quality control of medicines and themonitoring of compliance with Good Manufac-turing Practice (GMP) are important to ensurethat products meet the required standards. Somecountries, e.g. in the EU, already accept findingsof inspections that have been performed byappropriately qualified persons from anothercountry. However, not all countries have the re-sources to perform regular detailed inspections ofmanufacturing plants; consequently, these do notget inspected unless they are the target of aninspection by a team from another country intowhich the product(s) is/are exported. In these in-stances, there may be scope for more extensivesharing of inspection reports between the authori-ties of the originator country and the inspectingcountry. It may also be possible to set up interna-

tional GMP inspection teams, made up of em-ployees of larger agencies who might contribute alimited number of hours per year to the team. Suchteams might conduct inspections of a selection ofmanufacturing sites at the invitation of, and onbehalf of, licensing authorities in resource-poorcountries.

Assessment report sharing schemes

Drug licensing authorities in many resource-poorcountries are often willing to license new medi-cines on the basis of their prior approval by otherregulatory agencies, e.g. the US FDA or the EU.In other countries, where a formal national reviewof application dossiers is performed, the assess-ment of safety and efficacy of new medicinal prod-ucts has sometimes been assisted by the existenceof certain assessment report sharing schemes. Ex-pansion of such schemes might benefit regulatoryauthorities thereby expediting the licensing of newdrugs.

The WHO Certification Scheme is an inter-national voluntary agreement, devised to enablecountries with limited regulatory capacity toobtain partial assurance from exporting countriesconcerning the safety, quality and efficacy of theproducts they plan to import. The scheme requiresthat the regulatory authorities of exporting coun-tries issue certificates when requested by import-ing countries.

Counterfeits

Antimicrobials are among the most frequentlycounterfeited drugs (191). Such drugs havepotentially major clinical consequences in termsof treatment failure and prolonged, or even in-creased, suffering. Concerted action to reduce thedistribution of counterfeit drugs is beyond thescope of this document and will require the im-plementation of a separate coordinated packageof interventions. National and internationalauthorities should collaborate to ensure theenforcement of relevant laws.

International codes of good marketing practice

Adherence to national and international codes ofmarketing practices (240) is critical to maintain-ing and improving the quality and accuracy of drugpromotion practices. The effective policing ofadherence to these codes of practice requiresinternational commitment, cooperation andsupervision (see also Chapter 7).

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Research and development of new drugsand vaccines

Research and development of new drugs andvaccines is expensive and time-consuming. Theestablishment of international research networksand further international cooperation on thestandardization of new drug registration require-ments could assist pharmaceutical companies withdrug development programmes and so facilitatethe availability of new drugs and vaccines.

International collaboration to improve andstandardize clinical trial designs in order tooptimize the clinical relevance of the data pro-duced would be helpful. More trials are neededthat aim not only to demonstrate equivalence ofthe new drug to the comparative agent but also toassist in identifying regimens which optimize treat-ment while minimizing resistance emergence.Such studies are required for products already onthe market as well as for new antimicrobials.

There is currently a general lack of interestamong companies in developing therapies for in-fections that primarily affect resource-poor regionsof the world. Innovative incentives, both push andpull mechanisms, need to be carefully consideredin collaboration with the pharmaceutical indus-try, so as to facilitate research into drugs andvaccines that would have dramatic health benefitsbut would likely not be profitable to develop.International agreements and cooperation onintellectual property rights, and new approachesto patents and to time-limited exclusivity arrange-ments should also be considered, particularly as ameans to stimulate additional pharmaceutical andclinical studies to support the licensure of olderproducts for additional, previously unregistered,indications.

Research to address knowledge gaps

Understanding all the issues associated with anti-microbial resistance is probably impossible, but itis clear that there are a number of key knowledgegaps. A clear research agenda highlighting the mostimportant knowledge gaps needs to be defined toguide future research efforts. In this manner, newdata that are important to understanding and com-bating resistance can be channelled back to im-prove future containment initiatives. To avoidpotentially wasteful duplication of effort andfinances, international cooperation to develop acommon, shared research agenda should be en-couraged. Defining a summary of major gaps inthe current knowledge regarding antimicrobial

resistance and its successful containment, andkeeping this summary up to date, could aid thisprocess.

The various research-funding bodies have dif-ferent priorities in terms of geographical andscientific emphasis, and process individual appli-cation protocols rather than using one generic for-mat. The creation of a single entry point throughwhich researchers could access information aboutpotential funding agencies, including specific con-tact details, their areas of interest and applicationrequirements, could be extremely beneficial. Thismay also assist greater coordination of effortbetween the various grant-giving bodies and avoidunnecessary duplication. WHO may be wellplaced to provide such a service if grant-givingbodies were prepared to collaborate.

The quality of research proposals is the key totheir likelihood of getting funding and producinguseful data. Thus, programmes that educatepotential researchers on the preparation of high-quality research proposals would serve to improvethe overall quality of research and reduce wastedresearch time and money. Greater coordinationof international effort to provide such training,either via the Internet or by means of targetedworkshops, could be most beneficial.

International support for nationalantimicrobial resistance containment

Much of the responsibility for implementing in-terventions will fall on national governments andthere are certain actions that only governmentscan assure, including the provision of public goods.However, many countries will need significantfinancial and technical support to address theproblem of antimicrobial resistance within thewider priorities of strengthened health systems anddisease control and prevention programmes. Bydirecting bilateral support to antimicrobial con-tainment, international donors can play a majorrole in the containment of antimicrobial resist-ance, not only for the benefit of individual coun-tries, but for the global good.

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PART C

Implementation of the WHO

Global Strategy

Implementation of the WHO Global Strategy

to simply as interventions) set out in the WHOGlobal Strategy, there is a practical need to iden-tify priorities. The identification of a core set ofinterventions to contain resistance could providegreat assistance to governments and health careworkers charged with the responsibility of imple-menting national policy.

Prioritization and implementation

STEP 1

The diseases requiring antimicrobial therapy canbe used as the basis for the first step in priori-tization. National priorities for the containmentof antimicrobial resistance can be guided by iden-tifying those diseases that are major problems inthe country. On the basis of the evidence used toformulate the WHO Global Strategy, the factorsmost relevant for antimicrobial resistance inselected diseases can be identified (see Tables 2–5). For each of these factors, those groups of in-terventions that are likely to be most effective areindicated. In this manner, the process for select-ing the necessary interventions to limit emergingantimicrobial resistance can be based on thediseases most prevalent in the country. In someinstances, the interventions may be the most chal-lenging to implement. Countries in which allmajor disease infections are common will need toaddress all groups of interventions.

Bacterial infections (other than tuberculosis)

The bacterial infections which contribute most tohuman disease are also those in which emergingantimicrobial resistance is most evident. In thisdocument they are grouped as four key diseases:

— diarrhoea (Table 2)

— respiratory tract infections and meningitis(Table 3)

— sexually transmitted infections (Table 4)

— hospital-acquired infections (Table 5)

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Introduction

To control the most prevalent infectious diseases,especially those that are related to poverty and forwhich vaccines are not available, antimicrobialsneed to be used more wisely, and in some cases,more widely. Appropriate access to effective anti-microbial agents is a major public health issue.Although many patients, especially in sub-Saharan Africa, continue to die as a result ofinadequate access to antimicrobials, an emergingproblem globally is the widespread indiscriminateuse of antimicrobials, especially antibacterialagents. As a result, many antimicrobials have nowbecome less effective due to the emergence of re-sistance. Simply expanding access to antimicrobialsis thus not sufficient; priority must also be givento their appropriate use.

Antimicrobial resistance affects a very broadrange of human diseases, including tuberculosis,malaria, AIDS and infections caused by other bac-terial, viral, fungal and parasitic pathogens(12,13,14,43,247,248). Despite this wide rangeof pathogens, the factors responsible for the emer-gence of resistance are very similar, with excessiveand inappropriate drug usage being the key driv-ers. Thus the broad management approach to con-taining antimicrobial resistance is similar for eachof these pathogens and diseases, although thereare some differences such as clinical presentation,diagnostic difficulty, treatment strategies andresistance detection, which are summarized inTable 1. Effective implementation of the WHOGlobal Strategy needs to recognize and be coher-ent with these differences.

The various factors identified to be responsi-ble for the emergence of antimicrobial resistancehave been discussed in the Part B—Issues andinterventions, and recommendations for inter-ventions have been developed on the basis ofthese factors. However, the identification andprioritization of those factors especially relevantin each national and regional context is more dif-ficult. In addition, given the large number of rec-ommendations for intervention (hereafter referred

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The problems related to resistance to the treat-ments-of-choice for these diseases are presentedin detail in accompanying documents(19,20,21,101). Tables 2–5 summarize the impor-tant factors influencing the emergence and spreadof resistance and set out the groups of interven-tions which need to be implemented to make animpact.

Tuberculosis

Tuberculosis is a leading cause of morbidity andmortality worldwide and resistance to antituber-culous therapy has increased dramatically inrecent years with evidence of substantive clinicaltreatment failures and increased person-to-persontransmission (12,13,43). The spread of HIV in-fection, with its associated immunosuppression,has resulted in an enormous increase in TB cases,most frequently among resource-poor communi-ties and in regions with weak health care systems.Inadequate treatment, including insufficient drugs(inadequate supply or mono-therapy), poor qual-ity drugs, and/or poor adherence to treatmentregimens have been major factors in the emergenceof multi-drug resistant TB (MDR-TB).

Although tuberculosis is a bacterial infection,it is considered different enough to warrant a dis-tinct focus. In addition, WHO has initiated ap-proaches to the containment of anti-tuberculosisdrug resistance. Faced with the global emergencyof tuberculosis, WHO adopted the DOTS (di-rectly observed treatment, short-course) interven-tion strategy for effective TB control (245,249).The principles of DOTS are the following:

— government commitment to a NationalTuberculosis Programme

— case detection through case-finding bysputum smear microscopy examination ofTB suspects in general health facilities

— standardized short-course chemotherapy to,at least, all smear-positive TB cases underdirectly observed therapy (DOT) underproper case management conditions

— regular uninterrupted supply of all essen-tial anti-TB drugs

— monitoring system for programme super-vision and evaluation.

The implementation of DOTS, presently in119 countries (12,43), prevents the generation ofMDR-TB through the cure of drug-susceptibleTB patients, who will evolve to MDR-TB if they

are not properly treated under a DOTS-based pro-gramme. However, the control of existing MDR-TB also has an extremely high priority. The GlobalProject on Anti-Tuberculosis Drug ResistanceSurveillance (managed jointly by WHO and theInternational Union against Tuberculosis andLung Disease) has identified high prevalence ofMDR-TB in some countries of Eastern Europe,Latin America, Africa, and Asia (12,245,250).MDR-TB does not respond as effectively as drug-susceptible TB to short-course chemotherapy withfirst-line drugs (48). Therefore, WHO and itspartners have launched DOTS-Plus (43,247,251)to manage MDR-TB with second-line drugs.DOTS-Plus includes the five components ofDOTS together with other aspects regarding long-term (18–24 months) therapeutic regimens withsecond-line drugs, and the use of drug suscepti-bility testing for diagnosis and therapeutic follow-up. Recommendations for therapeutic regimensfor the treatment of MDR-TB were compiled bya panel of experts convened by WHO (245,249).Pilot projects with some of the recommendedtreatment regimens are underway to assess thefeasibility and cost-effectiveness of using second-line drugs under programme conditions. Surveil-lance for drug resistance at the pilot sites is aprerequisite. Data generated through this initia-tive will be used to design evidence-based policyguidelines for the management of MDR-TB,which in turn will play a critical role in the con-tainment of drug resistance in tuberculosis.

Thus, many of the interventions that will needto be implemented to contain resistance in otherbacterial infections, such as political commitment,improvement in national regulatory frameworks,drug distribution and educational initiatives re-garding antimicrobial resistance, are in line with,and will further support, current initiatives to con-tain drug-resistant tuberculosis. Interventionpriorities have been identified for tuberculosis(Table 6).

Malaria

The majority of deaths in malarious areas con-tinue to be due to the lack of drug availability(252). However, emerging resistance is also greatlyundermining the efficacy of antimalarial treatmentregimens in many regions and is likely to pose amajor problem worldwide in the future.

As summarized in Table 7, one of the key driv-ers behind the emergence of antimalarial resist-ance is poor patient understanding about the

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disease and its appropriate treatment, resulting inindiscriminate short-course therapy with antima-larial agents. In addition, inappropriate prescrib-ing/dispensing and ineffective drug distributionsystems encourage such behaviour. The frequentlack of appropriate diagnostic facilities makesthe decision to treat difficult, since malaria sofrequently presents in an undifferentiated man-ner, as fever with, or without, headache. Thus,without the ability to confirm the diagnosis, thetendency is to treat every patient with a fever withantimalarials if they reside in a malaria endemicregion. Systems for surveillance of antimicrobialresistance are often weak and thus unable to in-form about the need to change treatment guide-lines. Despite early promising data, it appears thatvaccines effective against malaria are still someyears away (253). The priority for the contain-ment of antimalarial resistance is thus to concen-trate on the implementation of interventiongroups 1, 2, 5 and 6. This is in line with WHOpolicy as expressed in a document in preparationby the WHO Regional Office for Africa (254).

Viral infections

With the increasing development and use ofeffective antiretroviral agents, resistance is becom-ing apparent. In vitro resistance to antiretroviralagents among HIV strains appears to correlate withprior antiretroviral therapy and with clinical treat-ment failure (255,256,257,258,259). Highlyeffective combination therapy is considered to beless associated with the emergence of resistance.However, this is a rapidly progressing area ofscientific research in which the factors that driveresistance are less clearly defined than for bacte-rial infections and malaria. As the knowledge baseexpands, a prioritization of interventions can bedeveloped. At present it seems clear that improvedpatient and prescriber education (InterventionGroups 1 and 2), government regulations regard-ing licensure and surveillance of resistance (Inter-vention Group 5) and issues of drug and vaccinedevelopment (Group 6) will all be important.

Conclusion of Step 1

Given the disease-specific aspects of containmentof antimicrobial resistance associated with tuber-culosis, malaria and HIV infections and the pro-grammes already in place, it is proposed that thefirst phase of implementation of the WHOGlobal Strategy should be directed to bacterial in-

fections other than tuberculosis. The valuablelessons that will be learned during this first phaseshould impact on the implementation approachesused for containment of resistance in tuberculo-sis, malaria and viral infections. However, due tothe commonality of factors leading to antimicro-bial resistance in all diseases, many of the inter-ventions, instigated for containing resistance inbacterial infections—such as political commit-ment, regulatory framework, laboratory strength-ening, surveillance and education—will alsocontribute to resistance containment in otherdiseases at national level.

STEP 2

Defining a core set of interventions to containantibacterial resistance

While prioritization by disease group providessome direction for implementation, the identifi-cation of a core set for national implementation isrequired, within each group of interventions. Thisis particularly relevant to intervention groups 1,2, 3, 5 and 7. Issues related to group 4 (use ofantimicrobials in food-producing animals) haverecently been the subject of an extensive consulta-tive process at WHO and primarily involve inter-ventions in the agricultural industry (2). Thus theyare not considered further here. Interventionsrelating to drug and vaccine development andinternational aspects of containing antimicrobialresistance are extremely important, but since theydepend on supra-national factors, a number ofwhich involve the (multi-national) research-basedpharmaceutical industry, their prioritization atnational level is less relevant.

Implementation of the WHO Global Strategyat national level therefore requires prioritizationamong interventions in groups 1, 2, 3, 5 and 7.The prioritization presented in Step 3 is based onavailable evidence (summarized in Part B); whereevidence is lacking, it is based on the consensus ofa suitably qualified group of experts convened byWHO for this purpose.

STEP 3

Intra-group prioritization of interventions

Interventions within each group have beenprioritized according to the relative merits of eachintervention and ranked according to sequenceand importance of implementation. This complextask required consideration of multiple factorsrelating to each intervention including:

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— overall importance of the intervention toimproving the appropriate use of antimi-crobials and containing antimicrobialresistance

— likely impact, allowing for the expected costof implementation

— complexity of implementation consideringthe capacity of various health care systemsand political realities

— time required for implementation and theexpected lag period before outcomes couldbe expected

— the accuracy with which most health caresystems could assess the efficacy of eachintervention

— the interrelationship between various inter-ventions, including the need to undertakesome interventions in a logical sequence.

Inter-group prioritization of interventions

Following the prioritization within each group,interventions were ranked according to their over-all importance and timing (sequence) of imple-mentation without consideration of their group.Although it was recognized that some prioritiesmight vary depending on the health care systemin which they are to be implemented, it was foundthat this consideration did not impact to anysignificant extent on the priority given to themajority of very high priority interventions.

The results of Step 3 are shown in Table 8. In-terventions are grouped according to those whichshould be undertaken first, through to thosewhich, although important, are either dependenton the implementation of the earlier interventionsor are of lower priority. Within each priority i.e.first, second, third, interventions are not rankedbut listed in numerical order only and should beconsidered of equal importance. For example, forgroup 1, both interventions 1.2 and 1.3 are con-sidered to be of similar priority for implementa-tion, but both 1.2 and 1.3 are given higher prioritythan either 1.1 (second priority) or 1.4 and 1.5(third priority).

Comparisons across the groups of interventionsare more difficult but are important to achieve alogical and effective implementation. Within thenational reality, consideration of the sectorsinvolved in implementation of the interventionsshould allow a plan of action to be elaborated.

It must be emphasized that this prioritization

process only provides a guide to implementationand is not a rigid set of rules. Differences innational circumstances, health care systems andburden of the different infections may influencethe practicality with which some interventions canbe implemented and the local importance of oneintervention over another in a manner that is notaccurately reflected in Table 8. However, Table 8provides a working guide to the prioritization andsequence of implementation of interventions ingroups 1, 2, 3, 5 and 7.

Implementation guidelines

Effective implementation requires a number of keyfeatures, including a clear action plan, delegationof authority and power to act, resources and soundmechanisms to assess the effectiveness of interven-tions, allowing feedback of results to influencefuture implementation strategies. Thus, interven-tions identified in the prioritization process asbeing of fundamental and first priority (see Table8) have been considered in greater detail, specifi-cally identifying the following aspects as impor-tant for successful implementation:

— the optimal approach to implementation

— who should initiate the intervention,undertake and manage the intervention,and evaluate the intervention

— what process and outcome indicatorsshould be used for evaluation.

The proposed guidelines for implementationare detailed in “Suggested Model Framework forImplementation of Core Interventions”.

Monitoring outcomes

Ability to monitor the process to ensure that in-terventions are appropriately designed and targetedand their impact on the use of antimicrobials andthe prevalence of resistance will be crucial to thesuccessful implementation of the WHO GlobalStrategy. Without accurate information aboutantimicrobial usage and antimicrobial resistanceand their respective trends, the impact of inter-ventions will be difficult to interpret. Thus, anearly priority in the implementation of the WHOGlobal Strategy for all countries should be the es-tablishment of an appropriate framework to moni-tor accurately antimicrobial use and antimicrobialresistance (Intervention Group 5).

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Summary

This model implementation plan for the WHOGlobal Strategy is a guide only. Differences innational circumstances, health care systems andprevalent diseases may influence the approachestaken by governments to contain antimicrobialresistance. However, this is a complex area in whichit is often difficult to see the wood for the trees.The stepwise approach described above attemptsto highlight the interventions that are most im-portant and to identify a logical sequence forimplemention. The manner in which the WHOGlobal Strategy for Containment of Antimicro-bial Resistance is implemented will depend largelyon the decisions and actions of each nation, butthe consequences are likely to be felt worldwide.

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Recommendations for intervention

1. PATIENTS AND THE GENERAL COMMUNIT Y

Education1.1 Educate patients and the general community on

the appropriate use of antimicrobials.

1.2 Educate patients on the importance of meas-ures to prevent infection, such as immunization,vector control, use of bednets, etc.

1.3 Educate patients on simple measures that mayreduce transmission of infection in the house-hold and community, such as handwashing,food hygiene, etc.

1.4 Encourage appropriate and informed healthcare seeking behaviour.

1.5 Educate patients on suitable alternatives toantimicrobials for relief of symptoms anddiscourage patient self-initiation of treatment,except in specific circumstances.

2. PRESCRIBERS AND DISPENSERS

Education2.1 Educate all groups of prescribers and dispens-

ers (including drug sellers) on the importanceof appropriate antimicrobial use and contain-ment of antimicrobial resistance.

2.2 Educate all groups of prescribers on diseaseprevention (including immunization) and infec-tion control issues.

2.3 Promote targeted undergraduate and post-graduate educational programmes on theaccurate diagnosis and management ofcommon infections for all health care workers,veterinarians, prescribers and dispensers.

2.4 Encourage prescribers and dispensers to educatepatients on antimicrobial use and the importanceof adherence to prescribed treatments.

2.5 Educate all groups of prescribers and dispens-ers on factors that may strongly influence theirprescribing habits, such as economic incentives,promotional activities and inducements by thepharmaceutical industry.

Management, guidelines and formularies2.6 Improve antimicrobial use by supervision and

support of clinical practices, especially diagnos-tic and treatment strategies.

2.7 Audit prescribing and dispensing practices andutilize peer group or external standard compari-sons to provide feedback and endorsement ofappropriate antimicrobial prescribing.

2.8 Encourage development and use of guidelinesand treatment algorithms to foster appropriateuse of antimicrobials.

2.9 Empower formulary managers to limit antimi-crobial use to the prescription of an appropri-ate range of selected antimicrobials.

Regulation2.10 Link professional registration requirements for

prescribers and dispensers to requirements fortraining and continuing education.

3. HOSPITALS

Management3.1 Establish infection control programmes, based

on current best practice, with the responsibilityfor effective management of antimicrobialresistance in hospitals and ensure that all hos-pitals have access to such a programme.

3.2 Establish effective hospital therapeutics com-mittees with the responsibility for overseeingantimicrobial use in hospitals.

3.3 Develop and regularly update guidelines forantimicrobial treatment and prophylaxis, andhospital antimicrobial formularies.

3.4 Monitor antimicrobial usage, including thequantity and patterns of use, and feedbackresults to prescribers.

Diagnostic laboratories3.5 Ensure access to microbiology laboratory

services that match the level of the hospital, e.g.secondary, tertiary.

3.6 Ensure performance and quality assurance ofappropriate diagnostic tests, microbial identifi-cation, antimicrobial susceptibility tests of keypathogens, and timely and relevant reportingof results.

3.7 Ensure that laboratory data are recorded, pref-erably on a database, and are used to produceclinically- and epidemiologically-useful surveil-lance reports of resistance patterns amongcommon pathogens and infections in a timelymanner with feedback to prescribers and to theinfection control programme.

Interactions with the pharmaceutical industry3.8 Control and monitor pharmaceutical company

promotional activities within the hospital envi-ronment and ensure that such activities haveeducational benefit.

4. USE OF ANTIMICROBIALS INFOOD-PRODUCING ANIMALS

This topic has been the subject of specific consulta-tions which resulted in “WHO global principles for thecontainment of antimicrobial resistance in animalsintended for food”*. A complete description of all rec-

* http:// www.who.int/emc/diseases/zoo/who_global_principles.html

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ommendations is contained in that document andonly a summary is reproduced here.

Summary4.1 Require obligatory prescriptions for all anti-

microbials used for disease control in foodanimals.

4.2 In the absence of a public health safety evalua-tion, terminate or rapidly phase out the use ofantimicrobials for growth promotion if they arealso used for treatment of humans.

4.3 Create national systems to monitor antimicro-bial usage in food animals.

4.4 Introduce pre-licensing safety evaluation ofantimicrobials with consideration of potentialresistance to human drugs.

4.5 Monitor resistance to identify emerging healthproblems and take timely corrective actions toprotect human health.

4.6 Develop guidelines for veterinarians to reduceoveruse and misuse of antimicrobials in foodanimals.

5. NATIONAL GOVERNMENTS ANDHEALTH SYSTEMS

Advocacy and intersectoral action5.1 Make the containment of antimicrobial resist-

ance a national priority.

— Create a national intersectoral task force(membership to include health care profes-sionals, veterinarians, agriculturalists,pharmaceutical manufacturers, govern-ment, media representatives, consumersand other interested parties) to raise aware-ness about antimicrobial resistance, organ-ize data collection and oversee local taskforces. For practical purposes such a taskforce may need to be a government taskforce which receives input from multiplesectors.

— Allocate resources to promote the imple-mentation of interventions to contain resist-ance. These interventions should includethe appropriate utilization of antimicrobialdrugs, the control and prevention of infec-tion, and research activities.

— Develop indicators to monitor and evaluatethe impact of the antimicrobial resistancecontainment strategy.

Regulations5.2 Establish an effective registration scheme for

dispensing outlets.

5.3 Limit the availability of antimicrobials toprescription-only status, except in specialcircumstances when they may be dispensed onthe advice of a trained health care professional.

5.4 Link prescription-only status to regulations re-garding the sale, supply, dispensing and allow-able promotional activities of antimicrobialagents; institute mechanisms to facilitatecompliance by practitioners and systems tomonitor compliance.

5.5 Ensure that only antimicrobials meeting inter-national standards of quality, safety and efficacyare granted marketing authorization.

5.6 Introduce legal requirements for manufacturersto collect and report data on antimicrobialdistribution (including import/export).

5.7 Create economic incentives for appropriate useof antimicrobials.

Policies and guidelines5.8 Establish and maintain updated national Stand-

ard Treatment Guidelines (STGs) and encouragetheir implementation.

5.9 Establish an Essential Drugs List (EDL) consist-ent with national STGs and ensure the accessi-bility and quality of these drugs.

5.10 Enhance immunization coverage and otherdisease preventive measures, thereby reducingthe need for antimicrobials.

Education5.11 Maximize and maintain the effectiveness of the

EDL and STGs by conducting appropriateundergraduate and postgraduate educationprogrammes of health care professionals on theimportance of appropriate antimicrobial useand containment of antimicrobial resistance.

5.12 Ensure that prescribers have access to approvedprescribing literature on individual drugs.

Surveillance of resistance, antimicrobial usageand disease burden5.13 Designate or develop reference microbiology

laboratory facilities to coordinate effectiveepidemiologically sound surveillance of antimi-crobial resistance among common pathogensin the community, hospitals and other healthcare facilities. The standard of these laboratoryfacilities should be at least at the level of rec-ommendation 3.6.

5.14 Adapt and apply WHO model systems for anti-microbial resistance surveillance and ensuredata flow to the national intersectoral task force,to authorities responsible for the national STGsand drug policy, and to prescribers.

5.15 Establish systems for monitoring antimicrobialuse in hospitals and the community, and linkthese findings to resistance and disease surveil-lance data.

5.16 Establish surveillance for key infectious diseasesand syndromes according to country priorities,and link this information to other surveillancedata.

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6. DRUG AND VACCINE DEVELOPMENT

6.1 Encourage cooperation between industry,government bodies and academic institutionsin the search for new drugs and vaccines.

6.2 Encourage drug development programmeswhich seek to optimize treatment regimenswith regard to safety, efficacy and the risk ofselecting for resistant organisms.

6.3 Provide incentives for industry to invest in theresearch and development of new antimi-crobials.

6.4 Consider establishing or utilizing fast-trackmarketing authorization for safe new agents.

6.5 Consider using an orphan drug scheme whereavailable and applicable.

6.6 Make available time-limited exclusivity for newformulations and/or indications for use ofantimicrobials.

6.7 Align intellectual property rights to provide suit-able patent protection for new antimicrobialagents and vaccines.

6.8 Seek innovative partnerships with the pharma-ceutical industry to improve access to neweressential drugs.

7 PHARMACEUTICAL PROMOTION

7.1 Introduce requirements for pharmaceuticalcompanies to comply with national or inter-national codes of practice on promotionalactivities.

7.2 Ensure that national or internationally codes ofpractice cover direct-to-consumer advertising,including advertising the Internet.

7.3 Institute systems for monitoring compliancewith legislation on promotional activities.

7.4 Identify and eliminate economic incentives thatencourage inappropriate antimicrobial use.

7.5 Make prescribers aware that promotion inaccordance with the datasheet may not neces-sarily constitute appropriate antimicrobial use.

8. INTERNATIONAL ASPECTS OF CONTAININGANTIMICROBIAL RESISTANCE

8.1 Encourage collaboration between govern-ments, non-governmental organizations, pro-fessional societies and international agencies torecognize the importance of antimicrobialresistance, to present consistent, simple andaccurate messages regarding the importance ofantimicrobial use, antimicrobial resistance andits containment, and to implement strategies tocontain resistance.

8.2 Consider the information derived from the sur-veillance of antimicrobial use and antimicrobialresistance, including the containment thereof,as global public goods for health to which allgovernments should contribute.

8.3 Encourage governments, non-governmentalorganizations, professional societies and inter-national agencies to support the establishmentof networks, with trained staff and adequateinfrastructures, which can undertake epidemi-ologically valid surveillance of antimicrobialresistance and antimicrobial use to provideinformation for the optimal containment ofresistance.

8.4 Support drug donations in line with the UNinteragency guidelines*.

8.5 Encourage the establishment of internationalinspection teams qualified to conduct validassessments of pharmaceutical manufacturingplants.

8.6 Support an international approach to thecontrol of counterfeit antimicrobials in linewith the WHO guidelines**.

8.7 Encourage innovative approaches to incentivesfor the development of new pharmaceuticalproducts and vaccines for neglected diseases.

8.8 Establish an international database of potentialresearch funding agencies with an interest inantimicrobial resistance.

8.9 Establish new, and reinforce existing, pro-grammes for researchers to improve the design,preparation and conduct of research to containantimicrobial resistance.

* Interagency guidelines. Guidelines for Drug Donations, revised1999. Geneva, World Health Organization, 1999. WHO/EDM/PAR/99.4.

**Counterfeit drugs. Guidelines for the development of measuresto combat counterfeit drugs. Geneva, World Health Organi-zation, 1999. WHO/EDM/QSM/99.1.

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TABLE 1. COMPARISON OF DISEASE-RELATED RESISTANCE ISSUES

Issues Bacterial infections TB Malaria HIV

Appropriate use important Yes Yes Yes Yes

Inappropriate use contributes

to ↑ resistance Yes Yes Yes Yes

Need for new drug development Yes Yes Yes Yes

Detection of pathogen Reasonably easy Easy Easy Easy

& feasible

Detection of in vitro resistance Reasonably easy Feasible but Difficult, expensive Difficult, expensive

& feasible expensive rarely feasible limited availability

Treatment indication Generally pathogen- Pathogen-based Frequently Pathogen-based

based (± resistance) syndromic

Observed treatment No Yes–DOT No No

Antimicrobial treatment Single agent Multiple agents ≥1 agent Multiple agents

Short duration Long duration Short duration Lifelong

HIV interaction Some: Massive: Possibly —

Especially Personal &

nosocomial risk nosocomial risk

Potential impact of one Yes Little Some Yes

programme on another Some antibiotics Except: e.g. doxycyline, e.g. cotrimoxazole +

could affect malaria Rifampicin use on sulphadoxine- isoniazid prophylaxis

resistance. Staph. spp. pyrimethamine

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TABLE 2. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS): DIARRHOEAL DISEASES

Pathogens Important factors

Human Human Misuse in animal Surveillance Vaccinesmisuse in misuse in & agricultural of antibacterial potentially useful

the community hospitals industry resistance important future option

Campylobacter spp. +/– – +++ ++ –

Shigella spp. ++ – +/– ++ –

Salmonella spp:S. typhi & S. paratyphi ++ – – +++ +Non-typhoidal salmonellae –/+ – +++ +++ –

Vibrio cholerae + – – +++ +

Diarrhoeal disease overall +/++ ++/++ +++ –/+

High High High Moderate priority priority priority priority

Intervention Intervention Intervention InterventionGroups Groups Group Group

1, 2, 5 & 7 4 & 7 5 6

High priority interventions:Group 1 Patients and the general communityGroup 2 Prescribers and dispensersGroup 4 Use of antimicrobials in food-producing animalsGroup 5 National governments and health systemsGroup 7 Pharmaceutical promotion

TABLE 3. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS): RESPIRATORY TRACT INFECTIONS AND MENINGITIS

Pathogens Important factors

Human Human Misuse in animal Surveillance Vaccinesmisuse in misuse in & agricultural of antibacterial potentially useful

the community hospitals industry resistance important future option

Streptococcus pneumoniae +++ + – +++ +++

Haemophilus influenzae ++ – – ++ +++

Neisseria meningitidis + – – + +

Respiratory disease overall +++ + ++/+++ +++

High Moderate High Highpriority priority priority priority

Intervention Intervention Intervention InterventionGroups Groups Group Group

1, 2, 5 & 7 3 & 7 5 6

High priority Interventions:Group 1 Patients and the general communityGroup 2 Prescribers and dispensersGroup 5 National governments and health systemsGroup 6 Drug and vaccine developmentGroup 7 Pharmaceutical promotion

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TABLE 4. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS): SEXUALLY TRANSMITTED INFECTIONS

Pathogens Important factors

Human Human Misuse in animal Surveillance Vaccinesmisuse in misuse in & agricultural of antibacterial potentially useful

the community hospitals industry resistance important future option

Neisseria gonorrhoeae +++ – – +++ –

Haemophilus ducreyi +++ – – +++ –

Treponema pallidum – – – – –

Chlamydia trachomatis – – – – –

Sexually transmitted disease overall +++ +++

High Highpriority priority

Intervention InterventionGroups Group

1, 2, 5 & 7 5

High priority interventions:Group 1 Patients and the general communityGroup 2 Prescribers and dispensersGroup 5 National governments and health systemsGroup 7 Pharmaceutical promotion

TABLE 5. BACTERIAL INFECTIONS (OTHER THAN TUBERCULOSIS) : HOSPITAL-ACQUIRED INFECTIONS

Pathogens Important factors

Human Human Misuse in animal Surveillance Vaccinesmisuse in misuse in & agricultural of antibacterial potentially useful

the community hospitals industry resistance important future option

Gram-positive spp:Staphyloccus aureus + +++ – +++ –Streptococci – + – – –Enterococci – +++ +/++ ++ –

Gram-negative spp:Escherichia coli + ++ + ++ –Enterobacter spp + +++ – +++ –Klebsiella spp + +++ – +++ –Pseudomonas aeruginosa – +++ – ++ –

Fungi – ++ – – –

Hospital-acquired infections overall + ++/+++ + +++

High High Moderate Highpriority priority priority priority

Intervention Intervention Intervention InterventionGroups Groups Group Group

1, 2, 5 & 7 3 & 7 4 5

High priority interventions:Group 1 Patients and the general communityGroup 2 Prescribers and dispensersGroup 3 HospitalsGroup 5 National governments and health systemsGroup 7 Pharmaceutical promotion

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TABLE 6. TUBERCULOSIS

Pathogens Important factors

Human Human Misuse in animal Surveillance Vaccinesmisuse in misuse in & agricultural of antibacterial potentially useful

the community hospitals industry resistance important future option

Mycobacterium tuberculosis ++ – – +++ +/–

Tuberculosis overall ++ +++ +

High High Moderatepriority priority priority

Intervention Intervention InterventionGroups Group Group1, 2 & 5 5 6

High priority interventions:Group 1 Patients and the general communityGroup 2 Prescribers and dispensersGroup 5 National governments and health systems

TABLE 7. MALARIA

Pathogens Important factors

Human Human Misuse in animal Surveillance Vaccinesmisuse in misuse in & agricultural of antibacterial potentially useful

the community hospitals industry resistance important future option

Plasmodium vivax / ovale / malariae + – – + –

Plasmodium falciparum +++ – – +++ +/–

Malaria overall ++ +++ +/–

High High Moderatepriority priority priority

Intervention Intervention InterventionGroups Group Group1, 2 & 5 5 6

High priority interventions:Group 1 Patients and the general communityGroup 2 Prescribers and dispensersGroup 5 National governments and health systems

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TABLE 8. PRIORITIZATION OF INTERVENTIONS: CORE SET FOR NATIONAL IMPLEMENTATION(EXCLUDING GROUPS 4 AND 6)

Intervention Group Priority of implementation

Fundamental First Second Third

1. Patients and the general community 1.2 1.1 1.4

1.3 1.5

2. Prescribers and dispensers 2.1 2.6 2.4

2.2 2.7 2.5

2.3 2.9 2.10

2.8

3. Hospitals 3.1 3.2

3.5 3.3

3.6 3.4

3.7

3.8

5. National governments and 5.1 5.3 5.2 5.6

health systems 5.13 5.5 5.4 5.7

5.8 5.12

5.9 5.14

5.11 5.15

5.16

7. Pharmaceutical promotion 7.1 7.4

7.2 7.5

7.3

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Suggested model framework for implementation of core interventions (excluding group 4)

INTERVENTIONS—PRIORITY OF IMPLEMENTATION : FUNDAMENTAL

Intervention 5.1 Make the containment of antimicrobial resistance a national priority.

● Create a national intersectoral task force (membership to includehealth care professionals, veterinarians, agriculturalists, pharmaceuti-cal manufacturers, government, media representatives, consumers andother interested parties) to raise awareness about antimicrobial re-sistance, organize data collection and oversee local task forces. Forpractical purposes such a task force may need to be a governmenttask force which receives input from multiple sectors.

● Allocate resources to promote the implementation of interventionsto contain resistance. These interventions should include the appro-priate utilization of antimicrobial drugs, the control and prevention ofinfection, and research activities.

● Develop indicators to monitor and evaluate the impact of the antimi-crobial resistance containment strategy.

Implementation: ● Develop a National Strategy and make it a national priority

Who should initiate: ● Ministry of Health

● Other interested parties should contribute (e.g. Professional Societies)

● WHO to assist and contribute

Who should undertake and manage: ● National Intersectoral Task Force appointed by the Ministry of Health

● Sufficient resources should be allocated

Who should evaluate: ● WHO through the Regional Offices

Process Indicators: ● Appointment of the National Intersectoral Task Force

● Allocation of sufficient resources

Outcome Indicators: ● Has a National Strategy been developed?

Intervention 5.13 Designate or develop reference microbiology laboratory facilities to co-ordinate effective epidemiologically sound surveillance of antimicrobialresistance among common pathogens in the community, hospitals andother health care facilities. The standard of these laboratory facilitiesshould be at least at the level of recommendation 3.6.

Implementation: ● Establishment by government mandate

Who should initiate: ● Ministry of Health

● Sufficient resources should be allocated

Who should undertake and manage: ● Reference laboratories—accountable to Government Health Depart-ment

Who should evaluate: ● Internal and external, (e.g. international), quality assurance pro-grammes and performance assessments

● National Intersectoral Task Force audit

Process Indicators: ● Evidence of overseeing national resistance surveillance

● Documentation of resistance data

Outcome Indicators: ● Regular communication of resistance data to National IntersectoralTask Force and Government Health Department

● Commitment to teaching and training of laboratory staff includingtechnology transfer

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INTERVENTIONS—INTERVENTION PRIORITY: FIRST

Intervention 1.2 Educate patients on the importance of measures to prevent infection,such as immunization, vector control, use of bednets, etc.

Implementation: ● Develop a National Strategy and make it a national priority

Who should initiate: ● Ministry of Health

● Other interested parties should contribute (e.g. Professional Societies)

● WHO to assist and contribute

Who should undertake and manage: ● National Intersectoral Task Force (e.g. appointed by the Ministry ofHealth)

● Sufficient resources should be allocated

Who should evaluate: ● WHO through the Regional Offices

● Ministry of Health

Process Indicators: ● Appointment of the National Intersectoral Task Force

● Allocation of sufficient resources

Outcome Indicators: ● Has a National Strategy been developed?

● Immunization rates

Intervention 1.3 Educate patients on simple measures that may reduce transmission ofinfection in the household and community, such as handwashing, foodhygiene, etc.

Implementation: ● Develop a National Strategy and make it a national priority

Who should initiate: ● Ministry of Health

● Other interested parties should contribute (e.g. Professional Societies)

● WHO to assist and contribute

Who should undertake and manage: ● National Intersectoral Task Force (e.g. appointed by the Ministry ofHealth)

● Sufficient resources should be allocated

Who should evaluate: ● WHO through the Regional Offices

● Ministry of Health

Process Indicators: ● Appointment of the National Intersectoral Task Force

● Allocation of sufficient resources

Outcome Indicators ● Has a National Strategy been developed?

Interventions 2.1 and 2.2 2.1 Educate all groups of prescribers and dispensers (including drugsellers) on the importance of appropriate antimicrobial use andcontainment of antimicrobial resistance.

2.2 Educate all groups of prescribers on disease prevention (includingimmunization) and infection control issues.

Implementation: ● Develop a National Strategy and make it a national priority

● Identify interested organizations and opinion leaders, educators andsources of appropriate information

Who should initiate: ● National Intersectoral Task Force

Who should undertake and manage: ● Organizations delegated by the National Intersectoral Task Force

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INTERVENTIONS—INTERVENTION PRIORIT Y: FIRST (continued)

Who should evaluate: ● Ministry of Health

● National Intersectoral Task Force

● Professional organizations, universities, delegated organizations

Process Indicators: ● Opinion leaders identified, quantitative and qualitative assessmentsof educational exposure

Outcome Indicators: ● Levels of knowledge, attitudes and beliefs about antibiotic use, aware-ness of antimicrobial resistance and disease prevention issues in tar-get populations

Intervention 2.3 Promote targeted undergraduate and postgraduate educational pro-grammes on the accurate diagnosis and management of common in-fections for all health care workers, veterinarians, prescribers anddispensers.

Implementation: ● Develop a National Strategy and make it a national priority

● Identify interested organizations and opinion leaders, educators andsources of appropriate information

● Create and/or strengthen in-service training, professional developmentand continuing education for all health care workers appropriate tolocal context and problems.

Who should initiate: ● National Intersectoral Task Force—delegating to suitable interestedorganizations and opinion leaders

Who should undertake and manage: ● Organizations delegated by the National Intersectoral Task Force

Who should evaluate: ● National Intersectoral Task Force

● Professional organizations, universities and organizations delegatedby the National Intersectoral Task Force

Process Indicators: ● Opinion leaders identified

● Curriculum developed and implemented; quantitative and qualitativeassessments of educational exposure

Outcome Indicators: ● Levels of knowledge, attitudes and skills regarding management ofcommon infections and containment of antimicrobial resistance

Intervention 2.8 Encourage development and use of guidelines and treatment algorithmsto foster appropriate use of antimicrobials.

Implementation: ● National Intersectoral Task Force—delegating to suitable interestedorganizations, opinion leaders and educators

● Use of evidence-based principles of effective guideline development,including maximal participation of health care providers most involvedin managing the condition, involvement of end-users, systematic re-view and appraisal of evidence, involvement of consumers

Who should initiate: ● National Intersectoral Task Force

Who should undertake and manage: ● Organizations delegated by the National Intersectoral Task Force

Who should evaluate: ● National Intersectoral Task Force

● Organizations delegated by the National Intersectoral Task Force

Process Indicators: ● Production of guidelines and dissemination plan

Outcome Indicators: ● Level of uptake and indicators of appropriate use of antimicrobialsamong target health care providers

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INTERVENTIONS—INTERVENTION PRIORIT Y: FIRST (continued)

Intervention 3.1 Establish Infection Control Programmes, based on current best practice,with the responsibility for effective management of antimicrobial resist-ance in hospitals and ensure that all hospitals have access to such a pro-gramme.

Implementation: ● Establishment by government mandate

● Where possible the infection control programme should be part ofhospital (public and private) accreditation

● Sufficient resources should be allocated for implementation

Who should initiate: ● Hospital management delegating to an infection control committee

Who should undertake and manage: ● Infection Control Committee

Who should evaluate: ● National Intersectoral Task Force

● Ideally, external audit by a competent authority delegated by the Na-tional Intersectoral Task Force; in the absence of external evaluation,use benchmarking to other comparable institutions

Process Indicators: ● Infection control strategies, policies, guidelines documented

● Evidence of relevant data collection

Outcome Indicators: ● Data being used to reduce rates of hospital-acquired infection andantimicrobial resistance below an agreed target

Intervention 3.5 Ensure access to microbiology laboratory services that match the levelof the hospital, e.g. secondary, tertiary.

Implementation: ● Hospital management, through government if appropriate

● Sufficient resources should be allocated for establishment and main-tenance of laboratories

Who should initiate: ● Hospital management—in consultation with appropriately trainedstaff and learned societies

Who should undertake and manage: ● Microbiologists, or medical/scientific staff adequately trained in micro-biology

Who should evaluate: ● Benchmarking by Microbiology and Hospital management to otherlaboratories servicing similar institutions about range of diagnosticand susceptibility tests

Process Indicators: ● Implementation of Recommendations 3.6 and 3.7

Outcome Indicators: ● Implementation of Recommendations 3.6 and 3.7

Intervention 3.6 Ensure performance and quality assurance of appropriate diagnostictests, microbial identification, antimicrobial susceptibility tests of keypathogens, and timely and relevant reporting of results.

Implementation: ● Microbiology laboratory

Who should initiate: ● Microbiology laboratory management

Who should undertake and manage: ● Microbiology laboratory management

Who should evaluate: ● An internal and external (national or international) quality assuranceprogramme

● National Laboratory accreditation schemes where they exist

Process Indicators: ● Evidence of participation in quality assurance activities

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INTERVENTIONS—INTERVENTION PRIORIT Y: FIRST (continued)

Outcome Indicators: ● Performance level in quality assurance activities

● Continuing laboratory accreditation, where accreditation schemesexist

Interventions 5.3 and 5.5 5.3 Limit the availability of antimicrobials to prescription-only status, ex-cept in special circumstances when they may be dispensed on theadvice of a trained health care professional.

5.5 Ensure that only antimicrobials meeting international standards ofquality, safety and efficacy are granted marketing authorization.

Implementation: ● Ministry of Health establishing and delegating to a Government DrugRegulation Authority

Who should initiate: ● Ministry of Health delegating to a Government Drug RegulationAuthority

● National Intersectoral Task Force

Who should undertake and manage: ● Government Drug Regulation Authority

● National Intersectoral Task Force

Who should evaluate: ● Ministry of Health via Government Drug Regulation Authority

● National Intersectoral Task Force

Process Indicators: ● Presence of appropriate legislation

● Categorization of drugs, GMP inspection in place, restriction of drugsto registered outlets

Outcome Indicators: ● Results of Regulations enforcement—number of inspections, prosecu-tions, etc.

Interventions 5.8 and 5.9 5.8 Establish and maintain updated national Standard Treatment Guide-lines (STGs) and encourage their implementation.

5.9 Establish an Essential Drugs List (EDL) consistent with the nationalSTGs and ensure the accessibility and quality of these drugs.

Implementation: ● National Intersectoral Task Force—to establish a suitable Committeeconsisting of interested organizations, opinion leaders and educators

● Government Drug Regulation Authority

Who should initiate: ● National Intersectoral Task Force—to establish a suitable Committeeconsisting of interested organizations, opinion leaders and educators

● Government Drug Regulation Authority

Who should undertake and manage: ● Ministry of Health

● National Intersectoral Task Force

Who should evaluate: ● Ministry of Health

● National Intersectoral Task Force

Process Indicators: ● Production of national Standard Treatment Guidelines and EDL

● Plan for implementation and dissemination

Outcome Indicators ● Level of uptake, including indicators of appropriate use ofantimicrobials among target health care providers and use of EDLs

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Intervention 5.11 Maximize and maintain the effectiveness of the EDL and STGs by con-ducting appropriate undergraduate and postgraduate education pro-grammes of health care professionals on the importance of appropriateantimicrobial use and containment of antimicrobial resistance.

Implementation: ● Ministry of Health

● National Intersectoral Task Force—delegating to universities and othertraining institutions, including suitable interested organizations,opinion leaders and educators

Who should initiate: ● Ministry of Health

● National Intersectoral Task Force

Who should undertake and manage: ● Training institutions and organizations delegated by the NationalIntersectoral Task Force

● Professional bodies responsible for registration of health care profes-sionals

Who should evaluate: ● National Intersectoral Task Force

● Training institutions and organizations delegated by the NationalIntersectoral Task Force

Process Indicators: ● Curriculum developed and implemented; quantitative and qualitativeassessments of educational exposure

● Presence of specific registration requirements for health care profes-sionals

Outcome Indicators: ● Levels of knowledge, attitudes and skills regarding appropriate anti-microbial use and containment of antimicrobial resistance

● Assessment of Registration suitability based on continuing educationon antimicrobial use and containment of antimicrobial resistance

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258. Swanstrom R, Erona J. Human immunodefi-ciency virus type-1 protease inhibitors: therapeu-tic successes and failures, suppression andresistance. Pharmacol Ther, 2000, 86:145–170.

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260. World Health Organization. Containing antimi-crobial resistance. Review of the literature and re-port of a WHO workshop on the development of aglobal strategy for the containment of antimicrobialresistance. Geneva, Switzerland, 4–5 February1999. Geneva, 1999. WHO/CDS/CSR/DRS/99.2.

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Annexes

ANNEX A

National Action Plans

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Canada:

http://www.hc-sc.gc.ca/hpb/lcdc/bid/nosocom/fact1.html

European Union:

http://www.earss.rivm.nl/

France:

http://www.invs.sante.fr/

Norway:

http://odin.dep.no/shd/norsk/publ/handlingsplaner/030005-990326/index-dok000-b-n-a.html

Sweden:

http://www.sos.se/FULLTEXT/0000-044/0000-044.htm

United Kingdom:

http://www.doh.gov.uk/publications/pointh.htm

USA (Centers for Disease Control and Prevention, Atlanta):

http://www.cdc.gov/drugresistance/actionplan/

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ANNEX B

Participation in WHO Consultations

Dr Keith Klugman, The South African Institute forMedical Research, PO Box 1038, Johannesburg2000, South Africa

Dr Richard Laing, Associate Professor, Department ofInternational Health, Boston University School ofPublic Health, 715 Albany St, Boston, MA 02118-2526, USA

Dr David Lee, Deputy Director, Drug ManagementProgram, Management Sciences for Health,Arlington, USA

Dr Joel Lexchin, 121 Walmer Road, Toronto, Canada

Dr Donald E Low, Microbiologist-in-Chief, MountSinai Hospital, The Toronto Hospital, Toronto,Canada

Dr Peter Mansfield, Director, MaLAM, Australia

Dr Shaheen Mehtar, Western Cape, South Africa

Dr Le Van Phung, Central Biomedical Laboratory,Hanoi Medical School, Hanoi, Vietnam

Dr Mair Powell, Medicines Control Agency, MarketTowers, Room 1534, 1 Nine Elms Lane, London,UK

Dr Gro Ramster Wesenberg, Norwegian MedicineControl Authority, Sven Oftedsalsvei 6, Oslo 0950,Norway

Dr Dennis Ross-Degnan, DACP, Drug Policy ResearchGroup, Department of Ambulatory Care and Pre-vention, Harvard Medical School, Boston, USA

Dr Budiono Santoso, Department of Clinical Pharma-cology, Faculty of Medicine, Gadjah Mada Uni-versity Sekip, Yogyakarta, Indonesia

Dr Anthony Savelli, Director, Rational Pharmaceuti-cal Management, Management Sciences for Health,Arlington, USA

Dr Ben Schwartz, National Center for Infectious Dis-eases, Centers for Disease Control and Prevention,Atlanta, USA

Dr Wing Hong Seto, Department of Microbiology,Queen Mary Hospital, Hong Kong

Dr Walter Stamm, Head, Division of Allergy and In-fectious Diseases, University of Washington, Seattle,USA

Professor Mark Steinhoff, Department of InternationalHealth, School of Hygiene and Public Health,Johns Hopkins University, Baltimore, USA

WHO Global Strategy for the Containmentof Antimicrobial Resistance

Workshop to develop the framework document (260)Geneva, 4–5 February 1999

List of participants

Dr Tasleem Akhtar, Pakistan Medical Research Coun-cil, Shahnaki-e-Jamurait Sector G5/2, Islamabad,Pakistan

Dr Susan Bacheller, Office of Health and Nutrition,USAID/G/PHN/HN/HPSR, Washington, USA

Dr Richard Bax, Director and Vice-President, Anti-infective Therapeutic Unit, Clinical Research andDevelopment, SmithKline Beecham Pharmaceuti-cals, Harlow, Essex, UK

Dr Tom Bergan, President, International Society ofChemotherapy, Institute of Medical Microbiology,Rikshospitalet (National Hospital), Oslo, Norway

Dr Nancy Blum, United States Pharmacopeia,Rockville, USA

Dr Otto Cars, Department of Infectious Diseases,Uppsala University Hospital, Uppsala, Sweden

Dr Keryn Christiansen, Clinical Microbiologist, De-partment of Microbiology & Infectious Diseases,Royal Perth Hospital, Western Australia

Dr Andres de Francisco, International Health Special-ist, Global Forum for Health Research, c/o WorldHealth Organization, 1211 Geneva 27, Switzerland

Dr David Fidler, Indiana University School of Law, 211South Indiana Avenue, Bloomington IN 47405-1001, USA

Professor Widjoseno Gardjito, Department of Surgery,Dr Soetomo Hospital, Jalan Professor Dr Moestopo6–8, Surabaya 60286, Indonesia

Dr Judy Gilley, (British Medical Association), Corn-wall House Surgery, Cornwall Road, London N31LD, UK

Dr Neal Halsey, Director of Division of Disease Con-trol, Johns Hopkins University, Baltimore, USA

Professor Pentti Huovinen, Antimicrobial ResearchLaboratories, National Public Health Institute,Turku, Finland

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Dr J Todd Weber, National Center for Infectious Dis-eases, Centers for Disease Control and Prevention,Atlanta, USA

Dr H Wegener, Danish Zoonosis Centre, NationalVeterinary Laboratory, Copenhagen, Denmark

Professor M Wierup, Swedish Animal Health Service,Johanneshov, Sweden

Representatives from USAID

Dr Susan Bacheller

Dr Anthony Boni

Dr Caryn Miller

WHO Global Strategy for theContainment of Antimicrobial Resistance

Prioritization and Implementation WorkshopGeneva, 12–14 September 2000

List of participants

Dr Samuel Azatyan, Head of the Department ofPharmacovigilance and Rational Use of Drugs,Armenian Drug and Medical Technology Agency(ADMTA), Yerevan, Armenia

Dr Luis Bavestrello, Infectious Diseases Specialist andClinical Pharmacologist, Jefe, Unidad deinfectología, Hospital dr. Gustavo Fricke, Viña delMar, Chile

Dr Mike Bennish, Director, Africa Centre for Healthand Population Studies, Mtubatuba, South Africa

Dr Richard E Besser, Respiratory Diseases Branch (C-23), Centers for Disease Control and Prevention,Atlanta, USA

Dr Christopher C Butler, Senior Lecturer, Departmentof General Practice, University of Wales College ofMedicine, Llanedeyrn Health Centre, Cardiff, UK

Dr John Chalker, Management Services for Health,Arlington, USA

Professor Ranjit Roy Chaudhury, National Institute ofImmunology, Shahid Jeet Sing Marg, New Delhi,India

Dr Narong Chayakula, Secretary General, Food andDrug Administration, Ministry of Public Health,Muang, Nonthaburi, Thailand

Professor Thomas Cherian, Christian Medical College,Vellore, India

Mrs Parichard Chirachanakul, Food and Drug Admin-istration, Ministry of Public Health, Muang,Nonthaburi, Thailand

Dr Scott Fridkin, Medical Epidemiologist, HospitalInfections Program (E-55), Centers for DiseaseControl and Prevention, Atlanta, USA

Dr Marcelo F Galas, Profesional Servicio Anti-microbianos, Instituto Nacional de Enferme-dadesInfecciosas—ANLIS—”Dr. Carlos G. Malbran”,Buenos Aires, Argentina

Dr Manuel Guzmán-Blanco, President of the Commit-tee on Antibiotics of the Sociedad Panamericanade Infectología, (Pan American Society of Infec-tious Diseases), Unidad de Microbiología y Enf.Infecciosas, Hospital Vargas, Centro Médico deCaracas, Caracas, Venezuela

Professor King Holmes, University of Washington,Harborview Medical Center, Seattle, USA

Dr Abdulrahman Hassan Ishag, Hospitals Administra-tion, Department of Curative Medicine, Ministryof Health, Riyadh, Kingdom of Saudi Arabia

Professor KK Kafle, Institute of Medicine, TU Teach-ing Hospital, Kathmandu, Nepal

Dr Adeeba Kamarulzaman, Associate Professor, Head,Infectious Diseases Unit, Department of Medicine,University Malaya, Kuala Lumpur, Malaysia

Dr Göran Kronvall, Clinical Microbiology—MTC,Karolinska Hospital, Stockholm, Sweden

Dr David Lee, Deputy Director, Drug ManagementProgram, Management Services for Health,Arlington, USA

Dra Alina Llop, Directora del Laboratorio Nacional deReferencia de Microbiología, Sub-DirectoraInstituto Medicina Tropical “Pedro Kouri”, LaHabana, Cuba

Mrs Precious Matsoso, Department of Health, Preto-ria, South Africa

Dr Thomas O’Brien, Microbiology Laboratory,Brigham and Women’s Hospital, Boston, USA

Dr David Ofori Adjei, Director, Nogouchi MemorialInstitute for Medical Research, University ofGhana, Legon, Accra, Ghana

Dr Philip Onyebujo, Department of Health, Pretoria,South Africa

Associate Professor Neil Paget, Royal Australasian Col-lege of Physicians, Sydney, Australia

Dr Ricardo Pérez-Cuevas, Investigador Asociado,Unidad de Investigacion Epidemiologica y enServicios de Salud CMN Siglo XXI, InstitutoMexicano del Seguro Social, Mexico, Mexico

Dr Mair Powell, Medical Assessor, Licensing Division,Department of Health, Medicines Control Agency,London, UK

Dr Dennis Ross-Degnan, Associate Professor, DrugPolicy Research Group, Department of Ambula-tory Care and Prevention, Harvard Medical School,Boston, USA

Professor Sidorenko Sergei, Department of Microbiol-ogy, Russia Medical Academy of PostgraduateStudies, National Research Centre of Antibiotics,Moscow, Russia

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Dr Richard Smith, Senior Lecturer, Health EconomicsGroup, School of Health Policy and Practice, Uni-versity of East Anglia, Norwich, UK

Soeparmanto, Dr Sri Astuti S, Kepala Badan LitbangKesehatan, Head, National Institute of Health Re-search and Development, Jakarta, Indonesia

Dr Christian Trigoso, Head of the Bacteriology De-partment, Instituto de Laboratorio de Salud, La Paz,Bolivia

Dr Peet Tüll, Medical Director, Division of Commu-nicable Diseases Control, The National Board ofHealth and Welfare, Stockholm, Sweden

Associate Professor John Turnidge, Women’s and Chil-dren’s Hospital, North Adelaide, Australia

Dr Kris Weerasuriya, Professor of Pharmacology andSecretary of the Drug Evaluation Sub-Committee(DESC), Ministry of Health, Department ofPharmacology, Faculty of Medicine, University ofColombo, Colombo, Sri Lanka

Representatives from WHO Regional Offices

Dr Massimo Ciotti, Communicable Diseases, WHORegional Office for Europe, Copenhagen

Dr Sudarshan Kumari, Regional Advisor, Blood Safetyand Clinical Technology, WHO Regional Officefor South East Asia, New Delhi, India

WHO Meeting on International Aspects ofthe Containment of AntimicrobialResistance

Geneva, 11–12 January 2001

List of participants

Alliance for the Prudent Use of Antibiotics (APUA)

Kathleen T Young, Executive Director, Boston, USA

American International Health Alliance

Thomas O’Brien, Head, Department of Microbiology,Brigham and Women’s Hospital, Boston, USA

James P Smith, Executive Director, Washington, USA

Centers for Disease Control and Prevention (CDC)

David Bell, Assistant to the Director for AntimicrobialResistance, National Center for Infectious Diseases,Atlanta, USA

Conféderation Mondiale de L’Industrie de la Santé Animale(COMISA)

Anthony J Mudd, Vice President/Secretary General,Representative Body of the Worldwide AnimalHealth Industry, Brussels, Belgium

European Commission—Luxembourg

Hartmut Buchow, Euroforum Building, Luxembourg

European Society for Clinical Microbiology and Infectious Dis-ease (ESCMID)

Peter Schoch, ESCMID Basel, Switzerland

Global Forum for Health Research

Andres De Francisco, Senior Public Health Specialist,c/o World Health Organization, Geneva, Switzer-land

International Association of Medical Laboratory Technolo-gists (IAMLT)

Martha A Hjálmarsdóttir, President, Reykjavík, Iceland

International Committee of the Red Cross

Ann Aerts, Head of Health Services, Geneva, Switzer-land

International Council of Nurses

Tesfamicael Ghebrehiwet, ICN Consultant, Nursing& Health Policy, Geneva, Switzerland

International Council of Women

Pnina Herzog Ph. C.M.R. Pharm.S., President, Jeru-salem , Israel

International Federation of Infection Control (IFIC)

Anna Hambraeus, Division for Hospital Control, Uni-versity Hospital, Uppsala, Sweden

International Federation of Pharmaceutical Manufacturers’Association (IFPMA)

Peter Hohl, Pharma Research Preclinical InfectiousDiseases, F. Hoffmann—La Roche Ltd, Basel, Swit-zerland

Patricia Hogan, Senior Manager, Pfizer Inc., New York,USA

Tony White, Anti-Infectives Strategic Product Devel-opment, Smithkline Beecham Pharmaceuticals,Harlow, Essex ,UK

International Pharmaceutical Federation (FIP)

Diane Gal, FIP Project Coordinator, Den Haag, TheNetherlands

International Society of Chemotherapy

Jean-Claude Pechère, Secrétaire général, Université deGénétique et Microbiologie, Université de GenevaCHU, Geneva 4, Switzerland

International Society for Infectious Diseases (ISID)

Keryn Christiansen, Co-Chair, ISID Antibiotic TaskForce, Department Microbiology and InfectiousDiseases, Royal Perth Hospital, Perth, Australia

Permanent Mission of Norway to the United Nations Officeand other International Organizations at Geneva

O Christiansen, Counsellor, Geneva, Switzerland

The Wellcome Trust

Robert E Howells, Director of Science Programmes,London, UK

Richard Lane, Head of International Programmes, Lon-don, UK

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UNICEF

Abdel W El Abassi, UNICEF, New York, USA

USAID Rational Pharmaceutical Management Project

John Chalker, Arlington, USA

UK Department of Health

Jane Leese, Senior Medical Officer, Skipton House,London, UK

US Department of Health and Human Services /National In-stitute of Allergy and Infectious Diseases

Marissa A Miller, Antimicrobial Resistance ProgramOfficer, Bethesda, Maryland, USA

World Self-Medication Industry (WSMI)

Jerome A Reinstein, Director-General, London, UK

World Trade Organization

João Magalhães, Counsellor, Agriculture and Com-modities Division, Centre William Rappard, Ge-neva, Switzerland

World Veterinary Association

Herbert P Schneider, Vice-President, AGRIVET Con-sultants, Windhoek, Namibia

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M Lindsay Grayson, Austin and Repatriation MedicalCentre, Melbourne, Australia

Stuart B Levy, President APUA, Boston, USA

Jean-Claude Pechère, also representing the InternationalSociety of Chemotherapy

Mair Powell, Medicines Control Agency, London, UK

Richard Smith, School of Health Policy and Practice,University of East Anglia, Norwich, UK

Representatives from WHO

David Heymann, Executive Director, CommunicableDiseases

Guénaël Rodier, Director CSR

Hans Troedsson, Director CAH