Apua, 2011

WHO/CDS/CSR/DRS/2001.
10
ORIGINAL: ENGLISH
DISTRIBUTION: GENERAL
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

Antibiotic resistance:
synthesis of
recommendations by
expert policy groups
Alliance for the Prudent
Use of Antibiotics
Copies can be obtained from the CDS Information Resource Centre World Health Organization
World Health Organization, 1211 Geneva 27, Switzerland
fax: +41 22 791 42 85 • email: cdsdoc@who.int
WHO/CDS/CSR/DRS/2001.10
ORIGINAL: ENGLISH
DISTRIBUTION: GENERAL
Antibiotic resistance:
synthesis of
recommendations
by expert policy groups
Alliance for the Prudent Use of Antibiotics
JL Avorn, JF Barrett, PG Davey, SA McEwen,
TF O’Brien and SB Levy
Boston, MA, United States of America
World Health Organization

TA OBI NT TEG FOR
SIS CR E RA T
NC AL OF Y
RE IMI AINM L ST MEN
T T A U
AN CON LOB DOC
G D
FO WHO OUN
E R
E
T H AC KG
AB
R
Acknowledgements
The World Health Organization (WHO) and the Alliance for the Prudent use of Antibiotics (APUA)
acknowledge the United States Agency for International Development (USAID) for their concern about
the issue of antibiotic resistance and their support in producing this report.
Stuart B. Levy, President of APUA, ensured that the report was accurate and comprehensive and that it
would benefit both Ministers of Health and health care workers at the local level who can make a differ-
ence.
Kathleen Young, the Executive Director of APUA, recognized the contribution that APUA could make to
support WHO’s Global Strategy through this project. She designed the initial format and assured the
quality of the report.
Barbara Souder, the Project Director, coordinated all aspects of this report and Margaret Kruse, a scientist
and writer, acted as chief technical writer and production engineer.
APUA gratefully acknowledges the assistance of its support staff: Sarann Bielavitz, for summarizing the
reports by the expert policy groups; Brian Price for the graphics; Jennifer Mills-Knutsen for administrative
coordination; and Ellen Wells for bibliographic and editorial assistance.
Julia J. Chuang, from Scientific Information Resources, Bristol-Myers Squibb, United States, is gratefully
acknowledged for her research work on Chapter IV.
© World Health Organization 2001

This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organiza-
tion. The document may, however, be freely reviewed, abstracted, reproduced and translated, in part or in whole, but not for sale or
for use in conjunction with commercial purposes.
The views expressed in documents by named authors are solely the responsibility of those authors.
The designations employed and the presentation of the material in this document, including tables and maps, do not imply the
expression of any opinion whatsoever on the part of the secretariat of the World Health Organization concerning the legal status of
any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on
maps represent approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by
WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary
products are distinguished by initial capital letters.
Designed by minimum graphics
Printed in Switzerland
WHO/CDS/CSR/DRS/2001.4 DRUG RESISTANC IN MALARIA
Contents
List of acronyms v
Executive Summary 1
Introduction Stuart B. Levy 11
Chapter I Improve and expand surveillance Thomas F. O’Brien 15
Chapter II Increase awareness: optimize patient and provider behaviour Jerry L. Avorn 33
Chapter III Strengthen sanitation, infection control, and regulatory measures Peter G. Davey 39
Chapter IV Encourage research and product development John F. Barrett 53
Chapter V Improve antibiotic use in animals Scott A. McEwen 65
Conclusion Stuart B. Levy 81
References 83
Some useful web sites 87
Appendix A Summaries of reports by expert policy groups (1987–2000) 89
Appendix B Local action around the world 125
Appendix C About the authors 153
iii
WHO/CDS/CSR/DRS/2001.10 ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS
List of acronyms
AHRQ Agency for Healthcare Research DTC Drug and Therapeutic Committee,
and Quality, United States Viet Nam
AIDS Acquired Immune Deficiency DVA Department of Veterans’ Affairs,
Syndrome United States
AIEPI Integrated Management of Child- EARS European Antimicrobial Resistance
hood Diseases, Pan American Surveillance
Health Organization EMEA European Medicines Evaluation
APO Audit Project Odense Agency
AR antimicrobial/antibiotic resistance ENT ear, nose, and throat
ARM antimicrobial resistance manage- EPA Environmental Protection Agency,
ment/manager/monitor United States
ASM American Society for Microbiology ESBIC European Society for Biomodu-
BBSRC Biotechnology and Biological lation and Chemotherapy
Sciences Research Council, United ESCMID The European Society for Clinical
Kingdom Microbiology and Infectious
BSAC British Society for Antimicrobial Diseases
Chemotherapy EU European Union
CA-SFM Comite de l’Antibiogramme de la FDA Food and Drug Administration,
Société Française de Microbiologie, United States
France FESCI Federation of the European
CDC Centers for Disease Control and Societies for Chemotherapy
Prevention, United States GAARD Global Advisory on Antibiotic
CEM/NET Centro de Epidemiologia Molecu- Resistance Data
lar, Portugal/Network for Epide- GAO General Accounting Office,
miological Tracking of Antibiotic United States
Resistant Pathogens, United States GPs General Practitioners
CISET Committee on International HACCP Hazard Analysis, Critical Control
Science Engineering and Technol- Point, United Kingdom
ogy, United States HCFA Health Care Financing Adminis-
CMO Chief Medical Officer tration, United States
CNS central nervous system HELICS Hospitals in Europe Link for
CPD continuing professional develop- Infection Control through Surveil-
ment, United Kingdom lance
DANMAP Danish Integrated Antimicrobial HGOH Hospital Gynecology-Obstetric
Resistance Monitoring and Hanoi, Viet Nam
Research Program HIV Human Immunodeficiency Virus
DDA Department of Drug Administra- HMG His/Her Majesty’s Government
tion, Nepal HMO Health Maintenance Organization,
DDD defined daily dose United States
DHHS Department of Health and Human HRSA Health Resources and Services
Services, United States Administration, Department of
DoD Department of Defense, United Health and Human Services,
States United States
v
ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS WHO/CDS/CSR/DRS/2001.10
ICARE Intensive Care Antimicrobial NNISS National Nosocomial Infections

Epidemiology, Centers for Disease Surveillance System
Control and Prevention, United OIE Office International des Epizooties
States OTA Office of Technology Assessment,
ICU intensive care unit United States Congress
ID infectious disease OTC over the counter
IDSA Infectious Diseases Society of PAHO Pan American Health Organiza-
America tion
IMF International Monetary Fund PCR polymerase chain reaction
IND investigational new drug PHCP/GTZ Primary Health Care Project/
IOM Institute of Medicine, United Deutsche Gessellschaft für
States Technische Zusammenarbeit
ISC International Society of Chemo- PHLS Public Health Laboratory Service,
therapy England and Wales
KOL key-opinion-leader PHON Pharmaceutical Horizon of Nepal
MDRTB multidrug-resistant tuberculosis PRP penicillin-resistant pneumonia
MIC minimal inhibitory concentration, PRSP penicillin-resistant Streptococcus
testing method pneumoniae
MRC Medical Research Council, QC quality control
England RCCDC Regional Center of Communicable
MRSA methicillin-resistant Staphylococcus Disease Control, Malmo, Sweden
aureus R&D research and development
MSH Management Sciences for Health, RTI respiratory tract infection
Boston, United States SIGN Scottish Intercollegiate Guideline
NAO National Audit Office, United Network
Kingdom SMA Scottish Microbiology Association
NARMS National Antimicrobial Resistance SMAC Standing Medical Advisory
Monitoring System, United States Committee, United Kingdom
NATAC National Antibiotic Therapeutic SRH Smolensk Regional Hospital,
Advisory Committee, Nepal Russia
NCCLS National Committee for Clinical STD sexually transmitted disease
and Laboratory Standards, Europe STRAMA Swedish Strategic Program for the
NEPI Network for Rational Use of Antimicrobial
Pharmacoepidemiology, Sweden Agents and Surveillance of
NHS National Health Service, United Resistance
Kingdom TB tuberculosis
NIAID National Institute of Allergy and TIGR The Institute for Genomic
Infectious Diseases, United States Research, Maryland, United States
NIBSC National Institute for Biological TSN The Surveillance Network,
Standards and Control, United California and Virginia, United
Kingdom States
NICE National Institute for Clinical USAID United States Agency for Interna-
Excellence, Great Britain tional Development
NICE Nosocomial Infection Control in USDA Department of Agriculture, United
Europe States
NIH National Institutes of Health, UTI urinary tract infection
United States VRE vancomycin-resistant enterococci
NINSS Nosocomial Infection National WB World Bank
Surveillance Scheme WHO World Health Organization
NISS Nosocomial Infection Surveillance WMA Welsh Microbiological Association
System WP Working Party
NME new molecular entity WTO World Trade Organization
NSG National Steering Group
vi
Executive Summary
In the not too distant past, antibiotics could be APUA also collected information from their in-
counted on to treat a bacterial infection. Those days ternational chapters about experiences at the local
are almost gone, as bacteria have emerged that are level; these reports, reflecting the views of APUA
resistant to each of the antibiotics currently on the Chapters and not necessarily reflecting national
market. Deaths have occurred as a result of untreat- policy, are included in Appendix B.
able bacterial infections. This trend is expected to After review, analysis and update, and with ad-
continue unless the problem of antibiotic resist- ditional insights from the authors of the individual
ance can be curbed. In response to this threat, the chapters of this review, the key recommendations
World Health Organization (WHO) has worked emanating from the 25 expert reports are summa-
with many partners, including the Alliance for the rized below under the following headings:
Prudent Use of Antibiotics (APUA), to develop the
• Increase awareness of the antibiotic resistance
WHO Global Strategy for Containment of Anti-
problem
microbial Resistance (26).
As part of the development process of the WHO • Improve surveillance of antibiotic resistance
Global Strategy, WHO commissioned a series of • Improve antibiotic use in people
technical reviews. APUA responded to WHO’s
request to review reports on antibiotic resistance • Regulate antibiotic use in animals
prepared by prestigious scientific and governmen- • Encourage new product development
tal organizations over the last two decades. The pur-
• Increase resources to curb antibiotic resist-
pose of this review is to identify areas of consensus
ance in the developing world
in the experts’ recommendations in the selected
reports, update the findings, consider the barriers • Increase funding for surveillance, research and
to concerted action and suggest ways to move from education.
recommendations to action.
Under each heading recommendations have
Twenty-five expert reports (1–25—see Table 1,
been organized on the basis of the suggested level
Table 3 and Appendix A) compiled by scientific
of decision-making necessary for implementation
and medical authorities were selected for this re-
of the intervention i.e., “who can do what”.
view by APUA because they are highly referenced
A more detailed analysis of these recommenda-
in the literature and reflect extensive deliberations
tions is provided by the author of each chapter.
by a wide variety of key expert policy groups. In
developing this synthesis, APUA consulted five
medical and scientific experts on antibiotic resist- Increase awareness of the antibiotic
ance who reviewed relevant sections of the reports. resistance problem
Their reviews are presented in Chapters I–V and For real reforms in the use of antibiotics to occur,
cover the major areas of intervention, i.e., surveil- individuals in the general public and in public
lance, education of patient and provider behaviour, health and provider groups at the international,
prevention (including sanitary and infection con- national, and local levels must take ownership of
trol), research and product development, and anti- the problem and provide leadership to reverse this
biotic use in animals. Each author focused on those public health crisis.
reports with extensive subject matter related to their
area of investigation. In addition to summarizing
International organizations
findings from the expert policy reports, updated
information, references and authors’ insights were • Obtain worldwide commitments to establish
added. prudent antibiotic use policies.
1
National and municipal organizations Health care workers

• Publicize the outcomes of programmes from other • Educate the general public:
countries: Communicate global trends in antibi-
— Physicians: Discuss proper antibiotic use
otic resistance with potential local impact, such
with all patients.
as the results of the European Union’s legisla-
— Veterinarians: Discuss ways to minimize an-
tion against use of antibiotics in growth promo-
tibiotic use with animal owners, such as im-
tion. Collect and publicize the economic
proved farm hygiene and alternatives to
consequences, or lack thereof, of Denmark and
antibiotics as growth promoters.
Sweden’s complete ban on growth promoters.
• Educate the general public: The United Kingdom’s Improve surveillance of antibiotic
campaign to “cherish and conserve your natural resistance
flora” pointed out the beneficial aspects of bac-
teria which can be obliterated by excessive anti- The urgent recommendation for surveillance of
biotic use. A campaign about proper antibiotic antimicrobial resistance and plans for performing
use should be aimed at young children, the surveillance have been elaborated upon over the past
parents of young children, workers in day care two decades. Over that same period a succession of
centres, schoolteachers, those who work in agri- unexpected, new and life-threatening resistance
culture, and policy-makers in all areas. problems have emerged and spread throughout the
world. These global outbreaks have had little
• Promote communication: Facilitate communication monitoring to support their ultimately failed con-
among academic institutions, government agen- tainment. Only inadequate and fragmentary
cies, those who pay for health care, and pharma- surveillance systems exist today.
ceutical manufacturers to reduce the extent to
which such groups act at cross purposes in rela-
tion to antibiotic use and infection control. National and municipal organizations
Provide materials to support intervention pro- • Coordinate local surveillance networks: Public health
grammes and utilize communication tools such departments can take the initiative to contact
as the media and the Internet. medical centres and develop a surveillance net-
• Evaluate the curricula of universities: Undergraduate, work. If an existing privately-initiated network
postgraduate and continuing education pro- exists, the public health department should sup-
grammes at veterinary, medical, pharmacy, and port and help that network to grow.
nursing schools should be evaluated to ensure • Recruit leaders for surveillance networks: The public
that prudent antimicrobial use and resistance are health department cannot pay for all the par-
given high priority. Courses should make ticipants that a surveillance network requires. It
students more aware of how to evaluate promo- has to find leaders within the network and use
tional materials and what questions to ask dur- their help to motivate all the participants to work
ing a sales presentation. together on the surveillance network.
• Support a reference laboratory: The public health
Health care institutions department should support a reference labora-
• Use effective teaching methods for educating pre- tory, hitherto lacking in many surveillance net-
scribers: works. The network initiator’s laboratory may
become the reference laboratory. With proper sup-
— Use group problem-solving sessions, role port, the reference laboratory can appreciably im-
playing, lectures. prove the performance of the network’s laboratories
— Focus on clinical issues one at a time. and connect, integrate, and interpret their data.
— Use an educational outreach worker for train-
• Share results of surveillance with international organi-
ing at the office.
zations.
— Use opinion leaders or district-level staff as
trainers. • Monitor resistance in food animals: Undertake regu-
— Repeat sessions to reinforce message. lar monitoring for resistant bacterial pathogens
— Apply community-based case management and commensals in food-producing animal
interventions. populations and animal-based food products.
2
• Monitor sentinel human populations: Evaluate the ers and detractors; how to reach goals, and
usefulness of monitoring sentinel human ways to build on existing audit systems.
populations (e.g. farm and abattoir workers) and
• Update guidelines based on surveillance data: Regu-
people in the community for infection and/or
larly update guidelines for antimicrobial use
colonization with resistant bacteria.
based on resistance surveillance data.
• Eliminate financial incentives that promote the misuse
Health care institutions
of antibiotics: In countries where governments
• Develop local surveillance networks: Medical centres subsidize the purchase of antimicrobial drugs,
can support data gathering within their centre legislative or regulatory changes in these subsi-
and join or start a local surveillance network. dies could lead to a decline in the use of the
• Maintain a laboratory with adequate quality assurance drugs. Governments could investigate the effect
and trained technicians. of changes in reimbursement on the prudent use
of antibiotics and on surveillance of prescribing
or resistance; for example, the United States
Health care workers Congress Office of Technology Assessment
• Initiate a local surveillance network: A microbiologist (OTA) identified a potential problem with Med-
or infectious disease specialist can initiate an icaid and Medicare reimbursement policies.
antimicrobial resistance surveillance network; • Monitor advertising: Develop and enforce ethical
most of the networks started in various coun- standards concerning advertising of antibiotics
tries began in this way. The leadership and in- to the general public to counteract the strong
terest of these individuals and their colleagues commercial pressures from manufacturers to in-
can keep these networks functioning. crease utilization of antibiotics and antibacterials.
• Consider the impact of new drugs on resistance during
Pharmaceutical companies the drug approval process: Consideration of resist-
• Undertake post-marketing surveillance to detect emer- ance issues should be required prior to drug
gence of resistance to new antibiotics. approval for human, animal, or plant use.
• Support surveillance networks: Support the work of • Limit general access to new drugs.
a local surveillance centre through funding and/ • Establish post-marketing surveillance accords with
or surveillance projects. producers to ensure early detection of emerging
resistance to new drugs.
Improve antibiotic use in people
National and municipal organizations Health care institutions
• Enforce the prudent use of antibiotics: For example, • Establish an Infection Control Committee for surveil-
the United States federal government could lance of infection; identification of outbreaks;
adopt a strategy making the implementation of implementation of effective control measures
state policies to curb the misuse of antimicro- (e.g., hand washing); sterilization and disinfec-
bial drugs mandatory before states could receive tion of equipment and supplies.
federal funds earmarked for public health.
• Establish a Drugs and Therapeutics Committee to evalu-
• Create national and regional guidelines: National ate antibiotic use data, resistance patterns,
standards and guidelines should be created for efficacy and cost; make recommendations for
community infection control management with proper antibiotic use that are appropriate to a
the following features: particular clinical setting and population.
— A requirement that every district health
• Establish guidelines for appropriate antibiotic use: For
authority should have at least one commu-
maximum benefit, such guidelines should be:
nity infection control nurse.
— The ability to be adapted at the local level. — Based on evidence.
— An implementation protocol that includes — Relevant and appropriate to the clinical and
who is being targeted; how to stage the im- microbiological issues of a given population.
plementation; how to manage the support- — Developed with the involvement of the prac-
3
titioners (and potentially the patients) who Health care workers

will be using them. • Prescribe antibiotics prudently through:
— Disseminated not simply via printed memo- — Avoiding antibiotics for simple coughs and
randa, but rather through the use of inter- colds.
active strategies oriented to change — Avoiding using antibiotics for the treatment
behaviour. of viral sore throat.
• Appoint an antimicrobial resistance monitor to: — Limiting antibiotic use in uncomplicated
— Serve as a local resource to follow the cur- cystitis in healthy women to three days.
rent literature on antibiotic resistance. — Limiting telephone prescription of antibiot-
— Analyse local data. ics to exceptional cases only.
— Propose and implement strategies for con- — Avoiding using broad-spectrum antibiotics
trol and resistance. when narrower-spectrum agents would work
— Work with clinicians on the care of specific as well.
patients. — Basing the antibiotic prescription on micro-
• Reduce the spread of infection: Adopt Centers for biological culture results whenever possible.
Disease Control and Prevention (CDC) recom- — Modifying the regimen over time as required.
mendations for isolation of patients colonized — Considering cost-effectiveness in choosing an
with resistant bacteria. antibiotic regimen.
• Improve hygiene: Perform regular hand washing.
• Create pharmacy reports: Hospitals should produce
Failure to cleanse hands after each patient con-
regular reports about pharmacy supplies to wards
tact spreads infection.
or clinics in the format of defined daily dose
(DDD) per 1000 beds. Review the pharmacy
reports periodically with the laboratory results Improve antibiotic use in animals
to detect problems of resistance early. Antibiotics are used not only to combat bacterial
• Establish and disseminate essential drugs lists: Based infections in animals but also as growth promoters
on those such as the World Health Organiza- in animals raised for meat (referred to as food ani-
tion Model List of Essential Drugs, to help mals). In some countries, about 50% of total anti-
simplify antibiotic choices for practitioners as microbial production by weight is used in animal
well as make them more clinically appropriate agriculture. As in people, the excessive antibiotic
and cost-effective. use in animals provides intensive training in
survival-of-the-fittest to the resident bacteria. A
• Educate employees: Promote education about the reservoir of antibiotic resistance is building in the
antibiotic resistance problem through: bacteria associated with animals which may be
— Providing ongoing supervision and monitor- transferred to the bacteria living in humans.
ing of practice.
— Instituting regular audit and feedback of
prescribing patterns. National and municipal organizations
— Teaching through the development of group • Increase awareness of the antibiotic resistance problem:
processes. Make veterinarians and animal owners aware of
— Developing standardized treatment guide- antibiotic resistance impact on humans, and of
lines. the costs of resistance to themselves, their fami-
— Using problem-oriented training. lies and animals, and to the public. People need
— Providing targeted in-service training of good reasons to modify their behaviours and
health workers. these should be provided to them.
• Maintain a laboratory: with adequate quality assur- • Regulate antibiotic prescriptions for animals: Evaluate
ance and trained technicians. Use sterile sup- the impact of making all systemic veterinary
plies and sterile procedures: Gloves and gowns antimicrobials available by prescription only. If
are important pieces of protective equipment. sufficient evidence exists that profits from sales
negatively impact on prescribing, take appropri-
ate countermeasures. Address the reluctance or
inability to regulate prescribing practices of
veterinarians at the national level.
4
• Restrict growth promoter use in animals: Stop using crobials are not used as a substitute for good farm
antimicrobials of a similar class to those used hygiene.
for treating humans as growth promoters in
• Reduce use of antibiotics as growth promoters: Reduce
animals.
exposure of animals to low doses of antimi-
• Regulate antibiotic use in animals: Establish a regu- crobials for long periods of time (i.e., growth
latory system to oversee the authorization, dis- promoters and prophylactics) if such uses select
tribution, sale and the use of antimicrobials in for resistance to drugs used in human medicine.
food-producing animals. Establish a system to
• Improve animal husbandry: Encourage farming
monitor the type and quantity of antimicrobials
practices that reduce the need for prophylactic
given to food animals, similar to that for
and therapeutic use of antibiotics. Alternative
humans.
ways to reduce infectious disease in animals, such
• Set a risk standard for resistance: Identify the public as improved vaccination programmes, enhanced
health risks from antibiotic resistance that are biosecurity measures, and reduced housing
acceptable to society. If acceptable levels for density should be promoted when appropriate.
microbial risks (or “risk standards”) can be agreed This could, however, increase the cost of food
upon internationally, quantitative risk assess- production in some countries.
ment could be used to identify resistance thresh-
olds, beyond which public health impacts Researchers
become unacceptable. If antibiotic resistance
increases above levels of concern, then incremen- • Risk-benefit analysis of growth promoter use: Evalu-
tal interventions up to withdrawal of the drug ate the nature and magnitude of the impact of
from the market should be considered. antimicrobial growth promoters and use the in-
formation to assist in risk-benefit assessments
• Consider human and non-human uses simultaneously: of each use.
A single, multidisciplinary government commit-
tee should oversee the regulation of anti- • Environmental impact: Conduct pilot studies to
microbials in both human and non-human assess the extent of environmental contamina-
fields. tion by antimicrobial residues and resistant
organisms that enter the soil or water from
• Monitor advertising: Advertising and promotion of human and animal waste.
animal health products should comply with
national guidelines and codes of practice. • Food processing and distribution methods: Evaluate
the effect of current food processing and distri-
bution methods on the emergence and spread
Veterinarians of resistant organisms.
• Promote the prudent use of antibiotics in animals, in
accordance with similar strategies for humans. Encourage new product development
Recommended dosages should be optimal for
As the current tools used against bacteria become
therapy and minimize the development of
less effective, protecting the public from bacterial
resistance. Prophylactic use should be regularly
infections requires new tools. Pharmaceutical com-
assessed for effectiveness and need.
panies and related industries must be encouraged
• Develop local guidelines for antibiotic use: Locally de- to pursue research and development of new pre-
rived treatment guidelines should include a list ventative and curative measures (such as vaccines
of antimicrobials for conditions commonly pre- and antibiotics) and new screening and surveillance
sented in various species, and offer a rational methods.
treatment choice based on scientific data. These
guidelines should address the use of antibiotics
National and municipal organizations
important to humans such as fluoroquinolones.
• Provide incentives to industry:
— Create policies that give pharmaceutical
Food animal producers companies an extended patent life in ex-
• Improve farm hygiene: Develop and implement change for increased restrictions on the sales
standards of practice to ensure that antimi- of antimicrobials.
5
— Provide incentives to companies to invest in — Screening methods.

research and development so as to remove — Surveillance tools, including computer pro-
the need to re-coup their investment in a grams for data management and reporting.
predictably poor selling, but medically
needed agent.
Increase resources to curb antibiotic
— Streamline the regulatory process for drugs resistance in the developing world
and products that are critically needed or
which address infection solutions without Antibiotic-resistant bacteria are found in industrial-
undermining resistance solutions. ized and developing countries alike and with inter-
— Provide a mechanism for a government or national travel, can pass easily from country to
not-for-profit organization to assume the country.
leadership (and risk) in developing an essen-
tial infectious disease therapy product International organizations
(vaccine or drug or diagnostic test) if pharma-
• Share results of surveillance internationally: Interna-
ceutical industries choose not to do so.This
tional cooperation is needed to disseminate the
would be analogous to the strategy of indus-
results of surveillance among all countries, so
try licensing-in from academia by establish-
that even those without the infrastructure can
ing the option for the reverse process to occur
use the results to conduct risk assessment, make
(license from the industrial concerns).
policy and manage risk.
— Encourage pharmaceutical companies that
had developed antibiotics but never commer- • Secure technical and financial support for developing
cially exploited them to pursue more anti- countries: Investigate methods for mandating
microbial research and development if their technical or financial support from industrial-
earlier antibiotics (now without patent pro- ized countries to developing countries.
tection) were given extra legal protection, • Invest in a worldwide vaccine strategy to reduce antibi-
either under patent law or a legal regime like otic use and combat antimicrobial resistance by
the Orphan Drug Act. preventing infectious diseases in humans.
— Introduce joint funding arrangement
schemes for research work between govern- • Ensure the availability of vaccines and quality drugs:
mental agencies and industry. — Initiate major worldwide programmes relat-
ing to formulation and delivery of vaccines.
• Protect intellectual property rights: International law — Strengthen national and international capac-
should provide intellectual property protection ity to ensure the availability and quality of
rights and enforcement to encourage industry anti-infective drugs.
to invest in antibiotic research, development, and
delivery in developing countries. • Facilitate communication among the countries of the
world:
• Facilitate networking: Encourage partnerships be- — Introduce a global alert system requiring
tween industry, academia, and government to national governments to inform worldwide
better exploit existing and new technologies to health authorities about outbreaks of resist-
combat antimicrobial resistance (drugs, vaccines, ant infections.
diagnostics). — Develop a global web site similar to the
Nosocomial Infection Control in Europe
Pharmaceutical companies web site at http://helics.univ-lyon1.fr.
• Increase research and development in several areas: • Safeguard privacy and human rights: International
— Vaccine research and drug discovery. human rights law must be taken into account
— Pharmacokinetics, pharmacodynamics, and to set effective public health policies.
dosage regimens in relationship to antimi- • Promote appropriate international laws: Consulta-
crobial resistance emergence probability. tions with experts in international law is impor-
— Basic research into the identification and tant when devising a global strategy for curbing
function of novel genes to provide industry antibiotic resistance.
with new, defined targets for therapeutic in-
tervention.
6
National and municipal organizations — Support developing countries in creating

• Decrease risk of infectious disease by: reliable supply systems.
— Improving the quality of life and health with
widespread immunizations. Increase funding for surveillance, research
— Improving sanitation and water supply and education
systems. Increasing understanding of the bacterial response
— Emphasizing alternate methods of infection to antibiotics and increasing operational research
control, such as bednets in areas at risk for into interventions to deal with the antibiotic re-
malaria. sistance are two major recommendations to help
• Ensure antibiotic availability: Availability of appro- curb the antibiotic resistance problem.
priate antibiotics for treatment of infections will
contain the spread of infection in general and National and municipal organizations
resistant strains in particular.
• Increase funding for a surveillance network: Public
• Share resources with other countries: Industrialized health departments need funding to build a sur-
countries should help developing countries build veillance network.
a quality infrastructure to address health needs
in the long term, including investment in • Increase funding for research: Basic and clinical
research and development. researchers need funding to identify new anti-
— Provide support to invest in diseases in the bacterial targets and to better understand anti-
developing world. biotic resistance mechanisms.
— Assist in implementing preventive strategies • Increase funding for education: Health care provid-
through improving social infrastructure and ers and the general public need to be educated
improving sanitation and water supply sys- about the antibiotic resistance problem.
tems in developing countries.
TABLE 1. REPORTS BY EXPERT POLICY GROUPS (1987–2000)
Year Study nature, location,

(ref no.) Document title Organization and time Conclusions
1987 Reviews of Infectious National Institutes Six Task Forces, comprised of A global, standardized surveillance system is
(1) Diseases Antibiotic Use of Health (NIH), representatives from different recommended as the best way to track
and Antibiotic Resistance Fogarty Center disciplines and countries, studied emerging resistance patterns. Expanded
Worldwide Sponsored by (USA) various aspects of antibiotic studies of the mechanisms of multidrug
the Fogarty International resistance between 1983 and resistance are supported. The authors also
Center, NIH 1986. encourage the expansion of central
surveillance systems and the development
of vaccines and more rapid diagnostic tests.
1990 Healthy People 2000: Public Health Convened consortium in 1987 The keys to meeting the government’s
(2) National Health Promotion Service (PHS) with 300 national organizations. objectives on infectious diseases include
and Disease Prevention. (USA) The 2000 Consortium was public education about hygiene and
Full Report, With facilitated by the National infection control, education of health care
Commentary Academy of Sciences and the providers about disease epidemiology and
Institute of Medicine to assist disease prevention, research on the
the PHS to convene 8 regional improvement of immunizations, diagnostic
hearings and take testimony techniques and therapies, as well as
from over 750 individuals. Over immunization and efforts to maintain safe
10,000 people responded to the food and water supplies.
review and comment period.
1992 Emerging Infections: Institute of Between February 1991 and Surveillance is crucial to the detection and
(3) Microbial Threats to Health Medicine (IOM) July 1992, a multidisciplinary control of infectious diseases. Coordinated
in the United States (USA) committee convened to identify efforts of public and private organizations,
significant emerging infectious individuals and government agencies must
diseases and develop recom- be expanded and improved.
mendations on how to deal with
them.
7

1994 Addressing Emerging Centers for Disease Plan developed by CDC in The creation of a comprehensive strategy is
(4) Infectious Disease Threats: Control and partnership with representatives necessary to address the threat of emerging
A Prevention Strategy for Prevention (CDC) from public and private health infectious diseases. To be most effective,
the United States (USA) organizations at the local, state, such a strategy should be integrated with
national and international plans for reform of the larger health care
levels. system.
1995 WHO Scientific Working World Health Summary of International Heavy usage of antimicrobial agents, poor
(5) Group on Monitoring and Organization Workshop held by WHO, Geneva, infection control standards, and
Management of Bacterial (WHO) Switzerland Nov. 29-Dec. 2, 1994. environmental contamination with
Resistance to Antimicrobial antimicrobial-resistant pathogens are key
Agents areas of concern.
1995 Impacts of Antibiotic- Office of Review of scientific literature, Infection control, the optimal use of existing
(6) Resistant Bacteria Technology exploration of biological antibiotics, and the development of new
Assessment (OTA) mechanisms behind ABR, and antibiotics should be the primary
(USA) research into availability of new approaches to antibiotic resistance.
antibiotics.
1995 Infectious Disease – National Science Report from the CISET Working In order for a global surveillance network to
(7) A Global Health Threat and Technology Group on Emerging and Re- be realized, it is necessary to coordinate,
Council (USA) emerging Infectious Diseases strengthen and link existing systems.
Convened December 1994. Electronic links would enhance the surveil-
lance capabilities of the US government’s
field stations.
1995 Report of the ASM Task American Society Report of a workshop held on The Task Force stresses the immediate need
(8) Force on Antibiotic for Microbiology July 6, 1994. for surveillance of resistance in humans and
Resistance (ASM) animals. They also advise the more prudent
use of antibiotics in human and veterinary
medicine; improved hospital infection
control and guidelines; improvement of
infection control curricula for all health care
professionals; better consumer education;
and more basic research.
1997 The Medical Impact of the World Health Report of WHO Meeting When creating any public health policies
(9) Use of Antimicrobials in Organization Berlin, Germany regarding the use of antimicrobials in
Food Animals (WHO) Oct. 13–17, 1997. livestock production, it is necessary to take
into account the benefits to production
versus the potential risks to human health.
More prudent use of antibiotics is the key
recommendation, especially when viable
alternatives exist.
1997 America’s Vital Interest in Institute of Report of a workshop conducted The improvement of global health, security
(10) Global Health Medicine (IOM) in November of 1995. and economic viability depends on
(USA) collaborations among US government health
agencies, as well as partnerships with US
industry, academia and non-governmental
organizations, other governments and NGOs.
1997 New and Reemerging American Society Analysis of documents on The report recommends increased funding
(11) Infectious Diseases: A Global for Microbiology emerging infectious diseases. for research efforts to develop improved
Crisis and Immediate Threat (ASM) diagnostic tests, new antibiotics, and
to the Nation’s Health. The vaccines.
Role of Research.
1997 Resistant Organisms: Global Royal Society of Proceedings of a conference The abatement of the problem of antibiotic
(12) Impact on Continuum Medicine sponsored by 3M Health Care resistance can only be achieved through
of Care (UK) and Regent Medical, London cooperation of prescribers, patients,
September 27, 1996. government, pharmaceutical, and
agricultural industries. Surveillance, infection
control, and improved prescribing practices
are all important components of any
collaborative effort.
8

1997 Joint Committee on the Society for Health Publication in Infection Control Antibiotic resistance must be considered a
(13) Prevention of Antimicrobial Care Epidemiology and Hospital Epidemiology, global health problem. Responsibility lies
Resistance: Guidelines for of America and Vol.18, No.4, pp. 275–291. with all hospital personnel to control
the Prevention of Antimi- Infectious Diseases infections and use antibiotics properly, to
crobial Resistance in Society of America help prevent its further spread.
Hospitals
1997 Antibiotic Resistance: CIBA Foundation Proceedings of a Symposium Reversal of antibiotic resistance and return of
(14) Origins, Evolution, (International and (#207) held at the Ciba susceptible organisms are possible. These
Selection, and Spread Scientific Charity) Foundation, London goals can be achieved through the
July 16–18, 1996. implementation of rational use guidelines for
new antimicrobials and through the
cooperation of prescribers and consumers.
1998 The Current Status of Anti- World Health Report of WHO Workshop (held Europe’s disparate surveillance networks
(15) microbial Resistance Organization in collaboration with the Italian would benefit from a pan-European
Surveillance in Europe (WHO) Associaizone Culturale Microbio- coordinating group. Such a group could help
logia Medica) Verona, Italy, to standardize surveillance methodologies
December 12, 1997. at the local, national and international levels.
1998 Emerging Infectious Centers for Peer-review Journal: Proceedings Basic research is crucial to the control of
(16) Diseases Special Issue Disease Control of the International Conference emerging and reemerging infectious
and Prevention on Emerging Infectious Diseases, diseases. Improvements in hygiene and
(CDC) (USA) Atlanta, GA, March 1998. immunization can be very effective methods
of infection control, although often difficult
to implement because of human nature.
1998 Preventing Emerging Centers for An evaluation and update of Implementation of guidelines from
(17) Infectious Diseases: Disease Control Preventing Emerging Infectious Preventing Emerging Infectious Diseases
A Strategy for the and Prevention Diseases. resulted in decreases in the prevalence of
21st Century (CDC) (USA) certain infectious organisms. The authors
expect this follow-up plan to be successful in
preparing the US public health infrastructure
to respond to infectious diseases, whether
they are familiar, of unknown origin, or the
result of bioterrorist attacks.
1998 Antibacterial Drugs in Food and Drug The criteria are suggestions for The criteria are meant to keep the
(18) Animal Feeds. Human Administration complying with regulations agricultural industry within what are thought
Health Safety Criteria, (FDA) (USA) mandated by Congress and the to be safe levels of antimicrobial use in food-
Guideline 18. Food and Drug Administration. producing animals.
1998 The Path of Least Department of Review of case studies, review The prescription of antibiotics often depends
(19) Resistance Health (UK) of the basis and impact of on the attitudes and expectations of patients;
resistance, commission of an the practitioner’s decision must take into
independent review of evidence. account the greater effect of the prescription,
in terms of increased selection for resistance.
A combined approach of practitioner and
public education is recommended.
1998 Antimicrobial Resistance British Medical Peer Review Journal Cooperation on the part of medical
(20) (Entire Journal for Journal (7 editorials and 4 papers). professionals, politicians, the pharmaceutical
September 5, 1998 devoted industry, and patients is necessary to improve
to Antimicrobial Resistance) the problem of antibiotic resistance.
1998 Resistance to Antibiotics House of Lords Between July 1997 and March The problem of antibiotic resistance must be
(21) and other Antimicrobial (UK) 1998, Sub-Committee members more widely recognized as a serious threat
Agents conducted interviews at the in order to be adequately addressed.
Public Health Laboratory Service Continuing professional education would
and with individual experts in help to achieve such recognition. Locally-
the US and UK. They also created antibiotic formularies and
gathered evidence from the guidelines, and improved access to micro-
agricultural and pharmaceutical biological testing, when practical, are other
industries, international and important tools for practitioners. The authors
regional health organizations urge caution in the use of antibiotic classes
and professional medical and that are prescribed in both human and
scientific societies. veterinary medicine.
9

1998 Antimicrobial Resistance: Institute of Report of a workshop conducted The participants stress the need for national
(22) Issues and Options Medicine (IOM) in July of 1997. and global surveillance of antibiotic
(USA) resistance in animals and humans; for more
prudent use of antibiotics, especially in the
area of food production; improved hospital
infection control and guidelines; patient
education; continuing education for
practitioners; and more basic research for
new antibiotics and diagnostic tests.
1998 Protecting the Crown Center for Science Compilation of statistics and The authors recommend changes on the part
(23) Jewels of Medicine: in the Public information from other of public and private institutions, as well as
A Strategic Plan to Preserve Interest scientific sources. consumers, to prevent the further spread of
the Effectiveness of (USA) antibiotic resistance. Prevention of infectious
Antibiotics diseases is emphasized over the develop-
ment of new drugs.
1999 The Agricultural Use of General Review consisting of interviews Despite 20 years of discussion among
(24) Antibiotics and Its Accounting with representatives from govt government agencies, consensus on the
Implications for Human Office (GAO) agencies, agricultural industry subject of antibiotic use in agriculture has
Health (USA) and agricultural associations; not been reached. The report recommends
also scientific review, and restriction of antibiotics as growth promoters
consultations with experts. in animals.
May 1998–April 1999.
1999 The Use of Drugs in Food National Research The Committee reviewed major The committee’s greatest concern is the
(25) Animals: Benefits and Risks Council classes of drugs used in food potential for development of resistance to
(USA) animals; reviewed scientific antibiotics used in human medicine due to
literature; heard testimony on misuse of antibiotics in food animals. To
animal drug-related issues and avoid any increase in such development, the
reviewed relevant federal committee recommends the development of
regulations. new antimicrobials, with possible restrictions
of their use to either human or animal
medicine.
10
Introduction
Stuart B. Levy
The introduction of antibiotics into medical prac- TABLE 2. ANTIBIOTIC DISCOVERY AND RESISTANCE
DEVELOPMENT
tice in the 1940s revolutionized man’s ability to cure
infectious diseases. Now, over fifty years later, health Antibiotic Discovered Introduced Resistance
practitioners around the world can no longer ex- into clinical use identified
pect their choice of antibiotic to work. Multidrug Penicillin 1940 1943 1940
resistance has become common in clinical settings. (methicillin 1965)
While some antibiotic resistance is a natural con-
Streptomycin 1944 1947 1947, 1956
sequence of antibiotic use, resistance as a clinical
threat to patient care can be prevented. More Tetracycline 1948 1952 1956
prudent use of these agents will restore and main- Erythromycin 1952 1955 1956
tain a bacterial environment where susceptible
Vancomycin 1956 1972 1987
strains can flourish.
The cavalier use of antibiotics has resulted in Gentamicin 1963 1967 1970
the progressive depletion of cost-effective agents Source: CIBA Foundation (14). Reproduced with the permission.
from our medical armamentarium. A dangerous
pattern has emerged in which, as a new antibiotic
is introduced, there is rampant overuse or misuse tion, rapid increases in vancomycin-resistant ente-
resulting in accelerated development of resistance rococci and the emergence of vancomycin-resist-
(Table 2). In the last quarter of the century, respi- ant Staphylococcus aureus have raised concerns that
ratory organisms, including Haemophilus even industrialized countries may be losing this an-
influenzae, and agents of sexually-transmitted in- tibiotic of last resort (Figure 1).
fections, such as Neisseria gonorrhoeae, have emerged In addition to considering the problem on local
as worldwide multidrug-resistant threats. In addi- and global levels, one must think of resistance in
FIGURE 1. PROPORTION OF ISOLATES ASSOCIATED WITH A NOSOCOMIAL INFECTION AMONG ICU (SOLID LINE) OR NON-ICU
(DOTTED LINE) PATIENTS WHO WERE INFECTED WITH ENTEROCOCCI RESISTANT TO VANCOMYCIN.
25
20
Percent resistance
15
10
0
1989 1990 1991 1992 1993 1994 1995 1996 1997
Year
Source: Fridkin S, Gaynes R. Antimicrobial resistance in intensive care units. Clin Chest Med 1999;20:306. Reproduced with permission.
11
terms of the broader environment in which focused on those reports with extensive subject
microbes live. Antibiotic resistance is an ecological matter related to their area of investigation (see
problem reflecting the fact that antibiotics are Table 3). For example, only McEwen (Chapter V)
societal drugs. Antibiotic use affects not only the reviewed those reports written specifically on
individual, but also the individual’s environment antibiotic use in animals and plants. O’Brien
of microorganisms, which is shared with the rest of reviewed additional reports (27,28,29,30,31)
society. Susceptible strains are removed and resistant because they were exclusively about surveillance and
strains replace them. Thus, any national or local introduced important data and principles revisited
strategy to curb antibiotic resistance must stress the in later reports. In addition to summarizing find-
prudent use of antibiotics so as to allow restoration ings from the expert policy reports, updated
of the susceptible flora in a particular community. information, references and the author’s insights
Recognizing the role that microbial ecology plays were added where considered appropriate and
in housing and propagating resistant pathogens and relevant by the author. The Summary of Reports,
commensal organisms will help enormously in with key conclusions from each, is presented in the
developing guidelines for antibiotic use. The micro- Executive Summary Table 1 together with the Key
biologist and clinician, working together as a team, Recommendations synthesized under a series of
can determine appropriate use in their facility or headings:
community.
• Increase awareness of the antibiotic resistance
problem
Selection of reports for this review • Improve surveillance of antibiotic resistance
As part of the process of development of the WHO • Improve antibiotic use in people
Global Strategy for Containment of Antimicrobial
Resistance (26), a series of technical reviews were • Improve antibiotic use in animals
commissioned. The Alliance for the Prudent Use • Encourage new product development
of Antibiotics (APUA) responded to WHO’s • Increase resources to curb antibiotic resist-
request and reviewed reports on antibiotic resistance ance in the developing world
prepared by prestigious scientific and governmental
organizations over the last two decades. Twenty- • Increase funding for surveillance, research and
five expert reports (1–25), compiled by scientific education.
and medical authorities, were selected for this review Each set of recommendations is categorized by
by APUA because they are highly referenced in the the levels of decision-making necessary to initiate
literature and reflect extensive deliberations by a action. A resumé of each of the expert reports re-
wide variety of key expert policy groups. There are viewed, prepared by APUA, is contained in Ap-
other excellent policy reports which have not been pendix A.
reviewed but which could supplement those In addition, APUA collected information from
considered here, such as those from Canada, their international chapters about a number of cur-
Australia, Finland and Denmark. rent national and local initiatives, as an illustration
of the power of local movements. Each of these
The review process programmes chose a particular feature of the anti-
biotic use and resistance problem and put together
In developing this synthesis, APUA consulted a team to address it. Their reports, reflective of
five medical and scientific experts on antibiotic APUA Chapters but not necessarily reflecting na-
resistance who reviewed relevant sections of the tional policy, are included in Appendix B.
selected expert reports. Their reviews are presented
in Chapters I–V and cover the major areas of
intervention: Chapter I. Improve and Expand Conclusion—A manageable approach at
Surveillance; Chapter II. Increase Awareness:
the local level
Optimize Patient and Provider Behaviour; Chapter Although concerned scientists and prestigious study
III. Strengthen Sanitation, Infection Control, and groups have met to document the problem of anti-
Regulatory Measures; Chapter IV. Encourage microbial resistance and suggest solutions, the key
Research and Product Development; and Chapter players who can impact the problem have some-
V. Improve Antibiotic Use in Animals. Each author how not been engaged. This review highlights the
12
TABLE 3
General review Control & prevention
Public health
Reference Trends in Causes & Antimicrobial Economic promotion & Public
No. (year of publication) diseases & mechanisms use in animals cost of prevention policy
Short title resistance of resistance & plants resistance strategies strategies Surveillance
1. (1987) Antibiotic use and anti-

biotic resistance worldwide:
report of a study sponsored by
the Fogarty International Center
of the National Institutes of
Health, 1983–1986 x x x x x
2. (1990) Healthy People 2000:

National Health Promotion and
Disease Prevention x x x
3. (1992) Emerging Infections:

Microbial Threats to Health in
the United States x x x x
4. (1994) Addressing emerging

infectious disease threats: A
prevention strategy for the
United States x
5. (1995) WHO Scientific Working

Group on Monitoring and
Management of Bacterial Resis-
tance to Antimicrobial Agents x x
6. (1995) Impacts of Antibiotic-

resistant bacteria x x x x x x x
7. (1995) Infectious Disease–

A Global Health Threat x x x
8. (1995) Report of the ASM Task

Force on Antibiotic Resistance x x x
9. (1997) The Medical Impact of

the Use of Antimicrobials in
Food Animals x
10. (1997) America’s vital interest

in global health: Protecting our
people, enhancing our economy,
and advancing our interests x
11. (1997) New and Re-emerging

Infectious Diseases: A Global
Crisis and Immediate Threat to
the Nation’s Health x x
12. (1997) Resistant organisms :

Global Impact on Continuum
of Care x x
13. (1997) SHEA Position Paper on

Prevention of Antimicrobial
Resistance in Hospitals x x x
14. (1997) Antibiotic Resistance:

Origins, Evolution, Selection
and Spread x x x x x x x
15. (1998) The Current Status of

Antimicrobial Resistance
Surveillance in Europe x
13
General review Control & prevention
Public health
Reference Trends in Causes & Antimicrobial Economic promotion & Public
No. (year of publication) diseases & mechanisms use in animals cost of prevention policy
Short title resistance of resistance & plants resistance strategies strategies Surveillance
16. (1998) Papers from the Inter-

national Conference on
Emerging Infectious Diseases x x x x x
17. (1998) Preventing Emerging

Infectious Diseases: A Strategy
for the 21st Century x x x x x
18. (1998) Human Health Safety

Criteria Guideline 18 x
19. (1998) The Path of Least

Resistance x
20. (1998) British Medical Journal

special edition on Antimicrobial
Resistance x x x x
21. (1998) Resistance to antibiotics

and other antimicrobial agents x
22. (1998) Antimicrobial Resistance:

Issues and Options x x x
23. (1998) Protecting the Crown

Jewels of Medicine: A Strategic
Plan to reduce the spread of
antibiotic resistance x x
24. (1999) The Agricultural Use of

Antibiotics and its implications
for human health x x x
25. (1998)The Use of Drugs in Food

Animals: Benefits and Risks x
need for action at the national and local levels to Despite these formidable barriers, it is the local
break this pattern and to reverse increasing rates of nature of the problem which provides optimism
resistance in communities and countries worldwide. that resistance can be contained and curbed if sus-
It also identifies a number of barriers to be over- ceptible microbes can be re-established within de-
come including: fined areas. Individual institutions and health
practitioners that use antibiotics more prudently
• The complex, and somewhat invisible, na-
will restore bacterial equilibrium in favour of sus-
ture of the problem;
ceptible bacteria and thereby preserve the effective-
• Financial incentives which foster misuse of ness of antibiotic therapy in their communities.
antibiotics; While the WHO Global Strategy (26) provides
• Lack of necessary coordination among many a thorough and comprehensive foundation, it is up
disciplines; to each nation, local institution and local provider
to tailor specific initiatives to their particular re-
• Lack of adequate funding, leadership, and sistance problems, resources, and practices.
accountability at the national level;
• The complexity and vast number of possible
interventions, making prioritization difficult.
14
CHAPTER I
Improve and expand surveillance

Thomas F. O’Brien
Abstract The groups made generally similar recommen-

Expert groups advising on control of antimicrobial dations over the two decades, although some of their
resistance have repeatedly emphasized the need for more recent reports have commented on how little
surveillance of resistance. This chapter reviews the these recommendations have been implemented.
discussions and recommendations on surveillance An obstacle may be that surveillance of resistance,
of resistance in reports issued by sixteen such groups as noted, requires an unusual degree of coopera-
over the past two decades. tion and integration between the efforts of care-
The problem of antimicrobial resistance is enor- givers and public health workers. Caregiving
mous because of the magnitude of the intercon- institutions are the predominant producers and
necting global bacterial populations it involves. It users of resistance surveillance data, but public
is intricate because of the diversity of resistance health leadership and support is needed to inte-
genes and genetic vectors responding to differing grate the data into larger systems and to collabo-
usage of antimicrobial agents on different parts of rate in understanding and containing resistance.
those populations in different parts of the world. It
is also peculiarly circular since an attempt to cure Synthesis and summary
one patient may eventually prevent cure of another.
For these reasons, as reflected in these reports, Do we need surveillance of antimicrobial resistance?
resistance presents different problems to a remark- The groups were nearly all emphatic about the need
ably wide range of caregivers, policy-makers, and for surveillance of antimicrobial resistance, as
researchers, and they need different kinds of infor- reflected in their statements:
mation from surveillance. The reports identify
• “without reliable information … it would be
needs for local information to guide local selection
impossible to find solutions”(2)
of agents for individual patients, infection control
in the hospital, public health in the community, • “more systematic surveillance on a much larger
and local antimicrobial usage strategy. Different scale is needed to provide explanations or
analyses are needed at the national level to over- remedies”(4)
view resistance epidemiology and to set drug policy.
• The US should “take the lead in promoting the
Global detection and tracing of emerging problems
development and implementation of a compre-
are also needed.
hensive global infectious diseases surveillance
The reports recognize that information for sur-
system.”(5)
veillance of resistance must ultimately begin with
data from microbiology laboratories and that these • “Distribute …software in laboratories to enable
laboratories need to be increased and improved. them to monitor their own results for test qual-
They look to advancing information technology to ity, for infection control problems and for local
link clinical laboratories in networks guided by trends in resistance, and to enable them also to
reference laboratories that would work to both merge their results into same-format, isolate-
generate and improve the data. They also seek to based databases for detailed national and inter-
integrate this information with additional patient national surveillance of resistance.”(6)
information, including patient antimicrobial usage,
• “There is an urgent need for effective domestic
in order to make better systems for the manage-
surveillance of antibiotic resistance in animals
ment of local resistance. Such data from multiple
and humans.”(7)
centres would also provide more detailed under-
standing of the relationship of antimicrobial use to • “A surveillance system is essential for understand-
the spread of resistance. ing the spread of antibiotic-resistant bacteria and
15
planning interventions so as to preserve the Clinical microbiology laboratory information

efficacy of currently available antibiotics.”(9) The essential basic element of surveillance is infor-
• “Establish a system for monitoring bacterial mation from microbiology laboratories. Antimicro-
resistance and antibiotic usage.”(10) bial resistance is ultimately about different kinds
• “Redressing these deficits”[in surveillance] “is of bacteria and their susceptibility to different
crucial in global and national public health terms, antimicrobial agents. Microbiology laboratories are
and the most powerful case possible must be the only source of such information, and most of it
made for urgent and substantial response.”(12) is generated by routine clinical microbiology labo-
ratories.
• “Systematic collection of epidemiological data The immediate users of such data from any
on resistance should be initiated imme- microbiology laboratory are health care workers in
diately…The costs to the NHS are likely to be the hospital and the community it serves. They need
modest compared with many other actions.”(13) this level of surveillance information to treat indi-
• “Comprehensive surveillance is required to meas- vidual patients, to update local treatment guide-
ure the public health impact of antimicrobial lines, to observe effects of their local interventions
resistance and of interventions (including those and to detect, monitor, and contain local spread of
proposed in this report) to minimize antimicro- resistant strains (3,6,12,14,15).
bial usage.”(14) The most direct, responsive, and useful way of
providing local health care workers with the sur-
• “A critical elemental in addressing the environ-
veillance information they need is to file the data
mental impact of antimicrobial resistance is
from their clinical microbiology laboratory in a
effective surveillance…With respect to antimi-
user-friendly, local electronic database, which they
crobial impact on the environment, surveillance
can query instantly, repeatedly, and in specific de-
involves not only data on bacterial pathogens,
tail, as problems arise. The World Health Organi-
but also data on other microorganisms that are
zation (WHO) provides free software for such a
part of the affected ecosystem.”(15)
database (WHONET) and additional software
• “Surveillance of antibiotic resistance (AR) is criti- (BACLINK) to translate data into the database
cal to provide early warning of emerging prob- from existing local computerized laboratory report-
lems, monitor changing patterns of resistance, ing systems that lack database capability (6,7,15).
and target and evaluate prevention and control
measures.”(16)
The need for antibiotic use data. In addition to resist-
ance data there is need for health institutions and
What kind of surveillance do we need? governments to collect and review antibiotic use
Systems for surveillance of antimicrobial resistance data. This would allow more precise analyses of
have many common and interrelated elements, relationships between antibiotic use and resistance.
which are mentioned frequently in the reviewed Much of the antibiotic use data reside within phar-
reports. Any one system will be a blend of and a maceutical companies which should be encouraged
balance between these elements. Report numbers to share this information with public health agen-
referenced below for each element do not cite all of cies. Also, governments could set up their own sys-
the reports that touched upon that element, but tems and requirements to collect the use data from
only some that are representative or most pertinent. health care providers and institutions. In addition,
Antimicrobial resistance is an enormously com- post-marketing resistance surveillance should be
plex subject, dealt with by microbiologists, clini- routine to detect resistance trends.
cians, epidemiologists, pharmacists, basic research
scientists, infection control workers and public Problems with quality of clinical microbiology laboratory
health workers, etc. They see the problem in dif- information. Several of the groups recognized prob-
ferent ways and, as members of these expert groups, lems with the existing quality of clinical microbi-
have wanted different kinds of information from ology laboratory data. Quality of testing may be
surveillance of it. Nonetheless, a general consensus uneven in many laboratories, and there is often no
about the elements of surveillance emerges from programme for quality assurance. These limitations
these reports, and their differences often seem com- may represent lack of funding, supplies, training
plementary. or oversight. Many regions lack microbiology labo-
16
ratories altogether, and where they do exist their also come to recognize the importance of early
services may be underutilized or improperly detection of such new problems (called “alert or-
utilized. Information is further diminished if a ganism surveillance” or “exception reporting” in one
laboratory reports only the interpretations of sus- report). Over the same period, moreover, the costs
ceptibility tests without their actual measurements of data storage and management have plummeted
(12,16). to near trivial levels (7,14).
Recognition of these limitations has prompted A similar question about what to include in the
recommendations in the reports reviewed for database further illustrates differences in viewpoint.
development, support, training, improvement and Those investigating the evolution or ecology of
quality assurance oversight of clinical microbiol- antimicrobial resistance see resistance as epidemics
ogy laboratories, and for more of them in some of resistance genes through vast populations of bac-
places. Their improvement is seen as essential for a teria that rarely infect. They want surveillance to
comprehensive surveillance system and, not inci- elucidate and trace how resistance genes emerge,
dentally, to improve care for the many patients get into vectors and become linked under selection
whose individual treatment is being directly affected and co-selection in reservoirs of environmental or
by tests done in those laboratories (6,12). colonizing bacteria before finally entering a patho-
genic strain that may infect someone. Their
Problems with analysis of clinical laboratory information. denominators are bacterial populations. They think
Another limitation of using only clinical microbi- that everything important for resistance happens
ology laboratory reports, cited by several of the in the bacteria before the infection begins and the
reports, is that it relates to an uncertain population epidemiologists start to count people for their
base. Prevalence of resistance is commonly expressed denominators.
as a percentage derived from the number of resist- Advancing information technology has the po-
ant isolates as the numerator with the number of tential to accommodate such diverse views. It can
both resistant and susceptible isolates as the facilitate entry of data that is well characterized, so
denominator. the database can be broadly inclusive at little cost
This is adequate for many practical uses of sur- and still allow subsequent analyses of any selected
veillance information, including many at the local subsets of the data to be sharply defined. Your
level such as infection control. It can, however, pathogens need not interfere with my commensals,
allow a sampling bias that overstates resistance by and we may both learn how they interact (4,12,15).
ignoring susceptible strains obscured by successful
treatment without culture, or by more culturing in
places where there is more resistance. It also limits The roles of microbiology reference
more formal epidemiological studies of resistance
laboratories
and its contribution to disease burden (14). The reviewed reports identified multiple roles in
The reports that mention this need for more resistance surveillance for microbiology reference
appropriate denominators do not specify how to laboratories (6,14,15).
get them. Presumably, the microbiology databases
would have to be linked to other databases con- Surveillance by the reference laboratory. Reference labo-
taining demographics, diagnoses, etc., which could ratories can themselves do surveillance of antimi-
better characterize the patients. The microbiology crobial resistance. The usual way is for a network
databases could also be linked with pharmacy of clinical laboratories to collect designated types
databases in order to identify those patients who of bacteria from among those they routinely iso-
were treated for infection without being cultured late and ship them to the reference laboratory. The
before treatment. Advances in informatics are now reference laboratory then retests the susceptibility
beginning to make this a real possibility (14). of those isolates and may also repeat their identifi-
Members of some groups wanted to specify in cation.
advance which bacterial pathogens should be in- Reference laboratory surveillance has the poten-
cluded in surveillance, presumably to minimize tial to test the isolates by more uniform methodol-
work or data storage costs. We have been repeat- ogy and against more agents. Testing against more
edly surprised in recent decades, however, by agents can distinguish fine differences between
resistance problems emerging in species where they agents and discriminate more resistance pheno-
had not been expected (e.g., enterococci). We have types. Having all of the isolates in one laboratory
17
also makes it easier to use newer methods to inves- Reference laboratory roles in coordinating multi-centre sur-
tigate their genetic relatedness and the molecular veillance networks. Organizing networks of medical
bases of their resistance phenotypes. centres and merging their individual susceptibility
The limitations of this model of reference labo- test databases can generate a national resistance
ratory surveillance is that it is expensive and there- surveillance database without great expense. The
fore can sample only a tiny fraction of a network’s organized network can then serve as a base for col-
clinical isolates. It is best at answering selected ques- laborative programmes that use continuing quality
tions or providing general overviews of specific control and benchmarking analyses of the shared
problems. Its information on population denomi- data to improve its quality, use, and interpretation
nators for the isolates it tests is no greater and may both locally and nationally.
be less than that of the network clinical laborato- Several of the groups discussed the roles that a
ries that contributed them. It also lacks the detail central reference laboratory could play in organiz-
needed for surveillance at the local level. Local ing and coordinating such a surveillance network.
infection control needs to know the locations of It could take the initiative in recruiting and setting
the last hundred patients who had methicillin- up the network. It could train participants in use
resistant Staphylococcus aureus (MRSA), and not just of the network software. It could develop or be the
of the two whose isolates were sent to the reference network distribution point for proficiency testing
laboratory. and other quality assurance programmes for net-
It would be valuable, however, for local surveil- work laboratories. It could give network laborato-
lance to know both the locations of their last hun- ries training courses shaped, in part, by problems
dred patients with MRSA, from their own local seen in the results of such quality testing results
database, and also how their local testing of the and in the analyses of the data flowing through the
two MRSA isolates sent to the reference laboratory network (6,14).
compared to its testing of them. It would addition- To the extent that a network reference labora-
ally be useful for them to know how their two iso- tory also conducted surveillance projects on the
lates related to the MRSA sent in from other centres. reference laboratory model sketched above, it would
Conversely, it would be useful for the reference labo- have the opportunity to further improve routine
ratory to know whether the two isolates they tested network data by the kind of cross-validation men-
from that centre represented only a few such iso- tioned above. Finally, the reference laboratory
lates at that centre or an extensive outbreak. would take the lead in the continuing analysis of
For such reasons, the value of integrating the total network data and in improving the local analy-
data from routine clinical laboratories and the data ses ongoing at each centre in the network (14).
from reference laboratories on the isolates they have
both tested was recognized by several of the groups Active surveillance. “Active surveillance” is a term
reviewed, and characterized as “cross-validating” by sometimes used in descriptions of epidemiological
one of them. It does not appear to have been much studies. Within the context of studies of resistance
exploited yet (14). Most existing reference labora- the term may be applied at a number of levels, for
tory surveillance has been proprietary, its large example: the identification and recruitment of a
budgets supported mostly by pharmaceutical com- patient or study population; the collection of
panies seeking information on particular issues. screening or diagnostic specimens; the performance
Cross-validation has thus not been a priority. of non-routine testing; and/or the in-depth analy-
It would seem easy, however, to extend the analysis of data. Used in this sense, active surveillance
ses of databases of such proprietary systems to cross- can often be accomplished within, and be a valu-
validation and to other questions framed by public able complement to, routine clinical practices. For
health concerns. There will undoubtedly be a need some purposes, however, it may also require
also to develop antimicrobial resistance reference special studies.
laboratories in the public health sector, not only to
do some specialized or “cross-validating” surveil- Special studies. Special studies to provide more
lance, but to also have multiple other roles in coor- surveillance information than is in routine clinical
dinating multi-centre surveillance networks, as isolate data usually undertake to obtain additional
discussed below. designated specimens for culture, or additional cat-
egories of patient information, or to perform more
elaborate isolate testing or data analysis.
18
Such studies might, for example, survey resist- mat is used by all the laboratories in a network,
ance of E. coli from stools of untreated healthy merging their databases, after ‘hashing’ for confi-
people, of S. pneumonia in nasopharyngeal swabs dentiality, into a database network costs almost
from children in a day-care centre, or the urinary nothing.
isolates of all untreated women presenting with Further development of such software could
symptoms of urinary tract infection. increase its usefulness for infection control data
Alternatively, they might seek to record all diag- management. Downloading discharge data on each
noses, or extensive demographic data or all antimi- patient’s diagnoses and pharmacy data on each
crobial therapy in a given population of patients. patient’s antimicrobial usage into additional fields
They might also perform extensive analyses of the in the same database would make it possible to
genotypes of isolates of one species or of the link- analyze what kinds of isolates preceded or followed
ages of different antimicrobial resistance phenotypes what kinds of antimicrobial therapy in patients with
in different bacterial species in various collections what kinds of diagnoses (7,14).
of isolates. Downloading pharmacy data on antimicrobial
Because such special studies have usually been usage by each patient at each medical centre in a
labour intensive, requiring extra effort and fund- multi-centre resistance network would also allow
ing, they have tended to be fragmentary and diffi- the network to capture that data for the whole net-
cult to sustain. They do, however, have the potential work, as it does the resistance data, by merging the
to enhance the information obtained from surveil- databases of all the centres. This could be one com-
lance and improve its epidemiological foundation, ponent of a national system for surveillance of an-
especially if they can be linked to one another and timicrobial usage. Such surveillance has been
to more routine surveillance to develop new kinds strongly recommended in several of the recent re-
of cross-validation (14). viewed reports, but none of them has offered much
Advancing information technology has the po- detail on how to do it (12,16).
tential to eliminate the extra effort required for some Information technology now makes it easier to
of these studies and so make them more widely implement such integrated information systems. A
utilized. Data on patients’ demographics and use type of software called a data conversion utility fa-
of antimicrobials are increasingly being filed in elec- cilitates matching of data fields and translation of
tronic reporting systems, along with their microbi- codes between the various electronic systems that
ology test results. Downloading all three into a report and store relevant data sets in different medi-
common database would routinize and so make cal centres and a common database that can analyze
widely available analyses previously kept rare by the all of their interrelationships. An example would
need for tedious chart review. be BACLINK, which facilitates translations of data
Participants interconnected in existing surveil- from various microbiology reporting systems into
lance networks may also be better organized, if not common WHONET files.
already self-selected, to collaborate in ongoing
projects requiring collection and culturing of ad-
Research on surveillance data
ditional specimens.
We can picture how resistance genes may emerge,
insert into genetic vectors and spread under selec-
Information systems for surveillance tion in one or many strains and species through
Many of the reviewed reports emphasized how the world’s interconnecting bacterial populations.
essential for the surveillance of antimicrobial re- The picture we have, however, is projected largely
sistance are computerized information systems, but from expectations based on the well-studied mo-
few explored their specifications. The needs seem lecular details of those genes and vectors. Plasmids
obvious and advancing information technology can transfer, and resistance genes should move in
should be making it easier to meet them and out of integrons, etc., but only rarely have we
(3,5,6,7,13,14). been able to observe them actually doing those
Software exists now, as mentioned above, to put things in the real world. The microbes’ resistance
any laboratory’s susceptibility test results and some system is operating all around us, but we cannot
basic demographics of the cultured patients into a observe its workings or the rates at which changes
database dedicated to that application. If software occur. If we could, we might manage it better.
with the same or easily matched codes and file for- The kind of systematic surveillance of resistance
19
recommended by many of these reports, coupled world’s huge but invisible bacterial populations.
with advancing molecular technology, should make Attempts to cure people drive a process that ulti-
it possible to do at least some surveillance at the mately prevents cure of other people. The fact that
molecular level. We should be able to trace line- it is confusing may have been a barrier to focusing
ages of resistance genes, genetic vectors, and strains attention on recommendations to contain resist-
of bacteria in different circumstances and under ance.
differing selection. The goal would be to improve The recommendations for surveillance made in
our ability to predict what will happen and to these reports require perhaps unprecedented coop-
intervene and avert problems (3,4,6). erative activity in any country between a small
Research and surveillance are each recommended number of public health officials and large num-
in nearly all of the reviewed reports, but only a few bers of diverse groups of health care workers. Anti-
make a connection between them. We need research microbial resistance is a public health problem.
on how best to do surveillance. We need further Most of the people who are causing it, trying to
development of surveillance software and research cope with it, and generating nearly all of the infor-
on how to use it fully. We also need to develop mation on it, however, are providing services to
surveillance linked to molecular technology as a individual patients. They produce, own, and have
research tool to elucidate the real world popula- the most immediate and varied uses for the data
tion biology and detailed epidemiology of antimi- that will have to be recycled into public health sur-
crobial resistance. veillance if there is to be any.
The two parties need to help each other. The
public health official on whose desk the recommen-
What have been the barriers to the implementation
dations arrive may not have a detailed grasp of the
of surveillance?
workings of the microbiologists, pharmacists, in-
The urgent recommendation for surveillance of fection control workers, and clinicians in the medi-
antimicrobial resistance and basic plans for how to cal centres and the communities they serve.
do it were made nearly two decades ago (2,3). Its Conversely, it may not occur often to these busy
urgency has been reemphasized and elaborated multi-specialty local health care providers that they
upon by each of the expert groups that has met are in part public health workers.
since. Over that same period, a succession of unex- Most of the antimicrobial resistance surveillance
pected, new, and very damaging resistance prob- networks that have gotten started in various coun-
lems have emerged and spread throughout the tries over the last decade or so were initiated by a
world. These global outbreaks, one after another, microbiologist or infectious disease specialist. He
have had only the sketchiest of monitoring to sup- or she began to file and analyse local susceptibility
port the ultimately failed attempts at containment. test results in a database in his or her own medical
As nearly all of the recent reports agree, only inad- centre, then persuaded colleagues at other centres
equate and fragmentary surveillance systems exist to do the same. Occasional funds and/or occasional
today. surveillance projects from pharmaceutical compa-
The reports reviewed do not examine the nies helped. The leadership and interest of these
reasons why prior reports’ recommendations for individuals and their colleagues have kept many of
surveillance of antimicrobial resistance had been these networks functioning, and some have grown
so little implemented, except for one that discusses to include thirty or more centres.
barriers and resources in one country (13). The Less often, a public health department has taken
nature of antimicrobial resistance, the types of rec- the initiative to contact medical centres and begin
ommendations made, and the experiences of those development of a surveillance network. What seems
surveillance systems that have been started may, to have worked best has been when a public health
however, suggest some of the barriers. department has established a relationship with one
Compared to other medical problems being of the beginning privately-initiated networks. In
brought to the attention of the public and public two such examples some relationship had existed
health officials, antimicrobial resistance is an ex- from the beginning, and the public health division
tremely diffuse subject and difficult to describe. It had later expanded its support when it came to
is not in one organ or one type of patient but car- realize the value of the growing network.
ried by all of us and in the environment. It is not a When a public health department has come to
disorder in people as much as it is a disorder of the support a surveillance network, substantial im-
20
provements have followed. Presumably two things The study compared, in multiple countries in
have happened. The first is that the network had great quantitative detail, both broth dilution and
been built with participants who were motivated, agar diffusion methods for antimicrobial suscepti-
in that they had been self-selected by their interest bility testing. It essentially began the development
and belief that a network could help their work of the framework for standardizing and interpret-
locally. ing test results and comparing results from differ-
The second is that the public health department ent countries, which are essential prerequisites for
could begin to support a reference laboratory, hith- surveillance of resistance, especially for international
erto lacking in those networks. In each of these two surveillance of resistance.
cases the network initiator’s laboratory became the Its 90 page report, published as a supplement to
reference laboratory. With this support, it could ACTA Pathologica et Microbiologica Scandinavia
begin to perform the reference laboratory functions (Section B 1971, Supplement No. 217) did not use
described above, and the networks improved ap- the word “surveillance” which may not then have
preciably. been applied to antimicrobial resistance, but for
Each of the two parties has its own barrier. The which the study began to build a foundation. It did,
public health department needs to be given fund- however, begin by listing as one of three purposes for
ing and accountability to build a surveillance net- standardizing the measurement of the sensitivity
work. The public health department, however, of microorganisms to antibiotics (along with
cannot begin to pay all the participants that a net- rational use and evaluation of new agents) as “for
work needs. Therefore, it has to exercise real lead- epidemiological studies.”
ership in finding leaders within the network, and,
with their help, motivate all the participants to work
(28) WHO Scientific Working Group on Antimicrobial
together on the network. Resistance, Geneva, 23–27 November 1981.
Similarly, none of the participants in the net- WHO/BVI/PHA/ANT/ 82.1
work would be able to fully support a reference labo-
ratory. Yet, the improvements in the network from The Working Group outlined the current situation
such a laboratory can enhance the work of the par- of antimicrobial resistance. It emphasized that the
ticipants. Cooperative mutual barrier removal increasing frequency of acquired resistance to anti-
between public health and local health care may be biotics among bacteria of medical importance is a
the most important process in implementing worldwide health problem that demands interna-
surveillance of antimicrobial resistance. tional attention. Its report concluded that without
Governments and their public health agencies reliable information about the susceptibility to
need to take the lead in removing these barriers antibiotics of important bacteria, it would be im-
and in encouraging clinical laboratories to partici- possible to find solutions to the problems created
pate fully in surveillance networks. They have rarely by antibiotic resistance.
done this because they have been slow to see the The Working Group therefore recommended
epidemic nature and the menace to health of anti- promotion of surveillance activities at both national
microbial resistance and thus slow to see it as a and international levels and suggested that WHO
public health responsibility, deserving priority and could play an important role in promoting these
adequate support. activities. It stressed the necessity of extending the
WHO activities in establishing a system for sur-
veillance of antibiotic resistance, and concluded that
Authors’ notes on reports there was a need for unification of methodology
(27) WHO International Collaborative Study of used for the surveillance.
Antibiotic Sensitivity Testing (1968–1970)
This study, carried out in 16 laboratories in differ- (29) WHO Consultation Group for Surveillance of
ent parts of the world, was set up in response to a Antimicrobial Resistance, Geneva, 22–26
recommendation of the WHO Expert Committee November 1982. WHO/BVI/PHA/ ANT/ 82.5
on Antibiotics.(1961) It was sponsored by WHO, This meeting was convened to respond to the rec-
initiated at a meeting in Geneva and coordinated ommendations on surveillance of the previous year’s
by the Karolinska Institute in Stockholm, with Scientific Working Group (above). Its purpose was
financial support for meetings and administrative to discuss the approaches to and objectives of na-
work provided by WHO. tional and international surveillance of antibiotic
21
resistance, and to make recommendations as to how (WHO, Ref, LAB/79.3 in Annex)”. It pointed out
such a surveillance programme might be designed the need to record the actual measurements of sus-
and implemented on a global scale. ceptibility, such as diameters of zones of inhibition
The plan proposed was to: around susceptibility test discs or minimal inhibi-
tory concentrations, rather than the interpretive
1. Develop systems to produce reliable data on
categories derived from them.
resistance in all parts of the world.
The Consultation Group also examined in some
2. Develop systems to ensure that the data are detail the management of the data from such
of good quality and comparability. surveillance. It recognized that nearly a dozen cat-
3. Analyse the resulting data in many different egories of data, such as type of sample, date of
useful ways on a continuing basis. sample, and the identified species and susceptibil-
ity measurements of each isolate were recorded in
4. Use the analyses to monitor, understand and
most laboratories.
control the spread of resistance.
Planning in advance a common software format
The Consultation Group identified three gen- for filing the data in these categories and common
eral sources of data for surveillance. One was the codes for the terms and measurements of that data
susceptibility test result data generated in enormous would thus greatly simplify the merging, manag-
volume by the world’s clinical microbiology labo- ing and analysis of data from many laboratories and
ratories. A second was the more specialized data sources.
generated by reference laboratories. A third would The report noted also that once such data are
come from special studies with epidemiologically electronically filed, it is easy and cheap to ana-
planned sampling not just of selected patient lyse and reanalyse it in many ways to fully extract
populations but also of healthy people in different from it practical understanding of the emergence
settings and of the environment. The group em- and spread of resistance. For illustration, it sketched
phasized that planning in advance to integrate out nine different types of such analyses. It went
analyses of data from these three general sources on to explain how results from these analyses could
would allow cross-referencing enhancement of the be extrapolated to insights about prevalence or
value of each. resistance in different places and different sub-
The report made general recommendations for populations, about prevalence of resistance genes
methods of susceptibility testing, and also for qual- and about the evolution and epidemiology of
ity control of that testing and for what anti- resistance plasmids. It summarized this with a
microbials to test, drawing upon an earlier WHO table (below) offering three examples of the kinds
report on “Guidelines for Antimicrobial Testing of observations that might be made from such
Level Observation Use
Local Frequency of resistance to each antibiotic Aid selection of antibiotics for individual patients
Frequency of resistance to each combination Identify cross-infecting strains, locally endemic resistance plasmids
of antibiotics
Local trends in resistance Aid re-evaluation of local antibiotic usage and infection control
practices
National More resistance to one antibiotic than usual Decrease use of the antibiotic, introduce alternative agents
in other countries
Variation in antibiotic resistance in different Seek regional differences in usage, vehicles of resistance spread,
regions of the country e.g., food or water, hygienic practices
General level and trend of national resistance Review, revise national antibiotic usage strategy to increase its
overall in comparison with other countries effectiveness, reduce resistance
Global Global trends in resistance to various antibiotics, Guide development, use of new antibiotics, ways of preserving
prevalence of different genera older ones. Compare countries’ practices
Early detection of new resistance to an antibiotic Global warning to detect, contain, treat the emerging strain,
in a particular strain in a particular area examine circumstances preceding emergence
Global trends in prevalence of distinctive Detection, prevention of international spread of particular resistance
combinations of resistance or resistance genes plasmids of resistant strains
22
surveillance at each of three levels, local, national, ance to antibacterial agents were barely adequate
and global, and then of the kind of corresponding to sketch ranges and suggest trends. More system-
practical responses that might be made by caregivers atic surveillance on a much larger scale is needed
and policy-makers at each level. to provide explanations or remedies. The World
Even though this Consultation Group was meet- Health Organization has developed detailed rec-
ing within about a year after the introduction of ommendations for such surveillance and is now
the IBM personal computer (PC), at a time when beginning integrated surveillance programmes in
applications of the PC were only beginning, the several regions of the world…This initiative should
group noted its potential significance. “Now, how- be exported and expanded.”
ever, rapid improvement and reduced costs of small Their second recommendation began by noting
computer technology may soon make it possible the growing understanding of the genetic elements
to enter the data directly on cassette tape or disc at of resistance. It then stated: “What are particularly
the testing laboratory.” They further observed that needed now are broadly based studies of the de-
this would make possible local analysis of the data ployment of these genetic elements in natural
for local management of resistance at each medical populations of bacteria that will provide an expla-
centre in addition to the more centralized multi- nation of the phenomena observed in surveillance
centre analysis, which was all that had been practi- and suggest practical strategies for containment and
cal previously with the big, expensive mainframe reduction of resistance.”
computers.
(3) Emerging Infections. Microbial Threats to Health
(1) Antibiotic Use and Antibiotic Resistance in the United States. Report of the Institute of
Worldwide, A study sponsored by the Fogarty Medicine. National Academy Press (1992)
International Center of the National Institutes of This report called attention to a whole group of
Health, 1983–1986 recently observed or recently worsening infectious
Nearly all reference to surveillance of antimicro- disease problems by creating a new category for
bial resistance in this study performed by five task them, Emerging Infections, and setting forth their
forces comprised of international experts was in the special features and similarities and the growing
report of Task Force 2, entitled “Resistance of Bac- seriousness of their threat to human health. It am-
teria to Antibacterial Agents.” The 13 members of plified the perceived importance of antimicrobial
that Task Force came from 5 continents, with only resistance by including it in this category of Emerg-
2 of its members from the same country. Many of ing Infections.
the members brought available data on resistance The report repeatedly emphasizes the impor-
from their own medical centres, from colleagues in tance of surveillance for the control of all emerging
their countries, or from published literature. Data diseases. They constitute such a large and diverse
were also presented from a computerized and iso- set of problems, however, that the report did not
late-based international surveillance system sup- attempt to delineate the special needs for the sur-
ported by the US Food and Drug Administration veillance of each, let alone for antimicrobial resist-
(FDA), which was then ongoing but discontinued ance, which probably differs most from the others
later when FDA found an international study in- in surveillance methodology. Surveillance of resist-
appropriate. ance is, however, mentioned in several places.
The work of Task Force 2 was to piece together
1. Additional resources are recommended for the
from this available information an overview of the
Centers for Disease Control and Prevention
current distribution and apparent trends of anti-
(CDC) to enhance its National Nosocomial In-
microbial resistance throughout the world. Their
fections Surveillance System (NNISS) in five
particular emphasis was to try to integrate what data
ways. The first is to “include data on antiviral
they had with growing understanding of the mo-
drug resistance.” The fifth is “to determine the
lecular basis of resistance and of its spread, so as to
reliability of antimicrobial susceptibility testing
be able to interpret one in terms of the other. Their
performed in NNISS member hospitals.” No
report attempts to do this by examining resistance
description is given of the current status of
to agents grouped according to their being inacti-
NNISS data on antimicrobial resistance.
vated by the same families of resistance mechanisms.
The first recommendation of Task Force 2 was: 2. Under “Agricultural Conditions and Practices”
“The available data on global prevalence of resist- is the somewhat tentative sentence: “It is con-
23
ceivable that surveillance of feedlot animals for The report noted that such local monitoring and
the development of resistant organisms might management was now possible because local resist-
be a means of early warning for the emergence ance databases could be maintained on local
of newly drug-resistant pathogens.” personal computers. Previously, local results had to
be sent to a single remote centre for multi-centre
3. In a section on Access to Surveillance Informa-
analysis on a mainframe computer, with standard-
tion, emphasizing that access to surveillance
ized printed overview results returned to the centre
databases is needed by many types of health care
later. In contrast, local databases can be queried
workers and researchers, it is noted that there
locally, frequently and very specifically on an ad
are now no such databases for many problems,
hoc basis as specific local problems arise. The tech-
including antimicrobial resistance.
nology was seen capable of inverting the older “top-
4. In a later section is a recommendation that the down” surveillance into a “bottom-up” model. In
US Public Health Service develop a comprehen- this newer “grass roots” model, actively used local
sive, computerized infectious disease database databases could, if they shared common file for-
that includes all of these components and mats and codes, be easily merged without loss of
ensure appropriate access to it. detail to produce higher level regional, national or
5. It later recommends that the US “take the lead international databases, as an inexpensive byproduct.
in promoting the development and implemen- Software dedicated to supporting such local but
tation of a comprehensive global infectious combinable antimicrobial resistance databases was
diseases surveillance system.” Another sentence demonstrated for the Group. This shareware, called
later in the report says that: “Should a global WHONET, had been developed to meet the needs
infectious diseases surveillance system be put in set forth by the WHO Consultation Group for
place, such as the one suggested in this report, Surveillance of Resistance of 1982 (see above).
tracking antimicrobial resistance worldwide may Another emphasis of this Scientific Working
be possible.” Group relating to surveillance was the need to build
professional infrastructure to support the monitor-
ing and management of resistance. Well-trained
(5) WHO Scientific Working Group on Monitoring microbiologists in adequately supported microbi-
and Management of Bacterial Resistance to ology laboratories were essential because they were
Antimicrobial Agents. Geneva (1994). the ultimate source of all of the surveillance data
WHO/CDS/BVI/ 95.7
and its quality, and of the information for treating
This Working Group added several new insights. individual patients. The microbiologists, in addi-
Meeting at this time, they were able to look back tion to infection control workers, infectious dis-
and recognize that resistance had worsened greatly ease clinicians and pharmacists, would constitute
over the previous decade due to an array of surpris- the ARM teams.
ing new problems, which they reviewed in detail. The report made separate recommendations for
They warned also that this was happening at a time each of three levels of organization. Those related
when pharmaceutical companies, represented at the to surveillance of resistance are quoted verbatim
meeting, appeared to have under development few below.
new antimicrobials to address these new problems.
For surveillance of resistance, a particular insight
and emphasis of this group was the primary im- Recommendations for WHO
portance of local surveillance linked to local man- Improve systems for surveillance of antimicrobial
agement of resistance for each medical centre and resistance.
its community. The group introduced the idea of a
• Assist nations in assessing status and specific
local antimicrobial resistance management (ARM)
needs of their laboratories for performing ad-
team comprised, to the extent available, of infec-
equate identification and susceptibility testing
tion control workers, microbiologists, pharmacists
of bacterial pathogens.
and infectious disease clinicians. They would work
together, applying their diverse skills to the ongo- • Distribute and facilitate the installation of
ing analyses of local resistance data, to treat patients WHONET software in laboratories to enable
and retard spread of resistance optimally within the them to monitor their own results for test qual-
special circumstances of their time and place. ity, for infection control problems, and for local
24
trends in resistance, and to enable them to merge needed, and open new laboratories in
their results into same-format isolate-based underserved areas.
databases for detailed national and international
• Integrate the work and data of reference labora-
surveillance of resistance.
tories with that of other laboratories monitor-
• Assist laboratories, through WHO Regional ing the spread of resistance.
Offices, in the development of quality control
and quality assurance programmes to help im-
prove the accuracy of antimicrobial susceptibil- Recommendations for local hospitals and reference
ity testing methods. laboratories
• Provide support and facilitate coordination • Develop a plan to monitor and control resist-
between reference laboratories for better strain ance.
typing and other specialized procedures in • Implement a user-friendly, multi-analysis isolate-
order to better characterize the epidemiology of based computer system, such as WHONET,
resistance. which allows detailed monitoring of local resist-
• Encourage the prompt reporting of culture and ance and flags isolates or clusters of isolates that
resistance data and analyses to clinicians, infec- may represent emerging outbreaks of resistant
tion control personnel, and public health strains.
authorities, and prompt transmission of selected • Appoint an antimicrobial resistance manager
isolates to reference laboratories when appropri- (ARM) responsible for monitoring and inter-
ate. preting local resistance and local antimicrobial
• Call attention to patterns of resistance in use and for alerting and working with infection
species of bacteria that may represent emerging control, pharmacy, administrators and clinicians
epidemics, such as vancomycin-resistant to refine and optimize antimicrobial therapy and
enterococci, penicillin-resistant pneumococci, to focus containment efforts.
fluoroquinolone-resistant Shigella, multi-resist-
ant Salmonella typhi, and others less obvious. (8) Report of The ASM Task Force on Antibiotic
• Develop an action plan for appropriate response Resistance (1995)
to outbreaks of resistant organisms. This report emphasized the need for surveillance
• Identify funding sources to help implement the of resistance in the US. It pointed out that: “There
above recommendations. is currently no national or global surveillance sys-
tem for monitoring antibiotic resistance in animals
or humans. In fact, the amount being expended is
Recommendations for individual countries totally inadequate.” It reviewed available figures
from 1992 and could find, outside of private-sec-
Same as for WHO plus:
tor investment in proprietary systems, only $55,455
• Encourage medical centre laboratories to develop from all sources dedicated to antibacterial and an-
isolate-based computer databases of their sus- tiviral drug resistance, out of a total of $76.4 mil-
ceptibility test measurements in a common file lion of federal, state and local funds for surveillance
format, such as WHONET, which can easily be activities of all kinds.
monitored at each centre and aggregated into a The first recommendation of the report is for a
national surveillance database. National Antimicrobial Surveillance System. It be-
gins with a list of things the surveillance system
• Designate one or more laboratories to help other
should do. The first block of suggestions includes
laboratories install and use the common soft-
focus on prevalent pathogens from clinical disease
ware, to provide them with test strains and other
cases and routine isolates, attention to upward
support for improving their testing, and to man-
“creep” of minimal inhibitory concentration (MIC)
age and share with them their shared surveil-
levels, monitoring of animal products at the super-
lance database.
market level, inclusion of Salmonella as reflecting
• Assess the quality, geographic distribution and antimicrobial usage in the animal world and Shig-
professional microbiological support of existing ella usage in the developing world, and monitor-
microbiology laboratories, improve them where ing of soil waste on farms.
25
The list further includes use of concurrent (VA) networks, or SCOPE (Surveillance and Con-
patient demographic profiles, the ability to flag trol of Pathogens of Epidemiologic Importance,
organisms with certain phenotypic or genotypic Medical College of Virginia and University of Iowa)
resistance patterns for further study at reference might serve as working models and that these in-
laboratories and for molecular typing, and the use ternational programmes might provide possible
of surveillance to target areas for intervention or collaborations. Another section sketches guidelines
epidemiological investigation, mostly at the local for analysis of and access to the data, which would
but also at national or international levels. It also be audited by the oversight panel or study admin-
suggests devising different benefits for different sets istrators.
of participants, making data available to pharma- A section on organization of the surveillance
ceutical companies and having a system that could system recommends that funding should be sought
be modified to address new areas of concern. from all parties that would benefit from the sys-
Under “monitoring of organisms”, the report tem, including CDC, FDA, NIH, USDA, VA,
discusses how to update the list of pathogens to DoD, pharmaceutical and health supply industries,
monitor, frequency of analyses, the need for drug and health care delivery companies, academic
significant numbers of isolates, and the need to institutions, professional societies, and university
include species that may not be pathogens but may medical centres. An oversight panel should include
be a source of transfer of resistance genomes to representatives of the organizations plus members
prevalent human pathogens. of the scientific community who are experts on
Sections on geographic representation discuss antimicrobial resistance, specialists in infectious
choosing participant laboratories by US population diseases and in vitro susceptibility testing or expe-
distribution, suggesting one site per one to two rienced in multi-laboratory surveillance, hospital/
million people with stratification by medical cen- health care epidemiologists, and computer and
tre size, type, and services, and with supporting help statistical analysts conversant with antimicrobial
from local and state laboratories, possibly in coor- issues. Location of the programme within CDC
dinating data from laboratories supporting com- would allow integration with other surveillance
munity practices. activities.
A section on methods recommends following A final section on immediate recommendations
Europe’s National Committee for Clinical and calls for an expert panel to develop a surveillance
Laboratory Standards (NCCLS) documents, using protocol and establish an annual budget, for which
where possible the disc-diffusion method with al- the ASM outline might serve as a preliminary or
ternative special tests including molecular testing, tentative plan. Federal funding should be immedi-
some at reference laboratories, guided by expert ately identified, with federal agencies and other
advisory panels and with rigid quality control. It sources involved in funding decisions. It calls also
also states that: “all data should be expressed as for appropriate expertise in statistical and compu-
quantitative endpoints regardless of method. This ter support and for an immediate search for earlier
dictates measurement of disc diffusion tests by resistance surveillance databases from the US or
calipers to the nearest whole millimeter and the use worldwide surveillance, if available.
of MIC endpoints in micrograms per millimeter
for dilution methods.” “Qualitative interpretations
shall be applied objectively by computer programs (7) Report of the US National Science and
based on current NCCLS tables. Similarly, quality Technology Council Committee on International
Science, Engineering, and Technology Working
control guidelines found in the NCCLS tables
Group on Emerging and Reemerging Infectious
should also establish the validity of each partici-
Diseases. Washington (1995)
pant’s/ referee’s data.”
A section on data entry and analyses emphasizes This US government interagency Working Group,
that all surveillance systems need well-structured chaired by the Undersecretary for Global Affairs of
computer systems. It cites the CDC’s NNISS and the Department of State and established under the
the WHO’s WHONET as examples of such soft- aegis of the Committee on International Science
ware used for resistance surveillance, available and Engineering and Technology (CISET) of President
modifiable. It also suggests that networks using such Clinton’s National Science and Technology Coun-
systems or others such as CDC’s sexually transmit- cil, had members representing more than 17 dif-
ted disease programme, Veteran Administration ferent Government agencies and departments. Its
26
charge was to review and make recommendations would decrease medical costs, including costs to
on the US role in detection, reporting and response medicare, Congress could consider funding a
to outbreaks of new and re-emerging infectious nationwide surveillance system.”
diseases. “The features of the current, limited systems can
The Working Group considered the entire range be incorporated and combined to produce a sys-
of emerging infections and emphasized the impor- tem of desired size, complexity and cost. It may be
tant role of surveillance for the whole group. The 2 advantageous to begin with a less complex system
of its 19 recommendations that mention surveil- (such as some of the operating systems described
lance for antimicrobial resistance specifically are in this report), and then add more features. Any
reproduced below. system must have a strong advisory group that in-
cludes diagnostic laboratory and computer experts,
• Assisting WHO to establish surveillance of antibiotic
clinicians, hospital administrators, pharmaceutical
resistance and drug use, as a first step towards the
company researchers, academic scientists, and fed-
development of international agreements on antibi-
eral and state regulatory and health officials. The
otic usage.
advisors could work to assure that the surveillance
WHONET, an international reporting system system collects and disseminates the information
for antibiotic resistance, provides WHO with a in the forms for its best use.”
starting point for this significant work. Taking
advantage of its overseas networks US Agency
for International Development (UASID) can (13) Society for Healthcare Epidemiology of America
provide support for surveillance of drug resist- and Infectious Disease Society of America Joint
ance that hinders the treatment of internation-
Committee on the Prevention of Antimicrobial
Resistance: Guidelines for the Prevention of
ally important diseases. In addition CDC can
Antimicrobial Resistance in Hospitals. (SHEA
contribute technical support and data manage- Position Paper) (1997)
ment resources (5).
The first two of the report’s seven recommenda-
• Identifying and strengthening WHO Collaborating tions for hospitals large and small are: “Establish a
Centres that serve as unique reference centres for system for monitoring bacterial resistance and anti-
diseases whose re-emergence is feared. biotic usage” and “Establish practice guidelines and
WHO Collaborating Centres operated in the other institutional policies to control the use of
United States by Government agencies or by antibiotics, and respond to data from the monitor-
American universities require support to build ing system.”
or rebuild their capacity to serve as reference
laboratories within a larger, more active infec-
(15) WHO Workshop on the Current Status of
tious diseases network (8).
Antimicrobial Resistance Surveillance in Europe.
Verona (1997). WHO/EMC/BAC/98.1
(6) Report of the Office of Technology Assessment of Participants in resistance surveillance networks in
the Congress of The United States on Impacts of
Europe filled out questionnaires in advance, and
Antibiotic Resistant Bacteria (1995)
their responses constitute the descriptions printed
The report does not use the word “recommend”, in this report. Twenty-nine surveillance activities
that presumably being the prerogative of the Con- or networks are described, approximately half of
gress, but instead presents “issues and options”, which targeted a single bacterial species. In the
usually expressed as “the Congress could.” Under workshop the participants reviewed, elaborated
the first of these in its summary (A. Surveillance) it upon and discussed these systems.
says that “Congress could support the establishment They found need to improve communication
of a national surveillance system, including proof results to decision-makers; to improve and har-
viding funding.” monize quality assurance standards throughout
It goes on to explain: “A surveillance system is Europe; to have adequate support for microbiol-
essential for understanding the spread of antibiotic- ogy and epidemiology training, laboratory infra-
resistant bacteria and planning interventions so as structure, data analysis and communication; and
to preserve the efficacy of currently available anti- to provide adequate funding for regional partner-
biotics. Because of these public health considera- ships. Lack of funding was the principal obstacle
tions, and the likelihood that a surveillance system for existing systems. They concluded that further
27
discussions were necessary to develop collaboration ity testing. It emphasizes that there are few labo-
between existing programmes. ratories, even when central laboratories are in-
cluded, where testing cannot stand improvement,
and an alarming number where improvement is
(22) Antimicrobial Resistance: Issues and Options.
Institute of Medicine Workshop Report (1998) essential. The need to improve is not just for sur-
veillance, but for the patients whose therapy is be-
The report’s section on surveillance begins by stating guided by these tests.
ing that its purpose is to provide information for In addressing what is needed the report sum-
action and that the information is “for several pur- marizes why no single global or national antimi-
poses at every level where health care is provided. crobial resistance surveillance system has the
Each level has different needs and all are critical.” qualities outlined here. Few of the multiple exist-
Examples are given of the many kinds of questions ing surveillance activities have been longitudinal
that need to be asked and a review of the problems and as a group they are almost totally uncoordi-
that have historically restricted efforts to monitor nated and unstandardized, so the magnitude and
antimicrobial resistance. impact of resistance remain poorly understood and,
The report makes the statement in its summary “…the most powerful case possible must be made
that: “No country, including the United States, has for urgent and substantial response.”
a reliable, longitudinal, full-service antimicrobial The report refers to the ASM Task Force of 1995
resistance surveillance programme with comprehen- (see above), the recommendations of which it in-
sive focus, nor is there a comprehensive database cludes as Appendix B. It comments that even
for monitoring trends in antimicrobial usage.” though those recommendations are straightforward,
A section on characteristics of an ideal resist-
their elaboration and implementation will require
ance surveillance system indicates that it should be
much coordination and compromise. “No single
prospective, active, timely and affordable, with the
system is likely to be able to perform the full range
broadest possible access. It should also provide
of necessary surveillance, so that harmonization of
accurate incidence and prevalence rates, exclude re-
multiple systems and guidelines for the production
peat isolates, distinguish infecting and colonizing
of comparable data will be ongoing challenges.”
organisms, and categorize data by location as well
“Real partnerships will be essential as people and
as by hospital or community, urban or rural. In
institutions with varying priorities try to achieve
addition, it should gather information on antimi-
goals that may be similar in many ways but diver-
crobial use and treatment outcomes (especially fail-
gent in others.”
ure); detect new resistance markers; and use reliable,
standardized test methods on appropriate specimens
with validation. It should be a national network (21) The British House of Lords Select Committee on
representing inpatients and outpatients in all Science and Technology Report on Resistance to
regions with all participating laboratories compu- Antibiotics and Other Antimicrobial Agents.
terized to collect, process, and report electronic data London (1998)
continuously, with all such databases integrated Chapter 5 of the report is on surveillance. Its first
nationally, and regional and local data made avail- 9 paragraphs are on general reporting requirements
able to practitioners. A separate section reempha- for infections and on liaison between agencies. Para-
sizes the need for local-level surveillance. graphs 10–13 emphasize importance of informa-
A section follows which describes several exist- tion technology, citing NNISS and Intensive Care
ing national surveillance systems, including: CDC’s, Antimicrobial Epidemiology (ICARE). Paragraphs
The Surveillance Network (TSN), Canada’s, Ice- 14–17 discuss recent problems with professional
land’s, and as international systems CEM/NET, infrastructure and its funding in the UK, includ-
WHO initiatives, and SENTRY. This partially over- ing declining financial support for the Public Health
laps with a lengthier inventory added as Appendix Laboratory Service (PHLS).
A. The last 5 paragraphs cover a national strategy
Another section points out that surveillance data for surveillance. Many groups agree that there is
are laboratory-dependent. It proceeds to give an no adequate systematic surveillance of resistance in
overview, based on extensive experience with qual- the UK now. Costs for such a system would be
ity control surveying largely in the US, of the kinds modest but no source has provided funding. There
of problems encountered in laboratory susceptibil- needs to be a consensus with PHLS, NHS,
28
academia and clinicians. The British Society for performed for every organism and the costs are
Antimicrobial Chemotherapy (BSAC) has set up a considerable.
Working Party on Resistance Surveillance, which Compilation of routine susceptibility testing
has proposed a multi-level approach and is seeking data can be a measure of public health impact be-
collaborative arrangements. The Minister for Pub- cause these data do have a population denomina-
lic Health said, “We support a strategic approach tor, but there remains the problem of non-standard
to this,” but was unable to make any commitment testing methodology. Such routine data represent
as to resources. a huge untapped source of inexpensive, accessible
In concluding their report, the Committee de- results, which could be analyzed at local, national,
clares surveillance of resistance to be vital to the and regional levels to give a measure of the public
fight against resistance. It makes multiple recom- health impact of antimicrobial resistance. The sys-
mendations for surveillance, most of which are ad- tem envisaged is one fed by regular downloads from
dressed to specific agencies or organizations in the laboratory computers of routine susceptibility data
UK about resource allocation rather than to ele- on a wide range of organisms and specimen types.
ments of system design. It does, however, stress the The aim would be to encompass the whole; an
importance of information technology in speeding essential facet would be linking the data to popula-
up exchange of compatible data locally, nationally, tion denominators. Although this is a new area of
and internationally. It also expresses approval of the work, the burden on individual laboratories would
UK’s NNISS system, hopes that it can acquire data be relatively low. Electronic downloading of data
on use of antimicrobials, and suggests it consider directly from microbiology computer systems is the
the ICARE model. ideal, and has been done in other places.
(19) Report of the British Department of Health (30) Report from the American Academy of
Standing Medical Advisory Committee Subgroup Microbiology: Antimicrobial Resistance, An
on Antimicrobial Resistance: The Path of Least Ecological Perspective (1999)
Resistance (1998) This report seeks to take a broad, ecological view
This incisive and comprehensive report visualizes of antimicrobial resistance and its distribution in
a multi-level surveillance system that integrates the environment. This emphasis is given to much
multiple methods of surveillance, “each cross-vali- of the discussion and to most of the recommenda-
dating the other.” It summarizes and critiques what tions for future scientific research. The ecological
exists at each level in the UK now and makes real- approach is reflected in the section on surveillance
istic suggestions about their improvement. It is ex- by the statements that “with respect to antimicro-
tracted, at times nearly verbatim, below. bial impact on the environment, surveillance
“Alert organism surveillance,” the detection of involves not only data on bacterial pathogens but
organisms with significant new features, has a role also data on other microorganisms that are part of
as an early warning system. It is in place now only the affected ecosystem.” The report also states “Dif-
to the extent that such isolates find their way to ferent types of surveillance are needed for each com-
reference laboratories. ponent of the biosphere.”
Reference laboratory elaboration of species or In discussing different existing types of surveil-
of resistance mechanisms is often elegant now, but lance it mentions sentinel surveillance for detecting
interpretations of epidemiological significance are rare or important events. An ecological dimension
beset by sampling problems and lack of a denomi- might be added to this if instead of noting only
nator. strains categorized resistant by existing clinical
Sentinel laboratory monitoring, meaning the breakpoints resistance could also be defined by
prospective collection of selected organisms for test- lower “thresholds” of change in susceptibility that
ing with standard methodology by a central labo- would “provide a selective advantage to a microor-
ratory, offers a high level of control but also lacks a ganism or risk for evolution toward greater resist-
denominator population and can test only small ance.”
numbers of isolates. The report continues its discussion of resistance
Special surveys are a good tool, particularly if surveillance methods by recognizing that special
they have prospective selection with a clinical case studies conducted with prospectively defined
definition in a defined population, but cannot be populations, e.g., surveying pharyngeal carriage of
29
pneumococci in a defined group of children, is “With partners design and implement a national
desirable but expensive because the survey has to AR surveillance plan that defines, national, regional,
pay for the culturing. state and local surveillance activities; the roles of
The same is true for surveillance of clinical iso- clinical, reference, public health, and veterinary
lates by sending them to a remote reference labora- laboratories; and is consistent with local or national
tory for uniform testing. surveillance methodology and infrastructure that
It acknowledges that the bulk of surveillance data currently exist or are being developed”.
will thus come from clinical isolate susceptibility “Develop and implement procedures for moni-
test results downloaded from routine clinical labo- toring patterns of antimicrobial drug use in human
ratory files. This approach has the potential disad- medicine, in agriculture, and in consumer prod-
vantage of variable test quality, but it costs little, is ucts.”
rich in local epidemiological detail, and so supports The section on surveillance in the report states:
local management of resistance while being a com- “At present the United States lacks a coordinated
ponent of regional or national surveillance. Analy- national plan for AR surveillance” and “Improved
sis of the resulting stream of test results, moreover, AR surveillance depends upon enhanced epidemio-
“can serve to continuously improve the quality of logic and laboratory capabilities at local, state and
the laboratory sampling and testing.” national levels, use of standardized and reliable labo-
Implicit, but not stated in this discussion, are ratory testing methods, and enhanced use of
two ways to enhance the value of such clinical informatics.”
isolate data for generating ecological or environ- The remainder of the section is an extensive
mental insights. One would be to not screen out outline of the general needs for developing and
non-pathogens from surveillance databases, as is implementing such a comprehensive system. The
sometimes suggested, but only exclude them from first block deals largely with allocation of general
particular analyses. The other, as supported above categories of tasks to specific coordinators and col-
for many other reasons, would be to file only full laborators.
range measurements of isolate susceptibility (inhi- The second block is on the development of
bition zone diameters or full-range MICs) rather standards and methodologies. It includes “stand-
than just the interpretive categories derived from ardized laboratory methodologies and data elements
those measurements. This would allow continuous that allow susceptibility test results and AR sur-
monitoring of the small increments in resistance veillance data to be compared across geographic
(e.g., creeping resistance by accumulating mutations jurisdictions. Similarly, use standardized definitions
to fluoroquinolones) that may “provide a selective and methodology to create an electronic surveil-
advantage….or risk evolution toward greater resist- lance system that health care institutions can use
ance.” to compare AR data from other local facilities.”
It also calls for development of “standards for
reporting quantitative data (e.g., MICs or zone di-
(31) US Interagency Task Force for a Public Health
ameters) in ways that will detect decreased suscep-
Action Plan to Combat Antimicrobial Resistance
(2000) tibility.” This is necessary because numerical AR
test results reported non-quantitatively (e.g., as sus-
Based on a public meeting held in Atlanta, Geor- ceptible, intermediate or resistant) as “susceptible”
gia, in July 1999, with representatives of CDC, may mask an emerging AR problem (i.e., microbes
FDA, NIH, AHRQ, USDA, DoD, DVA, EPA, with a small decrease in susceptibility may still be
HCFA, and HRSA and many other groups, the plan classified as susceptible).
lists issues, goals and actions that apply mostly to A block is devoted to the need, little mentioned
human (as opposed to non-human, such as agri- in previous reports, to allow the data within such a
cultural) antimicrobial resistance (AR) issues. For surveillance system to comply with patient confi-
each action item “coordinator” and “collaborator” dentiality policy. Subsequent sections recommend
agencies/departments are specified. Its Executive work to ensure that this is possible and to develop
Summary lists under 4 major headings 11 top new policy if needed.
priority action items to combat antimicrobial re- Other recommendations follow, such as: “Link
sistance. The first of the 4 headings is “Surveillance”, human drug-use data to clinical information (e.g.,
with 2 priority items under it: diagnosis, severity of illness and outcome). “Work
with accrediting agencies to address antimicrobial
30
drug-use monitoring as part of quality control as- involving animal and human populations. In con-
surance in health care delivery systems.” “Evaluate sultation with stakeholders determine how to re-
the performance of licensed, automated AR test- port AR data in a way that is useful to interested
ing devices in the context of changing resistance parties (e.g., clinicians, public health officials,
patterns and update their labeling where appropri- veterinarians, and researchers). Include sufficient
ate (e.g., changes in quantitative resistance that may detail in surveillance reports to permit local analy-
make a test result invalid).” sis and comparison with trends in drug use and
Under a section on state health and agricultural medical and agricultural practices.”
agencies is the recommendation that they “main- A final section on monitoring AR in agricultural
tain the capacity to test the drug-susceptibility pat- settings recommends expansion of the National
terns of resistant organisms of public health Antimicrobial Resistance Monitoring System
importance, especially for drug-microorganism (NARMS) and extension of its sampling to moni-
combinations for which testing methods are not tor transmission of resistant infections. It also rec-
routinely available at hospital and commercial labo- ommends monitoring of fruit and vegetable
ratories.” production and of environmental contamination
A section on dissemination of surveillance data by antimicrobial drug residues and drug-resistant
recommends: “Provide an accessible, centralized organisms that enter the soil from human and ani-
source of AR data from major surveillance systems mal waste.
31
CHAPTER II
Increase awareness: optimize patient

and provider behaviour
Jerry L. Avorn
Abstract • Minimal or nonexistent training of children at
Considerable evidence points to widespread prob- all levels of education in relation to health hab-
lems in knowledge, attitudes, and behaviour relat- its
ing to antibiotic use among both patients and • Aggressive marketing of antibiotics and
prescribers in the industrialized and the develop- antibacterials to both physicians and patients
ing worlds (19,32,33,34). Such evidence is drawn
• Inadequate or nonexistent continuing education
from numerous sources:
requirements concerning infection control and
• Inappropriate patterns of antibiotic use for a antibiotic utilization for most health profession-
variety of specific clinical conditions: als.
— Use of antibiotics to treat symptoms that are This chapter reviews the barriers for changing
clearly viral in nature physician and patient behaviour and suggests
— Reliance on excessively broad-spectrum an- effective intervention strategies.
tibiotics when narrower-spectrum agents
would be more appropriate
Disincentives and barriers to overcome
— Errors in the timing and duration of antibi-
otic prophylaxis at the time of surgery A number of specific problems have been identi-
— Poor adherence by patients to prescribed fied that present obstacles to the development and
antibiotic regimens, including premature dissemination of effective programmes of prescriber
cessation of therapy and “hoarding” antibi- and patient education concerning the prudent use
otics for future unsupervised use of antibiotics (7,21,22,39). These include:
• In the developing world, widespread use of an- • Inadequate support for publicly financed edu-
tibiotic injections when not clinically indicated cational programmes for either professionals or
lay people
• Erroneous responses by patients and physicians
to surveys concerning antibiotic knowledge and • Strong commercial pressures from manufactur-
attitudes ers to increase utilization of antibiotics and
antibacterials
• Under-use by physicians and consumers of
proven non-antibiotic means of infection con- • Low levels of literacy in the developing world,
trol, such as hand washing limiting the impact of verbally-based public edu-
cation messages
• Growing consumer demand for “antibacterial”
cleaning preparations which can actually increase • Fear of litigation in the United States which en-
bacterial resistance courages the practice of “defensive medicine”,
often leading to prescription of an antibiotic
• Low levels of use of products that can provide
when one may not be necessary
safe, effective alternatives to antibiotic use to
combat infection, such as condoms, bednets in • Pressures to shorten the length of a physician
malaria-prone areas, vaccines. visit, which in turn increases pressure for anti-
biotic utilization as a time-efficient means of
The causes of such educational and behavioural
ending the visit
deficits have also been well identified (8,35–38).
They include: • Poor regulation in the developing world of claims
made in promotional materials for antibiotics
• Inadequate training of health professionals in
rational antibiotic use (and non-use) • Physicians’ desire for autonomy, which can make
33
them disinclined to accept guidelines or antibi- by addressing either audience separately.

otic restrictions. Another overarching principle evident in many
studies and policy recommendations on improve-
Educational strategies which have been ment of medication use is the concept that educa-
shown to be ineffective tion/behaviour change interventions should be
tailored to the specific circumstances and needs of
One approach stands out as having remarkably lit-
the audience, rather than presenting a “one size fits
tle effect in altering antibiotic use. This approach,
all” formula which may not resonate with the indi-
the simple dissemination of printed guidelines or
vidual experience of the targeted prescriber or
educational messages, without other reinforcement,
patient.
is unfortunately among the most commonly used.
Ideally, programmes to change behaviour of
This has now been studied in a variety of
patients, physicians, or lay caregivers should be
randomized controlled trial settings with strikingly
grounded in solid behavioural science theory and
consistent results: physicians who are mailed printed
experience, as well as (equally practically) the theory
information on proper prescribing, but who do not
and experience of marketing (41). Specific theo-
receive any other kind of intervention, in general
ries relevant to the reduction in antibiotic misuse
do not change their practice any more than physi-
include the PRECEDE model, which considers
cians randomized to a control group (40). The fact
factors that encourage or prevent behaviour change,
that this finding has been so consistently reported
and the Transtheoretical Model, which takes into
makes it even more disturbing that this approach
account the various cognitive and behavioural stages
is probably the single most frequently employed
associated with adopting changes in a specific area
strategy for changing antibiotic prescribing.
(42,43).
Another common approach, that of having an
While it is not easy to reduce inappropriate an-
expert lecture a passive audience with minimal
timicrobial use, some encouraging data exists about
opportunity for interaction, has also been report-
the efficacy of some programmes in improving
edly shown to result in little or no change in medi-
problematic practices. Overall, there is good news
cation use behaviour.
about the efficacy of such programmes in improv-
Fortunately, other methods of improving anti-
ing drug use. In a review of 59 studies of interven-
biotic utilization have been well studied and found
tions to improve medication use (primarily
to reliably improve the appropriateness of prescrib-
antibiotics) in the developing world, Ross-Degnan
ing. These are described in the section that follows.
(44) found that among studies which had an evalu-
While the term “appropriate antibiotic use” will be
ation design adequate to permit comparison of
used consistently, it should be pointed out that such
outcomes, 43% of studies had an impact classified
broadly-defined education would also include such
as “large” (>25% improvement compared to con-
topics as the appropriate use of vaccines and the
trols), and 36% had a moderate impact (10–25%
use of alternative methods of infection control, such
improvement compared to controls). Only 21% of
as hand washing.
the studies had low or no impact (<10% improve-
ment). The most common approach in this latter
Strategies which have been demonstrated group of minimal impact was the dissemination of
to be effective in improving the printed materials recommending rational utiliza-
appropriateness of antibiotic use tion.
Most studies and published recommendations have
considered education and behaviour change inter- Interventions directed at prescribers
ventions separately by the audience targeted:
patients, prescribers, or (in the developing world) In that review (44), the following types of inter-
non-physician drug vendors. These categories will ventions were found to produce significant im-
be used in the sections which follow. However, it is provements in prescribing, as measured in
evident that the ideal approach would constitute a randomized intervention trials:
combination strategy aimed at both the prescrib- • Multiple training modalities applied together
ers and the users of antibiotics. In fact, some (group problem-solving, role playing, lectures,
recent research has shown that such a “double- opportunity to practice skills)
barrelled” targeting of both audiences can produce
• Focusing on one clinical issue at a time
a synergistic effect much greater than that achieved
34
• Training at the work site tibiotic education programmes are equally straight-
forward, and contain messages such as the follow-
• Use of opinion leaders or district-level staff as
ing:
trainers
• Do not use broad-spectrum antibiotics when
• Repeated sessions focusing on reinforcement of
narrower-spectrum agents would work as well
the message
• Base the antibiotic prescription on culture
• Community-based case management interven-
results whenever possible
tions (their use in acute respiratory infections
and diarrhoea was so effective that a mortality • Modify the regimen over time as required
benefit could be demonstrated). • Consider cost-effectiveness in choosing an anti-
Administrative interventions were found to work biotic regimen.
well in improving antibiotic utilization if they had In the industrialized world, computers have been
the following attributes: put to good use in guiding choices of antibiotics
• Were based on group process for hospitalized patients. In one system, a compu-
ter “consultant” is given all pertinent facts concern-
• Involved ongoing supervision and monitoring
ing a patient’s infection and clinical condition, and
of practice
then offers antibiotic recommendations. These have
• Provided regular audit and feedback of prescrib- been found to have a very high degree of clinical
ing patterns. accuracy when compared with the “gold standard”
recommendations of infectious disease specialists
In a similar evaluation, Laing and Hogerzeil (un-
(45).
published) reviewed the experience of a number of
The ordering of all medications, including anti-
programmes in the developing world and concluded
biotics, on computer terminals will become com-
that the following strategies had strong records of
mon in many institutions in the industrialized
success in improving prescribing of antibiotics and
world over the next few years. Initial experience
other drugs:
with such systems in hospitals where they are al-
• The development and effective dissemination of ready in place indicates that they can be used to
lists of essential drugs and standardized treat- good advantage in reducing antibiotic utilization
ment guidelines by reminding the ordering physician at the time the
order is being written that such a choice is not in
• The creation and empowerment of pharmacy
conformance with available evidence and/or insti-
and therapeutics committees in hospitals
tutional guidelines, and offering more reasonable
• Problem-oriented training alternatives. Such systems can also be used to flag
• Targeted in-service training of health workers. orders which require further consultation or ap-
proval by an infectious disease consultant (46,47).
In addition to these observations about effec- Other educational approaches less dependent on
tive strategies, consensus has also developed con- technology have also been demonstrated to be
cerning the clinical content of programmes to effective in improving antibiotic use. In the 1980s,
improve antibiotic use. Some of these are quite researchers in the United States began to apply the
straightforward, such as the basic British recom- powerful behaviour change interventions employed
mendations advocated as a simple starting-point by the pharmaceutical industry, but put in the serv-
for reducing inappropriate antibiotic use (20): ice of restrained prescribing rather than promotion
• Avoid antibiotics for simple coughs and colds of sales of a given product. In this approach, which
came to be known as “academic detailing,” clini-
• Do not use antibiotics for the treatment of viral cian/educators were trained from a medical school
sore throat base to become expert in the drug therapy required
• Limit antibiotic use in uncomplicated cystitis in for specific conditions, and also received training
healthy women to three days in strategies of “social marketing” and behaviour
change. These educational outreach workers were
• Limit telephone prescription of antibiotics to
then sent to visit with physicians in their offices at
exceptional cases only.
a convenient time, much as industry sales repre-
Other recommended content areas for such an- sentatives do. They presented the need for appro-
35
priate prescribing in terms which were concise, tral role played by the patient (or parent of a
clinically relevant, and behaviourally appropriate; pediatric patient) in the implementation of antibi-
the presentation was supplemented by engaging, otic regimens, strategies directed at consumers can
well-designed, graphic print materials. Initially, such be of particular importance in reducing antibiotic
educational outreach workers were primarily phar- use (48). Such education can take numerous forms:
macists, but this role has also been filled effectively
• In pediatrics, caregivers can be educated to rec-
by physicians, nurses, and—in the developing
ognize patterns of symptoms that can indicate
world—by lay people as well. The communication
whether a child should be brought in for medi-
is designed to be interactive rather than didactic,
cal care and potentially for an antibiotic prescrip-
which offers the educator an opportunity to un-
tion. Such education encourages appropriate
derstand the specific informational and attitudinal
utilization and discourages inappropriate use.
situation of the targeted prescriber and to modify
the educational session accordingly. Following its • Better recognition of the symptoms of malaria
initial demonstration in the United States, this can allow for earlier referral to a health care pro-
approach has spread throughout the world, and has fessional, earlier diagnosis, and treatment.
been found to be equally effective in both industri- • Education about the non-drug management of
alized countries and the developing world. In April routine diarrhoea in children (e.g., with oral re-
1997, a four-day conference in Chiang Mai, Thai- hydration solutions) can replace unnecessary re-
land, focused on improving medications in the ferrals to scarce medical resources, as well as
developing world; a number of such successful pro- inappropriate requests for antibiotics.
grammes were described in detail. Cost-benefit
analyses have demonstrated that such programmes • In adults, conditions susceptible to such educa-
can save more than twice their expenses in terms of tion about appropriate health-seeking behaviour
reduction of unnecessary prescribing (44). include viral upper respiratory symptoms, vagin-
itis, and recognition of the early symptoms of
Human Immunodeficiency Virus (HIV), among
Education of students in the health others.
professions
Public education programmes have focused on
Current training about rational antibiotic use is broad themes, such as the lack of utility of antibi-
widely regarded as inadequate in most pre-profes- otics in viral conditions and the need to adhere
sional settings throughout the world. More relevant carefully to the prescribed regimen if an antibiotic
and critical education about infection control and is ordered, rather than starting or stopping therapy
treatment has been called for not just for medical on an as-needed basis.
students, but also for students of nursing, phar- A particularly interesting approach has been
macy, and veterinary medicine. Beyond the spe- taken in the United Kingdom to encourage the
cific scientific content in pharmacology and public to “cherish and conserve your natural flora,”
microbiology that must be taught, students also pointing out the beneficial aspects of bacteria which
need to be taught to critically evaluate promotional can be obliterated by excessive antibiotic use. Other
materials for medications to become more “media groups have advocated the education of the public
savvy” in evaluating printed advertisements and concerning the risks of unnecessary antibiotic use
prepared to ask the right questions during sales pres- in animals and agriculture as well as humans; the
entations for antibiotics. Problem-based education Alliance for the Prudent Use of Antibiotics (APUA)
has been found by many health professions educa- has been particularly active in this regard.
tors to be a useful and powerful method of com-
municating such information.
Other audiences for interventions
Beyond the obvious targets of physicians and pa-
Interventions directed at patients, tients, other important groups have been identi-
families, and consumers fied as appropriate audiences for education about
The patient is a vital link in the pathway of antibi- antibiotic use, including workers in day care cen-
otic utilization; it is often patient demand which tres, schoolteachers, those who work in agriculture,
triggers inappropriate antibiotic prescribing in the and policy-makers in all these areas as well as health
first place. Because of this, and because of the cen- care.
36
System-wide interventions A number of strategies for improving the knowl-

In addition to strategies directed at prescribers and edge base of physicians and the public concerning
patients, a number of effective educational strate- antibiotic use have pointed to the need for capac-
gies have targeted the health care delivery system ity building on a number of fronts to make such
itself, whether in the form of governmental health programmes possible. Such infrastructure require-
care services or private sector health practices or ments fall into several categories. First among these
systems. This section will not deal with regulatory is the capacity to devise, validate, and modify evi-
approaches to improve the antibiotic use, which dence-based guidelines on rational antibiotic use,
are discussed elsewhere in this report (See Chapter since this is necessary to provide the content needed
III). Rather, it will focus on means of educating to drive any educational programme. These pro-
the participants and leaders of such systems in or- grammes can be governmentally sponsored, as is
der to encourage them to adopt more enlightened the case with the British National Institute for Clini-
policies at a systems level (31,49). cal Excellence (NICE), or the guidelines develop-
ment process of the US Agency for Health Care
• The creation of drugs and therapeutics commit- Policy and Research before it was disbanded under
tees (or pharmacy and therapeutics committees) political pressure several years ago. Similar activi-
can be a very useful strategy at the level of indi- ties have been conducted by the US Centers for
vidual health centres as well as at the level of Disease Control and Prevention as well as WHO,
national health care programmes. Such groups and antibiotic guidelines have been widely dissemi-
can evaluate all available evidence concerning nated in Australia. In addition, professional socie-
utilization data, resistance patterns, efficacy, and ties have also developed their own evidence-based
cost, in order to make recommendations for guidelines for appropriate antibiotic use. These have
proper antibiotic use which are appropriate to a included the American Society for Microbiology,
particular clinical setting and population. and a variety of specialty societies (e.g., the Ameri-
• Dissemination of essential drug lists, such as can Heart Association guidelines for the use of pro-
those promulgated by the World Health Organi- phylactic antibiotics in patients with valvular heart
zation (WHO), can help simplify antibiotic disease, or the American College of Gastroenterol-
choices for practitioners as well as make them ogy recommendations concerning regimens for the
more clinically appropriate and cost-effective. eradication of H. pylori infection).
WHO has identified a number of other infra-
• Facilitation of communication among academic structure-related issues that bear directly on the
institutions, government agencies, those who pay capacity to mount successful educational pro-
for health care, and pharmaceutical manufac- grammes concerning antibiotics. These include:
turers can sometimes reduce the extent to which
such entities act at cross purposes in relation to • Control of the promotional activities of drug
one another in relation to antibiotic use and manufacturers
infection control. • Training of a new category of health professional,
• Beyond the drug lists themselves, guidelines for the antimicrobial resistance manager/monitor
the use (or non-use) of antibiotics in particular (ARM), to serve as a local resource to follow the
situations can improve the rationality of prescrib- current literature on antibiotic resistance,
ing. For maximum benefit, such guidelines analyse local data, propose and implement strat-
should be: egies for control and resistance, and work with
clinicians on the care of specific patients
— Evidence-based
— Appropriate to the clinical and microbiologi- • Development and enforcement of ethical stand-
cal issues relevant to a given population ards concerning advertising of antibiotics
— Developed with the involvement of the prac- • Analysis of data on local resistance patterns
titioners (and potentially the patients) who
will be using them • Communication of global trends in antibiotic
— Disseminated not simply via printed memo- resistance with potential local impact
randa, but rather through the use of interac- • Development of information systems to moni-
tive strategies oriented to changes in behaviour, tor and feed back data on utilization and resist-
as described elsewhere in this section. ance patterns.
37
Similarly, the US Agency for International Conclusions

Development (USAID) (39) has also focused on Just as considerable progress has been made in
the need to build local capacity in developing coun- microbiology and clinical infectious diseases in the
tries to provide the infrastructure needed to encour- last two decades, similar progress has been made
age rational antibiotic use. This includes training during this period in understanding why antibiot-
of personnel and creation of systems to: ics are misused by prescribers and by patients, and,
• Perform surveillance equally important, which strategies are most effec-
tive in preventing such misuse. Rigorous data are
• Manage data
available describing the effect of such innovative
• Conduct educational programmes programmes in patient and caregiver education,
• Choose which antibiotics to purchase computer-based prescribing guidelines, academic
detailing of prescribers, and community-oriented
• Develop policies concerning regulation, reim- educational programmes; such studies have amply
bursement, and financing of antibiotic purchases demonstrated their utility and, for some, even their
• Provide unbiased drug information cost-effectiveness. Similarly consistent data are avail-
able describing the poor track record of many con-
• Establish field sites for innovative demonstra- ventional practices in changing practice patterns,
tion projects (e.g., tuberculosis surveillance and such as the mailed transmission of expert guide-
control) lines. It is unfortunately true that such older, con-
• Train microbiology laboratory personnel ventional practices remain the norm, while more
innovative programmes, though becoming more
• Prepare training and advocacy materials for
widely adopted each year, still form the minority
local government officials on the burden of
of intervention programmes. This is probably the
disease related to resistance and the need for
combined result of habit and tradition, as well as
specific programmes to combat it
the lower costs required to conduct programmes
• Develop and enforce quality control standards that are print-only in nature, and skepticism con-
for drug manufacturing and microbiology labo- cerning the cost-effectiveness of more interactive
ratories. person-based programmes. As the stakes become
higher each year in terms of the clinical and eco-
Internet access makes it possible for patients and
nomic consequences of antibiotic misuse, it is to
practitioners throughout the world to have instan-
be hoped that educational interventions in this
taneous access to current information about medi-
arena are subjected to the same critical evaluation
cations, patterns of resistance, and other data
and evidence-based use as are the medications
relevant to appropriate antibiotic use. One such
whose utilization they attempt to improve.
guide has been made available on the Internet
through WHO (http://www.who.int). For other
relevant web sites see the section, Some Useful Web
Sites.
38
CHAPTER III
Strengthen sanitation,infection control,

and regulatory measures
Peter G. Davey
Abstract • Failure to cleanse hands after each patient con-
Governmental and private health management sys- tact
tems, at national, regional, and local levels provide • Limited use of gloves and gowns
the basis for the delivery of health care. These sys-
• Lack of sterile supplies and poor sterilization
tems are critical to the curtailment of antimicro-
practices
bial resistance because they help determine the
availability and usage of antimicrobials. They also • Increased movement of patients within and be-
play a role in developing and enforcing programmes tween hospitals.
to reduce the spread of microbial infections, There is a broad consensus among the expert
whether in hospitals or in the community. policy groups (see Table B) on the need to establish
Limiting microbial infections is a key step to-
an infection control programme in order to more
wards the goal of reducing the current prevalence effectively control hospital infections. Elements of
of antimicrobial-resistant organisms. The respon- such a programme identified in the reports are:
sibility of carrying out the daily routines of infec-
• Surveillance of infection
tion control and sanitation programmes falls to
hospital management and health care providers. • Identification of outbreaks
These routines range from proper hand washing to • Implementation of effective control measures
reporting surveillance data. (e.g., hand washing, gowns)
This chapter reviews the expert groups’ (1,5,6,7,
11,13,19,20,21,22,24) findings and strategies re- • Sterilization and disinfection of equipment and
lating to 1) sanitation and infection control, and supplies.
2) government and health system regulation. This Most of the reports reviewed recommended
review outlines what is covered in previous expert some form of a committee or programme to be re-
policy reports, and provides guidelines from the sponsible for the improvement of infection con-
expert policy groups on a global strategy. The re- trol. The general statements about infection control
view also designates specific programme compo- improvements within hospitals need to be supple-
nents and models that countries might consider in mented by the specific recommendations for im-
developing their national strategies for infection provement of infection control which were
control and regulation of antibiotics. Areas of con- addressed in some of the previous expert reports
cern from previous reports and additional recom- (see Tables C and D). Developing countries in par-
mendations from the expert policy reports are ticular face the challenge of improving their public
noted. health infrastructure, community sanitation and
health education in order to decrease the emergence
I. Sanitation and infection control and spread of infections. This is a priority need in
order to decrease the spread of resistant organisms.
Control and prevention of microbial infections and All countries could improve education of health care
improved sanitation in the health care setting are and day care workers (5,49). The previous expert
imperative to decrease the spread of resistant reports also make strong recommendations about
organisms and minimize the need for antibiotics. mandating hospital infection control within pur-
As cited in the expert reports reviewed (1,5,6,7, chasing and commissioning agreements (see Tables
11,13,19,20,21,22,24) (Table A), the major fac- C and D).
tors contributing to the spread of infection and
antibiotic resistance transfer in health care settings
are:
39
Other national models for antibiotic resistance • Adapt for local use the HELICS Methodology for Measur-
intervention ing the Status Quo for National Initiatives in Infection
Several programmes and guidelines related to health Control
care management and the control of infections have This is consistent with the recommendation
been developed after most of the policy reports were from the WHO Scientific Working Group (5):
published. Since infection control is a key strategy “Develop methods and standards for evaluating
in containing antibiotic resistance, local govern- hospital infection and antimicrobial resistance
ments and professional societies could consider control programmes, leading ultimately to
adapting the following programmes to their own national accreditation systems.”
needs, within the limits of available resources (other • Adapt the epic Evidence Based Guidelines (http://
examples of local initiatives are outlined in Appen- helics.univ-lyon1.fr) for implementation in other coun-
dix B). tries
• The epic project: Developing National Evidence- The evidence reviewed in these guidelines is a
Based Guidelines for Preventing Healthcare- comprehensive review of the published world
Associated Infections. The epic project has literature. However, there may be existing local
developed guidelines, approved by the UK guidelines that could be reviewed and incorpo-
Department of Health, which include the fol- rated into country-specific guidelines. These
lowing topics: standard principles (hospital en- would also need to take account of existing clini-
vironmental hygiene, hand hygiene, the use of cal practices and facilities.
personal protective equipment, and the use and
• Encourage governments to accept accountability for
disposal of sharps); short-term indwelling urethral
infection control at the national level by making hospi-
catheters in acute care; and central venous cath-
tal management accountable for local implementation
eters. The guidelines are targeted at the United
Kingdom and are thought to be practical and This direction is consistent with the recommen-
affordable within that context. However, the dation from the WHO Scientific Working
structure of the guidelines would facilitate Group (5): “Link the prevention and control of
adaptation to other countries, including devel- antimicrobial resistant organisms in hospital to
oping countries. The second phase of the epic national and local quality assurance efforts.”
programme will concentrate on control of in- The concept of clinical governance is having con-
fection in the community. More information can siderable impact in the United Kingdom. The
be found at the following web site: http:// UK Government has put infection control and
www.epic.tvu.ac.uk/ antimicrobial resistance into the list of national
• The HELICS project: (Hospitals in Europe Link priorities for public health, and used initiatives
for Infection Control Through Surveillance). on clinical governance to make it clear to hospi-
HELICS has produced infection control recom- tal management that they are responsible for
mendations for hospitals in the European action in their hospitals. This approach is now
Union (EU), annexes describing various national being extended to managers responsible for com-
infection control programmes, and the current munity health services.
national policies concerning antibiotic resistance • Emphasize the importance of infection control in the
from each EU member state. This information community
can be found at the Nosocomial Infection Con-
In addition to the recommendations of the
trol in Europe web site (http://helics.univ-
WHO Scientific Working Group (5), develop-
lyon1.fr).
ment of related interventions to contain anti-
microbial resistance in the community include
Summary and conclusions: infection control educational programmes and hygienic standards
experiences for day care and extended-care facilities, and
The statements about hospital infection from the promotion of hygiene in the community, includ-
various expert reports discuss important actions at ing safe water and food hygiene.
the local and national level to curb antibiotic re- As noted in the UK House of Lords report (21),
sistance. This author suggests that they should be infection control beyond the hospital is an area
followed by these specific actions: of particular weakness. Communities should
40
consider improvements in antibiotic use and Table E). Major issues cited by the WHO report
infection control in nursing and residential (50) include the following:
homes, which can act as reservoirs of methicil-
• Lack of regulation and informal sector sales of
lin-resistant Staphylococcus aureus and other re-
antibiotics
sistant organisms which are carried back and
forth between the hospital and the community. • Absence of lists of essential drugs
• Absence of national standard treatment guide-
lines
II. Regulatory measures
• Poor communication and implementation of
The regulations developed and enforced by gov- national policies
ernmental and health organizations can have a very
• Ineffective regulatory mechanisms.
large impact on the use of antibiotics and the preva-
lence of antibiotic-resistant bacteria. The need to A helpful classification of regulatory mechanisms
develop strong national health system regulations and their implementation is given in “Task Force
is mentioned in many of the expert reports (see Reports on Antibiotic Use Worldwide.”(1). The
TABLE 1. LAWS AND REGULATIONS PERTAINING TO ANTIBIOTICS (ADAPTED FROM 19)
Category and designation Basis for assignment
A. Comprehensive 1. No free sale allowed.

2. Professional limits placed on prescription practices by law.
3. Statutory control of advertising; no advertising allowed to lay public.
4. Content of advertising limited by law.
B. Partial 1. No free sale allowed.

2. At least one of controls 2-4 above.
C. Minimal 1. No free sale allowed.

2. None of controls 2–4 above.
D. None 1. Free sale allowed without any restrictions.
Application in practice and enforcement of compliance with regulation
A. Complete Tightly controlled availability; regulations rigorously enforced.
B. Partial Incomplete enforcement of controls, associated with limited availability of antibiotics to the
public for other reasons, such as economics and/or logistic factors.
C. Minimal Incomplete enforcement of controls, associated with widespread availability of antibiotics as a

result of failure to apply regulations in practice, and absence of other constraining factors.
D. None No restrictive legislation; widespread availability.
TABLE 2. GROUPING OF 35 COUNTRIESa BY LAWS/REGULATIONS AND ENFORCEMENT/COMPLIANCE ASSESSED BY

QUESTIONNAIRE IN 1986.
Laws/Regulationsb Enforcement/compliance 1986
1. Complete 2. Partial 3. Minimal 4. None
Comprehensive 11 (31.4%) 2 (0.6%) 5 (14.3%) 1 (0.3%)

Partial 2 (0.6%) 1 (0.3%) 3 (0.9%) 1 (0.3%)
Minimal 2 (0.3%) 1 (0.3%)
None 6 (1.7%)
Source: Levy SB, Burke JP, Wallace CK (1)

a
Countries were selected from Eastern and Western Europe; North, Central and South America; Africa; Asia and Oceania. Data were reported
anonymously (locality within each category not reported).
b
See Table 1 for an explanation of categories of Laws/Regulations and Enforcement/Compliance.
41
report reviewed policies about antibiotics in thirty- Additional issues concerning government and health
five countries and found that only eleven (31%) management systems
had comprehensive laws and regulations that were Additional specific issues and recommendations
completely enforced (Tables 1 and 2). This evidence from individual expert reports fall into two main
supports the need for more effective regulatory areas (detailed in Tables G and H). The first area
mechanisms. The data in “Task Force Reports” are concerns suggestions for additional legislation to
nearly fifteen years old; nonetheless, there is broad improve the prudent use of antimicrobials, for ex-
consensus among the experts on the need to ad- ample, granting antimicrobial use licenses contin-
dress the five problems listed above (see Table E). gent upon implementing antimicrobial-use
There is also broad historical consensus in support monitoring programmes, or, where applicable,
of effective national regulation of antibiotic qual- adjusting subsidies for antibiotics to encourage a
ity, dissemination, and promotion. more prudent use (20,51).
The second area concerns legal issues that may
Elements of a national policy to combat antibiotic impact implementation of infection control or an-
resistance timicrobial use measures. One example is improv-
ing personal human rights laws, especially in
Additional regulatory recommendations proposed
developing countries, so that they have a positive
in the recent WHO report (50) are also repeatedly
impact on a population’s public health (19,51). The
suggested by previous expert reports (see Table F)
document by Fidler (51), is a particularly rich source
and suggest a basic framework that each country
of issues about legislation, encompassing trade regu-
should establish to minimize the emergence and
lations, patient rights, data privacy, and patent pro-
spread of antibiotic resistance in their country:
tection.
• Adopt the WHO model legal framework for Another example is creating economic incentives
antimicrobial licensing, sale, supply, distribution, for pharmaceutical companies to develop new an-
and promotion timicrobial medications (51). The listed statements
• Introduce legal requirements for collection of also include good practice guidelines for antimi-
data on antimicrobial production, distribution, crobial use, such as assisting poorer countries to
sales, and consumption in human, veterinary, gain supplies of appropriate antimicrobials, as well
and agricultural use as creating international alert systems concerning
antimicrobial resistance (7,49,51).
• Introduce formal training for personnel in anti-
microbial dispensing outlets and registration
schemes for such outlets. Conclusions: Regulatory measures
Additionally, the WHO document (50) makes In the management of distribution, availability and
the following recommendation: “identify and elimi- use of antimicrobials, several factors—legal, eco-
nomic, and scientific—should be considered, as
nate economic incentives (i.e., reimbursement prac-
tices) that encourage inappropriate antimicrobial summarized below:
use.” This recommendation was apparently over- • Development of guidance documents by government
looked by the other expert policy groups and is only and health systems on policies for antimicrobial use
endorsed by one of the other documents (6, Table Local ownership of guidelines adds to their suc-
F). Nonetheless, it is an important global issue and cess. Guidelines can be applied to infection con-
a key consideration for national governments trol and can also be part of general antibiotic
attempting to control antibiotic use. policies, where local microbial epidemiology can
Finally, the importance of involving inter- justify variations in prescribing and where there
national organizations is noted in the WHO are legitimate concerns about the selection pres-
recommendation: “Target advocacy for action sures created by uniform national prescribing
encouraging prudent use of antimicrobials among policies. These guidance documents should be
relevant organizations, such as the World Trade readily adaptable for use in developing countries.
Organization, the World Bank and the Interna-
tional Monetary Fund” (50). • Assessment of policies, laws, and regulations and their
implementation
The 1987 report by the US Department of
Health and Human Services (1) could be up-
42
dated. The original report did not reveal the In the United States the most powerful strategy
identity of the countries that submitted data. would be to make implementation of state poli-
This author would query whether secrecy about cies to curb the misuse of antimicrobial drugs
such an important global issue either necessary mandatory before states receive federal funds
or justifiable. earmarked for public health. Similar opportu-
nities should be explored in other countries.
• Review opportunities for improving prudent use of an-
tibiotics by changing the licensing process • Investigate methods for mandating technical or finan-
Extend patents in exchange for industry support cial support from developed countries to developing
of programmes to limit the use of antibiotics countries
and support license extension of older drugs with Fulfilment of legal duties often hinges on suffi-
activity against resistant pathogens through fast cient resources. In many developing countries,
tracking or orphan drug programmes. public health systems may be inadequate. Thus,
financial and technical leadership is needed from
• Investigate the effect of changes in reimbursement poli-
national governments towards local authorities,
cies on prudent use of antibiotics and on surveillance of
and from international organizations towards de-
prescribing or resistance
veloping countries. A precedent can be found
This is an important recommendation in “Con- in the proposed Convention on the Provision
taining Antimicrobial Resistance”(50) but does of Telecommunication Resources for Disaster
not appear in the other WHO documents. It is Mitigation and Relief Operations, which obli-
endorsed by US Congress Office of Technology gates the parties, where possible, to lower or
Assessment (6), which identifies a potential remove regulatory barriers for using telecommu-
problem with Medicaid and Medicare reim- nication resources during disasters.
bursement policies. This issue deserves wider
consideration in a global context. In addition to • Investigate international law on personal control and
considering reimbursement for prescribing, the data protection issues relating to antimicrobial resist-
extent to which privatization of laboratories ance
threatens the surveillance of antibiotic resistance At a time when antimicrobial resistance may have
or infection control should be investigated. created a greater need for personal control meas-
ures for public health (e.g., with multidrug-
• Consider recommendations (51) about trade restrictions
resistant tuberculosis), the status of international
against countries that systematically neglect recognized
law on the scope and nature of a government’s
principles and practices for antimicrobial use
power to undertake such measures should be
In the context of environmental protection, trade reviewed. Lessons from international environ-
restrictions seeking to change a production proc- mental efforts suggest that international law
ess in another country, rather than to protect must play a major role in setting international
against health dangers from a particular prod- standards for implementation at the national
uct, have been ruled incompatible with interna- level, and creating the political, technical, and
tional trade law. As part of a general strategy to financial conditions necessary to integrate in-
combat antimicrobial misuse, legitimate trade ternational and national law.
restrictions against countries that systematically
neglect recognized principles and practices for • Build on experience in EU countries of legislation against
antimicrobial use might be considered; such a use of antibiotics in growth promotion
move would elevate the status of Codex’s Code The EU has passed legislation to eliminate anti-
of Practice for Control of the Use of Veterinary biotics that are used in humans from being used
Drugs and Guidelines for the Establishment of as growth promoters in animal feeds. However,
a Regulatory Program for Control of Veterinary Denmark and Sweden have banned growth pro-
Drug Residues in Foods (52), in the same way moters entirely. If other governments are to fol-
as the Sanitary Phytosanitary (SPS) Agreement has low that lead, they will need to be reassured that
elevated the importance of Codex’s Maximum there are no adverse economic consequences.
Residue Levels for Veterinary Drugs in Foods. Therefore, data about the impact of legislation
in Denmark and Sweden should be collected and
• Identify opportunities to link financial incentives to im-
publicized (see also Chapter V).
plementation of policies at the national or regional level
43
TABLE A. SANITATION AND INFECTION CONTROL RECOMMENDATIONS FROM THE WHO REPORT “CONTAINING ANTIMICROBIAL
RESISTANCE”(50) AND ENDORSEMENT BY EXPERT POLICY GROUP REPORTS
Document Cleanse hands Movement of patients within and Correct the lack There are several Improve hand Additional issues
after each patient between hospitals is increasing and of sterile supplies proven methods washing and/ or raised by this
contact to prevent contributes to the spread of infection and poor for improving use of gloves and document
the spread of sterilization hand washing gowns to decrease
infection infection rates
(5) WHO 1995 Endorsed Endorsed Endorsed Endorsed Endorsed
(49) WHO 2000 Endorsed Endorsed; stresses international travel. Endorsed Endorsed Endorsed
(21) House of Lords Endorsed Endorsed Endorsed Endorsed Endorsed Yes

(UK)
(1) USA DHHS Endorsed Endorsed
(6) US Congress Endorsed Importance of coordinating infection Endorsed Endorsed Endorsed

Office of Technology control measures between acute
Assessment hospitals and long-term care facilities.
(20) Antimicrobial Endorsed Endorsed. Emphasizes blurred Endorsed Yes

resistance boundaries between community and
hospital and increased travel.
(51) Fidler While microbes move freely around

the world, unhindered by borders,
human responses to infectious
diseases are conditioned by
jurisdictional boundaries.
(19) UK Department These issues were outside the remit of this report. Nonetheless, there is strong endorsement of the critical role of infection control in the
of Health hospital and community in the containment of antibiotic resistance.
(13) Shlaes, et al. Yes
(24) USA General Endorsed; stresses international travel.

Accounting Office
TABLE B. SUGGESTED INFECTION CONTROL INTERVENTIONS FROM THE WHO REPORT “CONTAINING ANTIMICROBIAL RESISTANCE”(50) AND
ENDORSEMENT BY EXPERT POLICY GROUP REPORTS
Key components of an Infection Control Committee
Establish an Surveillance of Identification of Implementation Sterilization and

effective infection infection outbreaks of effective control disinfection of Additional issues
control measures (e.g., equipment and raised by this
Document programme hand washing) supplies document
(5) WHO 1995 Endorsed Endorsed Endorsed Endorsed Endorsed Yes
(49) WHO 2000 Endorsed
(21) House of Lords (UK) Endorsed Endorsed Endorsed Endorsed Endorsed Yes
(6) US Congress Office of Technology

Assessment Yes
(20) Antimicrobial resistance Endorsed Endorsed
(7) National Science and Technology

Council (USA)
(13) Shlaes, et al. Endorsed Endorsed Endorsed Endorsed Endorsed Yes
(31) Centers for Disease Control and

Prevention (USA) Yes
44
TABLE C. SANITATION AND INFECTION CONTROL: ADDITIONAL INSIGHTS AND RECOMMENDATIONS

BY EXPERT POLICY GROUP REPORTS
Document Additional issues raised
(49) WHO 2000 1. Emphasizes the importance of community sanitation for infection control in developing countries.
(21) House of Lords (UK) 2. Infection control beyond the hospital is an area of particular weakness (paragraphs 4.20–25). This is
especially true of nursing and residential homes, which can act as reservoirs of MRSA and other
resistant organisms, which are then carried back into hospitals.
(20) Antimicrobial resistance 3. Economic costs of infection control in the community (increased cost of hygienic production).
4. Importance of sanitation in developing countries.
(13) Shlaes, et al. 5. Adopt CDC recommendations for isolation of patients colonized with resistant bacteria.
TABLE D. SANITATION AND INFECTION CONTROL: ADDITIONAL SUGGESTED INTERVENTIONS

Document Additional issues raised
(5) WHO 1995 1. Link the prevention and control of antimicrobial-resistant organisms in hospitals to national and local
quality assurance efforts.
2. Develop methods and standards for evaluating hospital infection and antimicrobial resistance control
programmes, leading ultimately to a national accreditation system.
3. Develop educational programmes and hygienic standards for day care and extended-care facilities.
4. Promote standards of hygiene in the community, including safe water and food hygiene.
(49) WHO 2000 5. Promote other means of infection control (such as bednets in malaria endemic countries), education,
and support for those living in developing countries.
(21) House of Lords (UK) 6. Purchasers and commissioning agencies for hospital services should put infection control and basic
hygiene where they belong, at the heart of good hospital management and practice, and should
redirect resources accordingly; such a policy will pay for itself quite quickly. NHS Executives should
assure themselves that every NHS hospital is covered by a properly trained infection control team, as
recommended in the Cooke Report (paragraph 11.26).
7. The NHS should draw up national standards and guidelines for community infection control
management, along the lines of the Cooke Report for hospitals. These should include a requirement
that every district health authority should have at least one community infection control nurse
(paragraph 11.28).
8. Those responsible for the review of the Public Health (Control of Disease) Act 1984 should consider
the shortcomings of the provisions for compulsory medical examination and detention in hospital,
and the case for a more humane regime, and for extending the legislation to provide also for
supervised treatment at home (paragraph 11.29).
(6) US Congress Office of 9. Hospitals should consider instituting antibiotic-use subcommittees in the infection control
Technology Assessment committees.
(13) Shlaes, et al. 10. Make hospital administration accountable for the implementation and enforcement of policies
adopted by hospital committees.
(31) Centers for Disease Control 11. Top priority action item: Support demonstration projects to evaluate comprehensive strategies that
and Prevention (USA) use multiple interventions to promote judicious drug use and reduce infection rates, in order to assess
how interventions found effective in research studies can be applied effectively on a routine basis, on
a large scale, and cost-effectively.
45
TABLE E. WHO SUGGESTED RECOMMENDATIONS FOR GOVERNMENT AND HEALTH SYSTEMS AND ENDORSEMENT
Items from “Containing Antimicrobial Resistance”(50)
Document End poor commu- Institute effective Regulate sales, Establish Essential Establish national Additional issues
nication and regulatory including informal Drugs Lists standard raised by this
implementation mechanisms sector sales treatment document
of national policies guidelines
(5) WHO 1995 Endorsed Endorsed Endorsed Endorsed
(49) WHO 2000 Endorsed Endorsed Endorsed Endorsed Endorsed
(21) House of Lords Endorsed Endorsed Not a problem in Endorsed WHO Endorsed need for Yes
(UK) the UK; efforts in national approach
condemned any developing on implementing
OTC availability of countries. prudent use of
antibiotics. antimicrobials.
(1) USA National Endorsed Endorsed Endorsed Endorsed

Institutes of Health
(6) US Congress Office Endorsed

of Technology
Assessment
(20) Antimicrobial Especially in Endorsed Endorsed Restricting access Yes

resistance developing to a specific drug
countries. leads to excessive
use of alternatives;
policies need to
address overall pre-
scribing as well as
use of specific
drugs. Guidelines
will not be effective
unless they are
evidence-based.
(51) Fidler Endorsed Endorsed Yes
(19) UK Department Endorsed

of Health
(13) Shlaes, et al. Endorsed
(22) Institute of Endorsed Yes

Medicine (USA)
(11) American Society Comments on Comments on

for Microbiology developing developing
countries only. countries only.
(39) USAID This document is a statement of intent rather than a review of the literature or set of recommendations. One of the
statements of intent covers this current review and synthesis of information or recommendations.
46
TABLE F. WHO (50) ADDITIONAL SUGGESTED INTERVENTIONS FOR GOVERNMENT AND HEALTH SYSTEMS AND ENDORSEMENT BY EXPERT
POLICY GROUP REPORTS. SEE ADDITIONAL ISSUES LISTED IN TABLES G AND H.
Document Identify and eliminate Target advocacy for Adapt WHO model Introduce legal require- Introduce formal Additional issues
economic incentives action towards legal framework for ments for collection of training and raised by this
(i.e., reimbursement relevant license, sale, supply, data on production, registration schemes document
practices) that organizations distribution, distribution, sales and for dispensing outlets
encourage inappro- (WTO, WB, IMF) promotion consumption for human,
priate antimicrobial use veterinary and agricul-
tural use
(5) WHO 1995 This document covers the same issues, but sets them out as a series of general recommendations rather than specific
suggestions for policy or implementation. For example it is suggested that countries should “develop information
systems” but a legal requirement is not suggested. Regulation of promotion of antimicrobials is endorsed, but a legal
requirement to monitor supply and distribution is not covered.
(50) WHO 2000 Endorsed Endorsed Endorsed
(21) House of Lords (UK) Focus was on the UK, but endorsed UK Endorsed, particularly Endorsed, supports Yes
support for WHO activities:“The Govern- emphasizes the more coordinated
ment’s exemplary support for the WHO inadequate data about approach in the UK.
Division of Emerging Diseases should be hospital or veterinary
maintained, and the United Kingdom use. Commends the work of
Government’s example should encourage the WHO in the
other nations and agencies to contribute to developing world
this vital work.“ (paragraph 11.10).
(6) US Congress Office Congress should review Yes

of Technology effects of Medicaid and
Assessment Medicare reimburse-
ment policies on anti-
biotic prescription
patterns.
(51) Fidler Endorsed (especially Endorsed Yes

WTO)
(7) CISET (USA) Endorsed (p7, p26) Endorsed (p7, p26) Endorsed (p7) Yes
(24) USA General Most countries do not

Accounting Office have measures of total
antibacterial use.
(22) IOM (USA) Endorsed Endorsed (p64) Yes
(31) CDC (USA) Primarily concerned with surveillance, prevention and control of resistance in the US, where regulation of license and promotion already
exists. However, does not deal with legislation compelling manufacturers to measure and report sales and consumption data.
47
TABLE G. GOVERNMENT AND HEALTH SYSTEMS: ADDITIONAL INSIGHTS AND RECOMMENDATIONS BY EXPERT POLICY
GROUP REPORTS
Document and levels of

responsibility Additional issues raised
(49) WHO 2000
International Cooperation Emphasizes the importance of making antibiotics available for treatment of infections in developing
countries as a means of containing spread of infection in general and resistant strains in particular.
(21) House of Lords (UK)
National and Local Governments The evidence is clear (paragraphs 2.26–30) that prudent use is much harder to achieve if antimicrobials
for internal use are available over the counter.
Hospitals It is notoriously difficult to manage what cannot be measured; and we have heard much about the
contrast between the excellent data on general practitioner prescribing, captured by both the Prescription
Pricing Authorities and general practitioners themselves, and the lack of data on antimicrobial use in
hospitals (paragraphs 10.4–7).
Doctors and Patients We acknowledge the dilemma facing doctors and patients alike (paragraph 2.9), that what is prudent
from the point-of-view of public health may be highly imprudent from the point-of-view of the individual
patient, and vice versa.
Animal Health Regulators The United Kingdom led the world in addressing the threat to human health posed by antibiotic use in
farming practices with the Swann Report in 1969. Unfortunately, some of the recommendations of Swann
were not acted upon and many believe that, had action been taken then, our present concerns would be
much less than they are now, at least as regards the situation in the United Kingdom.
The evidence that we have heard (paragraphs 3.7–13) strongly suggests that there is a continuing threat
to human health from imprudent use of antibiotics in animals.
(20) Antibiotic Resistance
National Government Limit general access to new drugs (e.g., fluoroquinolones).

Governments should make and provide materials to support intervention programmes (e.g., materials
available from CDC).
Grant licenses conditionally based on monitoring of resistance (especially in veterinary use).
Hospitals Limit general access to new drugs (e.g., fluoroquinolones).
(51) Fidler
International Cooperation Private initiatives are building global information-sharing networks on various disease issues through the
Internet and other information technologies; private companies are starting to monitor and test bacterial
resistance globally; and some for-profit companies gather and sell epidemiologically useful information.
These private efforts raise legal questions: privacy issues arise with the dissemination of epidemiologic
data by private companies; this dissemination is treated differently in different countries; jurisdictional
problems arise regarding legal regulation of information-sharing in cyberspace.
The notion of personal control measures against drug-resistant malaria patients in Africa seems far-
fetched, given the scale of the problem. Nevertheless, the importance of international human rights law to
effective public health policies (as seen in the context of HIV/AIDS) demonstrates that complacency
towards individual rights in any public health policy is dangerous legally and medically.
International legal harmonization of principles for prudent antimicrobial drug use must include
monitoring and enforcement, as well as financial, technical, and legal assistance provided by industrialized
countries to developing countries.
In the context of environmental protection, trade restrictions seeking to change a production process in
another country, rather than to protect against health dangers from a particular product, have been ruled
incompatible with international trade law.
To avoid losing trade restrictions as part of a general strategy to combat antimicrobial misuse, legitimate
trade restrictions against countries that systematically neglect recognized principles and practices for
antimicrobial use might be considered; such a move would elevate the status of Codex’s Code of Practice
for Control of the Use of Veterinary Drugs and Guidelines for the Establishment of a Regulatory Program
for Control of Veterinary Drug Residues in Foods, as the SPS Agreement has elevated the importance of
Codex’s Maximum Residue Levels for Veterinary Drugs in Foods.
International law on intellectual property protection is a critical piece of the overall strategy against
antimicrobial resistance.
48
TABLE G. CONTINUED

National and Local Governments Especially in federal systems, countries often divide authority for public health among various levels of
government.
Privatization of laboratory services by state legislatures may compromise national surveillance of
emerging infectious diseases and investigation of outbreaks, because many surveillance systems rely on
data from state laboratories.
Increased surveillance for antimicrobial resistance may heighten privacy concerns with respect to other
diseases, such as multidrug-resistant tuberculosis (MDRTB).
In the United States, Congress could regulate use of antimicrobial drugs by monitoring interstate
commerce in these products. Congress probably does not have the authority to regulate antimicrobial
prescription practices directly; such authority rests with the states.
Perhaps the most powerful US federal strategy would be to make implementation of state policies to curb
the misuse of antimicrobial drugs mandatory before states receive federal funds earmarked for public
health.
National Government In countries where governments subsidize the purchase of antimicrobial drugs, legislative or regulatory
changes in these subsidies could lead to a decline in the use of the drugs.
Pharmaceutical companies that had developed antibiotics but never commercially exploited them might
pursue more antimicrobial research and development if their earlier antibiotics (now without patent
protection) were given extra legal protection, either under patent law or a legal regime like the Orphan
Drug Act.
(22) Institute of Medicine (USA)
National Government Existing antibiotics may have activity against resistant pathogens but have not undergone clinical trials;
advocates accept surrogate indicators of efficacy.
Explore the value of extending patents as an incentive to prudent use.
Animal Health Regulators Need to address ambiguities about registration of antibiotics in agricultural products and incorporate
antibiotic resistance into discussions of food safety and the regulation of imports.
TABLE H. GOVERNMENT AND HEALTH SYSTEMS: ADDITIONAL SUGGESTED INTERVENTIONS BY EXPERT POLICY GROUP
REPORTS

(5) WHO 1995
National and Local Governments Support programmes to improve access to treatment and thus earlier detection and interruption of
outbreaks of resistant bacteria.
National Government and Prohibit the use for growth promotion in animals of any antimicrobial agents used in human therapeutics
Agricultural Industry or potentially selecting cross-resistance to antimicrobial agents used in human medicine.
Define acceptable levels of antimicrobial agent residues in food from animal sources and ensure
compliance with national standards.
(49) WHO 2000
International Cooperation Support countries in developing reliable supply systems.
International and National Make effective medicines accessible to the poor.

Governments
Strengthen national and international capacity to ensure the quality of anti-infective drugs.
All Levels of Government and the Increase the availability of essential drugs.
Pharmaceutical Industry
49
TABLE H. CONTINUED

(21) House of Lords (UK)
International Cooperation We commend the Government and the ABPI for their firm stand against over-the-counter antibiotics, and
urge them not to give way. Since this is an area of EU responsibility, and the position in several other
Member States appears to be different, we recommend that the Government should engage in active
diplomacy to ensure that, should the issue be raised in the Council of Ministers, their position is
understood and their allies are in place; and, in the long term, to induce those Member States which are
currently more relaxed about over-the-counter antibiotics to introduce more controls.
National Government The Government and the health authorities must do more to educate the public about the proper use of
antimicrobials. In particular, we recommend a campaign targeted at mothers of young children.
The Education Committee of the General Medical Council and the medical Royal Colleges should review
the evidence that undergraduate curricula give insufficient emphasis to infectious diseases and
antimicrobial therapy, and the Royal Colleges should increase the attention paid to antimicrobial therapy
in their programmes of postgraduate education and vocational training (paragraph 11.6).
The Medicines Control Agency should consider whether the drug licensing system could be used more
effectively to encourage prudent use in the interest of public health (paragraph 11.9).
The Government should respond positively to the EU proposal for an “orphan drug” regime, and should
seek to ensure that the scheme gives the pharmaceutical industry a real incentive to work on novel
treatments for problem diseases, particularly diseases of the world’s poor, such as malaria (paragraph
11.40).
Local Government The NHS Executive must work towards the goal of compatible and interconnected information technology
for every general practitioner, every hospital ward and infection control team, and every clinical
microbiology laboratory. They must accept the considerable cost involved; and they must give a strong
lead from the centre to ensure compatibility (paragraph 11.51).
Hospitals All hospitals should install computer systems for patient-specific prescribing information at ward level.
Doctors We do not recommend that general practitioners should be required to establish antimicrobial
susceptibility before prescribing (paragraph 2.22). This, we believe, would at present be impracticable, and
would overload diagnostic services which are already stretched. But improved access to microbiological
testing clearly reduces uncertainty in prescribing.
Veterinarians The veterinary profession must address the use of potent agents important to human medicine (e.g.,
fluoroquinolones), by introducing rapidly a Code of Practice on when such compounds should be
prescribed (e.g., when other agents have failed) and how (e.g., for no longer than necessary); we
recommend self-regulation in preference to legislation.
(1) USA National Institutes of Health
National Government In countries with more restrictive legislation and more effective enforcement of antibiotics prescriptions,
studies should be carried out on the effects of such legislation on requirements for training of health-care
personnel and on economic and other consequences for patients and national health-care delivery
systems.
Legal restrictions on the use of antibacterial drugs may exert positive or negative effects on mortality and
morbidity, especially among children.
National Government and Hospitals Longitudinal studies must determine whether regulations and effective enforcement have any effect on
the emergence of resistance.
National Government and The public health consequences of restrictions on antibacterial use in food production and animal
Agricultural Industry husbandry should be investigated.
(6) US Congress Office of Technology Assessment
National Government Congress can provide FDA with authority to negotiate extended market exclusivity to manufacturers that
agree to restrictions on marketing of antibiotics.
Congress could authorize FDA to extend market exclusivity for “off-patent” antibiotics that are effective
against drug resistant bacteria.
Congress could provide research support for a federal programme to conduct clinical trials of antibiotics to
determine if they have uses against antibiotic resistant bacteria.
50
TABLE H. CONTINUED

Veterinarians The document is skeptical about the possibility of reaching consensus about veterinary use of antibiotics
based on existing data, and about the value of additional studies.
(20) Antibiotic resistance
National Government Make assessment of resistance potential of new compounds part of their licensing.
(51) Fidler
International Cooperation The International Health Regulations mandate, for example, that Member States of the World Health
Organization (WHO) report outbreaks of plague, cholera, and yellow fever to WHO.
WHO has proposed including surveillance of antimicrobial resistance in the revision of the International
Health Regulations and requiring drug resistance reporting.
Creation of a legal duty does not ensure the success of a policy. WHO Member States have routinely
ignored required outbreak reporting of plague, cholera, and yellow fever.
Lessons from international environmental efforts suggest that international law must play a major role in
setting international standards for implementation domestically and creating the political, technical, and
financial conditions necessary to integrate international and national law.
The importance of Codex food safety standards to international trade law was seen in the Beef Hormones
Case, in which the WTO held that the EU violated the SPS Agreement for not providing scientific
justification for a beef hormone regulation stricter than the relevant Codex standards.
National Government Fulfilment of legal duties often hinges on sufficient resources. In many developing countries public health
systems may be inadequate. Thus, financial and technical leadership is needed from national governments
for local authorities, and from international organizations for developing countries.
A precedent can be found in the proposed Convention on the Provision of Telecommunication Resources
for Disaster Mitigation and Relief Operations, which obligates the parties, where possible, to lower or
remove regulatory barriers for using telecommunication resources during disasters.
The comprehensive statutory and regulatory system in the US that governs the acquisition, use, and
transfer of biological agents that pose a threat to public health might serve as a model for legislation in
other countries.
At a time when antimicrobial resistance may have created a greater need for personal control measures
for public health (e.g., with MDRTB), the status of US law on the scope and nature of the government’s
power to undertake such measures seems unsettled.
(19) UK Department of Health
National Government Licensing authorities should consider an antimicrobial agent’s potential to select for resistance in addition
to its safety and efficacy.
Pharmaceutical Industry Consider finding ways, through pricing and other mechanisms, of ensuring that investment in the
development of new antibiotics remains commercially viable.
(7) National Science and Technology Council (USA)
National and International Introduce a global alert system requiring national governments to inform worldwide health authorities
Governments about outbreaks.
National Government Establish a private sector subcommittee of the Interagency Task Force.
(22) Institute of Medicine (USA)
International Cooperation Explore International Conference on Harmonization (p59) as a forum for a global approach to rational
antimicrobial use.
Initiate dialogue, led by WHO with representation from WTO, EU and US Departments of State and
Commerce, about regulation of antibiotics in agricultural products.
51
CHAPTER IV
Encourage research and product development

John F. Barrett
Abstract and deterioration of public welfare as infectious

The areas of research and development offer disease concerns continue to increase worldwide
tremendous possibilities to have an impact on the (1,5,6,7,8,11,19,20,21,22,39,49,50,53). In addi-
antimicrobial resistance crisis worldwide. A histori- tion, many reports address antibiotic resistance in
cal review of support for antimicrobial resistance specific circumstances and microorganisms, and all
research and development, as a subset of infectious identify antibiotic resistance as a growing problem
disease research including tuberculosis research, has (54–69).
determined a gross under-funding of this area, in The 1992 Institute for Medicine’s (IOM) report
academic, governmental and industrial laboratories on “Emerging Infections: Microbial Threats to
over the past 10–15 years. There is a need to Health” (71) indicates that “changes in technology
encourage federal, university, and private sector col- and industry” are among those risk factors that have
laboration in basic and applied research. contributed to the inability to prevent or control
Consensus points by governing bodies review- microbial diseases. This IOM report (70) lists six
ing antimicrobial resistance over the past five years, general factors leading to the emergence of infec-
consistent with current key-opinion-leader senti- tious diseases and antimicrobial resistance:
ment, show that the major needs include: basic • environmental change and land use;
research is needed to delineate the genetic and meta-
• breakdown of public interest health measures;
bolic pathways, microbial physiology, and the causes
of antimicrobial resistance; an increase in research • international travel (transporting infectious
for the identification and development of new drugs diseases globally);
to fight antimicrobial resistance; and an increase in • changes in social behaviour;
basic and applied research for new vaccines and
other preventive measures. • changes in technology and industry; and
In broader terms, research and development • microbial adaptation and change (including
needs to cover a more global effort to provide com- resistance development).
pelling evidence for the prudent use of antibiotics,
including the use in humans, animals and plants; The world is no longer simply a matter of geo-
provide incentives for the discovery and develop- graphical division of diseases, as the spread of
ment of agents to combat antimicrobial resistance; infectious diseases continues to be demonstrated
facilitate innovative approaches to fight against re- with the emergence of “developing nation diseases”
sistance; and build worldwide alliances and part- in specific geographical centres in the industrial-
nerships to increase sensible access to antimicrobials ized world (e.g., tuberculosis, dysentery, etc.).
(1,5,6,7,8,11,19,20,21,22,39,49,50,53). A practical way to look at emerging diseases is
that a disease in one geographical area could easily
be transmitted to the unaffected area, by simple
Introduction delivery of the infectious disease by human carrier.
There is significant consensus among research pro- Thus it is naive to believe that antimicrobial resist-
fessionals that the US Surgeon General, William ance in any part of the world is an “isolated prob-
Stewart, was wrong in 1969 when he was quoted lem”.
as saying that we (the US population) could The industrialized countries, by virtue of
“…close the book on infectious diseases…” in ad- advanced technology and improved basic living
dressing public concerns (from a health standpoint). standards, are privileged to not be subject to the
All position-piece documents reviewed for this massive outbreaks of infectious diseases that we see
chapter make observations about the seriousness in the developing world. Basic sanitation, basic edu-
53
cation on maintaining good health, and widespread • Improvement in basic research training in
immunization against disease, provides a tremen- academia to ensure a critical mass of researchers
dous advantage to the occupants of the industrial- in the antimicrobial resistance field of research.
ized world. Short- and long-term gains are a matter
of basic education and building a foundation so
Infectious disease and microbial pathogenicity
the next generation of developing countries’ chil-
dren have the same advantages as industrialized • Improvement in understanding of how to pre-
countries’ children in sanitation and health care. vent the infectious disease state and to treat new
However, research and development in the devel- infectious diseases; basic research related to new
oping countries is virtually non-existent, and the and re-emerging pathogens/infections and
short-term possibilities for changing this are remote. better understanding of the infectious disease
This chapter reviews the expert reports (1,5,6,7, link to chronic diseases
8,11,19,20,21,22,39,49,50,53,54) and other rel- • Basic research in molecular pathogenesis, includ-
evant literature from the viewpoint of research ing:
(basic and applied) and product development and — the evolution of pathogenicity;
attempts to summarize their recommendations. — the epidemiology and spread of pathogens
and infectious disease transmission;
Basic and applied research • Resources to enable the sequencing of the entire
Identification of research needs genome of additional microbial pathogens
(including problem pathogens in developing
All the expert reports reviewed made at least some
countries).
mention of research and many had extensive sec-
tions devoted to research needs both to improve
the understanding and management of antimicro- Antimicrobial resistance
bial resistance and to develop new drugs, vaccines • Research into the source of antibiotic resistance
and diagnostic tools. Recommendations from Wise genes; the mechanisms/frequency of ‘reassort-
and colleagues in the British Medical Journal’s ment’ of these genes, the emergence and trans-
special (1998) issue on antimicrobial resistance fer of resistance genes among pathogens in vivo
include the need for increased understanding of an- (in the host), and the distribution and dissemi-
timicrobial resistance processes; and for encourage- nation of specific antimicrobial resistance genes
ment to the pharmaceutical industry to increase its over time, and factors affecting the loss of
commitment to antimicrobial research (71,72). resistance determinants;
Huovinen and Cars (73) emphasize research [both
basic and applied] as “…a cornerstone in the fight • Research on the correlations between resistance
against bacterial resistance.” From a better under- determinants in normal flora and the prevalence
standing of the microbiology and genetics of our of resistant pathogens;
endogenous flora, we may better understand the • A better understanding of the ability of genetic
collateral damage of normal antibiotic usage in fa- material to transfer in the bacterial ecosystem;
cilitating the evolution of resistance and the mecha-
• Studies on the ability of bacteria to amplify genes
nism of transmissibility of resistant bacteria. More
and exchange genes leading to multiple drug
prudent use of antibiotics will be attained by the
resistance in bacteria;
development of diagnostic technologies to enable
rapid identification of bacterial versus viral patho- • Mechanisms of antimicrobial resistance emer-
gens. gence, acquisition, spread, persistence, and de-
A synthesis of the key research needs identified cline of multidrug-resistant microorganisms;
in the expert reports reviewed (1,5,6,7,8,11,
• Research on factors that accelerate the develop-
19,20,21,22,39,49,50,53,54) follows:
ment of drug resistance and methods to delay
or reverse drug resistance;
Infrastructure and training
• The need for more research examining ways to
• Improvement in basic and applied research in- decrease resistance frequency.
frastructure (academic and industrial);
54
New technologies • Effect of preventative, therapeutic and growth-

• Provide technologies to researchers to allow for promoting agents used in the animal use field
the identification of quality, novel targets; on the community microbiota.
• Develop tools such as microbial genome

sequence data, comparative genomics, DNA
Surveillance and information management
chip technology, and bioinformatics; • Research to improve of surveillance tools, includ-
ing computer programmes for data management
• Research in molecular genetics to identify novel
and reporting;
targets.
• Research in methods for monitoring drug resist-
ance;
New antimicrobials, vaccines, disease prevention and
diagnostics • Development and assessment of computerized
• Provide opportunities to translate basic research decision-support systems in hospitals;
findings into applied, medically useful products/ • Encourage sharing of antimicrobial resistance
devices/technologies (i.e., drugs, diagnostics, data between industry, universities, and govern-
vaccines, and other tools to inhibit antimicro- mental authorities.
bial resistance);
• Research the role of host factors and immuno- Additional research areas to consider
modulation in clinical resistance and the human
Understanding the costs of resistance
immune response to infectious diseases;
a) to the bacterium
• Basic research towards the development of
effective vaccines; One of the major research areas only minimally
touched on in the reports reviewed was that of the
• Research of development of vector control cost of resistance to the bacterium (1,74). The
interventions; understanding of the cost to the bacterium that
• Basic research on other disease preventative receives or adapts to the resistant state is better
measures; understood in terms of the change in pathogenic-
ity as the ‘expense’ of increased resistance. Where
• Support of research and development and stand-
previously, resistance acquisition was viewed as a
ardization of diagnostic tests;
crippling event, it is now understood that it may
• Research to discover/design/develop more reli- actually confer a selective advantage to the patho-
able, rapid diagnostic techniques for identifica- gen (74).
tion of infections causing specific disease states;
• Increased research into methods to detect resist- b) costs to the health care system
ance to antimicrobial agents;
A new field of marketing research and business
• Tools for the clinical/epidemiological researcher management has arisen over the past years dealing
that can be used to more accurately and effi- with the pharmacoeconomics of health care (75),
ciently identify optimal therapeutic options for in which factors indirectly related to outcomes may
treatment of antibiotic resistant strains. be drawn into the value of one action over the other.
For example, the ‘cost’ of antimicrobial resistance
in the patient population may take into account
Research on antimicrobial use
loss of work time, allowing a quantitative assess-
• Links between prescribing and resistance at both ment of the ‘cost’ of infection beyond the drug costs
the individual and population levels; alone. If a treatment regimen gets the patient out
• Concepts concerning antibiotic use and their of the hospital on oral medication, rather than con-
influence on delivery and compliance; tinuation of therapy by intravenous administration,
then the ‘cost’ of therapy overall, in terms of meas-
• Factors leading to inappropriate prescribing; uring the ‘cost’ of antimicrobial resistance, may
• An understanding of variation in antimicrobial factor in the absence of 2–5 additional hospital days
use patterns that affect emergence and spread of (that may range from $1500–$2500 per day). Even
resistance; the selection of the ‘right’ first-line antibiotic the
55
first time by the practicing physician, versus requir- whereas Davey provided evidence directly linking
ing a follow-up visit because the ‘older’ or generic resistance to overall usage. In contrast to Reeves,
antibiotic (with cost saving) did not work, has a Levin was quoted (21) that resistance is a one-way
‘cost’ associated with the patient’s return to the street, that if antibiotic use is cut back sharply, the
physician, as well as the cost to the physician. One proportion of resistant strains wanes slowly (if at
of the criticisms of the for-profit-managed health all).
care delivery systems may be that by providing an
allotment of dollars per patient per year to the phy-
sician by contact regardless of the true cost, pushes
Effective efforts
the physician to cost-cutting methods (including The review of the expert reports seems to indicate
the choice of an inappropriate antibiotic). the effectiveness of basic research in increasing our
understanding of antibiotic resistance and the de-
velopment of new drugs. Extensive research efforts
Areas where there is lack of consensus in academia continue, albeit dwarfed by support
There is no consensus as to the cause, effect, or to AIDS research, and have yielded excellent re-
solution to the worldwide antimicrobial resistance sults from a better understanding of the molecular
problem, nor as to the origin of antimicrobial re- mechanisms responsible for antibacterial resistance,
sistance genes. However, it is clear that antimicro- (72, and references cited therein) to new medicinal
bial resistance stems from the use of antibiotics. chemistry approaches to combat resistance in bac-
While there is no high-level disagreement about teria (76, and references cited therein). Historically,
the unmet medical need posed by antimicrobial basic research has provided numerous advance-
resistance, there are differences in opinion vis-a-vis ments in understanding of microbes which has been
the scientific priorities. applied to the engineering of drugs by pharmaceu-
Not surprisingly, there is no consensus as to the tical companies.
specific ‘cause-and-effect’ and assignment of ‘blame’
on the increase in antimicrobial resistance (1,5,6,7,
8,11,19,20,21,22,39,49,50,53,54,60–69); more
Ineffective efforts
basic and applied research is needed to answer this Many of the US reports indicate funding (that is
complex question definitively. However, it is clear US-based) is woefully lacking for basic and applied
to virtually all opinion leaders that antimicrobial research concerning antimicrobial resistance. As
resistance begins with the routine use of antibiot- pathogens can vary greatly in industrialized versus
ics for human health care, animal health, and agri- developing countries (77), the priorities of ‘medi-
cultural purposes. There is most probably a link to cal need’ are often misaligned. Priorities for fund-
the resistance emergence to the most frequently ing have shifted away from bacteria-associated
prescribed antibiotics and the alarming increase in research to AIDS research over the past fifteen years.
resistant bacteria (11). For example, greater than The lone exception appears to be the increase in
90% of Staphylococcus aureus were resistant to peni- TB research support (although this is still dispro-
cillin and other β-lactams as of 1994, and there is portionately small considering the worldwide mor-
an notable increase in vancomycin resistance in bidity and mortality due to TB).
enterococci. Likewise, but of unknown clinical rel- Research and development efforts to provide
evance, there is an increase in the resistance to compelling support for the ‘prudent’ use of antibi-
penicillins by Streptococcus pneumoniae. otics have failed to translate into prudent use;
Concerning resistance and selective pressure, Reducing inappropriate use of antibiotics with sup-
there is not consensus among scientists as to portive basic and applied research (1,50,39,78,79)
whether removal of an antibiotic from the treat- has proved ineffective.
ment regimen will: reduce the risk and/or expan-
sion of resistance in the pathogen population;
reverse the resistance frequency or prevalence in the
A critical role for new technologies
bacterial population; or have no effect on the re- There is consensus (1,5,6,7,8,11,19,20,21,22,
sistance frequency. In the House of Lords report 39,49,50,53,54) that the molecular detection of
(21) Reeves is quoted as stating “There is plenty of genes that are associated with antimicrobial resist-
evidence, that if you remove the selection pressure, ance is expected to be ascertained by the analyses
the organisms will slowly revert [to susceptible]….”, of microbial genomes (22). The principles and
56
implications of mapping the prokaryotic genome(s) most probably the best approach and will most
are to acquire the full sequence of microbial genes likely provide the greatest opportunities for ad-
and to manage great volumes of sequence data vancements in the short-term. The expanded and
through bioinformatics. It is hoped that once this coordinated use of resistance surveillance systems
‘raw’ data is collected in analysable form (hence the such as SENTRY or the Alexander Project (80,81)
‘informatics’ in bioinformatics), this ‘knowledge’ would provide ‘live’ tracking of antimicrobial re-
(as opposed to raw data) will provide a foundation sistance, allowing action to be taken as appropriate
for the discovery and development of new antimi- to contain antimicrobial resistance, as well as pre-
crobial agents, new vaccines, and new diagnostic dict emerging deleterious trends or appearance of
tools for infectious diseases. emerging pathogen susceptibility problems.
Consensus throughout the documents (1,5,6,7, There is agreement (1,5 ,6,7,8,11,19,20,21,22,
8,11,19,20,21,22,39,49,50,53,54) holds that com- 39,49,50,53,54) that practical applications arising
parative genomics (i.e., the ability to compare full from genomic analyses and bioinformatic tallying/
length sequences of different bacterial, or even annotation of sequence function of microbial
eukaryotic, genomes) may present the opportunity genomes may be limited only by the imagination
for the informatic-assignment of ‘putative’ essen- of the researcher. From these analyses a selection of
tial function in microbes based on consistency of high quality novel targets is expected to emerge,
sequence similarity, but wet-biology proof is needed allowing the applied research groups to select any
to confirm this informatics assignment. The best of the following subsets of data: 1) essential genes;
example of successful gene sequencing/bio- 2) virulence/pathogenicity genes (non-essential
informatics may be The Institute for Genomic genes); 3) broad spectrum genes (gram-positive and
Research (TIGR), with the intention to sequence gram-negative); 4) narrow spectrum genes (gram-
50–100 microbial genomes within just a few years. positive or gram-negative); and 5) targeted spec-
But beyond the cataloging of raw sequences, TIGR trum genes (i.e., Mycobacterium tuberculosis,
and other groups are developing gene array tech- Chlamydia pneumoniae). In addition, selectivity
nology that will allow for the simultaneous assess- and specificity may be ascertained by comparative
ment of expression of all genes in a microbe under genomic analyses, such as comparison to eukaryotic
different environmental conditions (growth consequences, to determine minimal sequence overlap
dition changes, stress, antibiotic insult, etc.). as a surrogate “in silico” indication of selectivity
Among the data expected to be ascertained are: 1) for the microbial target (i.e. decrease in toxicity)
the identification of genes involved in susceptibil- (22).
ity or resistance to antimicrobial agents; 2) specific Additionally, molecular technologies can and
knowledge of gene function, including regulatory have been employed downstream to identify “in
functions of different genes; 3) the identification silico” essentiality of genes, and subsequently proven
of polymorphism shifts signaling the evolution of by so-called “knock-out” approaches in which the
infectivity (virulence) and/or susceptibility/resist- selective inhibition of expression of individual genes
ance to antimicrobials; and 4) the identification of and monitoring of survival and/or growth of the
potential antigens/proteins against which vaccines knock-outs, is a surrogate of ‘essential function’ in
may be devised (22). vitro (albeit negative selection data-based). Alter-
The genetic basis of resistance in bacteria may natively, genomic footprinting methodologies and
supersede the phenotypic (macro-) detection of temperature-sensitive mutants also provide surro-
resistances, frequently based on microbiological gate assays for ‘essentiality’ determination in bac-
susceptibilities (minimal inhibitory concentrations, teria.
etc.). Undertaking the identification of the geno- Consensus throughout the documents (1,5,6,7,
typic cause for changes in susceptibility may 8,11,19,20,21,22,39,49,50,53,54,55) holds that
provide insight into the development of novel taking genomic sequence information to practical
approaches to combat resistance. A shortcoming application of screen design has provided a variety
of genotypic characterization of resistance factors of high-throughput screening assay formats includ-
is that it provides but a ‘snapshot’ of genotypic char- ing cell-free biochemical or genetic assays, assays
acter; it gives a single time point of ‘data’, but not based on phenotypic changes, binding assays,
necessarily a proven link to the resistance pattern, enzymatic assays, etc. Genetic technologies may
or an understanding of antimicrobial resistance. A ultimately allow multiplexing of prokaryotic tar-
match of both genotypic and phenotypic data is gets, which in turn may increase the chances of
57
success and decrease overall research and develop- ted diseases and vaccine-preventable diseases (7).
ment costs (22). Thus these new technologies are
seen to play a critical role in future discovery Product development—antibiotics,
efforts for new antimicrobials. vaccines and diagnostics
Antibiotics
Funding for research
The UK Standing Medical Advisory Committee
The estimate for infectious disease deaths through- was commissioned to examine the issue of antimi-
out the world in 1998 was over 13 million (54) or crobial resistance in relation to clinical prescribing
almost a quarter of all deaths worldwide. Of these practices (19). Their mission was to examine all
deaths, 3.5 million were due to pneumonia, 2.2 factors that may contribute to antimicrobial resist-
million to diarrhoeal disease, 1.5 million to M. ance, including the role of research. From this re-
tuberculosis, 2.3 million to AIDS, 1.1 million to port, one very relevant observation is made: “The
malaria, and 1 million to measles (54). The first thrust of this report is focused on the conservation
three of these diseases, totaling 7.2 million deaths, of present antimicrobial agents. However, it must
were the top infectious disease killers as well as the be recognized that the way in which past resistance
overall top three causes of deaths worldwide in 1900 problems have been overcome (if only temporar-
(54), indicating little impact of research and devel- ily) has been by the development of new agents.”
opment on reducing this infectious disease The “Report of the ASM Task Force on Antibi-
burden.The current estimate is that less than 2% otic Resistance” (8), based on the workshop on
of the total health research expenditures through- “Antibiotic Resistance: Current Status and Future
out the world is devoted to antimicrobial usage, directions” held in 1994, drew consensus from a
delivery, and resistance (49). To quote from the group of almost three dozen scientists from
WHO report (49): “Incentives are needed to en- academia, government and industry. It states: “The
courage pharmaceutical companies to discover and relative utility of antibiotics is eroding, tipping the
develop new compounds, as well as intensify re- balance in favor of multidrug-resistant pathogens,
search into dosage regimens calculated to minimize and there appears to be few new drugs in the pipe-
the likelihood of selecting for resistance.” lines of the USA pharmaceutical companies. These
developments amount to an incipient public health
emergency, albeit one that is poorly appreciated or
US funding of infectious disease, AIDS, and
recognized” (8).
tuberculosis research
Also from the Task Force report (8), “…it should
The priorities for research in the United States can be realized that the research-intensive pharmaceu-
be clearly identified in a review of funding amounts tical industry is the source for most new drugs and
from 1993 through 2001 (estimated), in which over that industries need to profit from their investments
an 8-year period the total research budget doubled in order to pay for the research.” As marketing pro-
from $9.765 billion (1993) to $18,812 billion jections are primarily based on historical usage, they
(2001, estimated). The AIDS research portion of may be misleading. Marketing and business
this budget increased by 1.97-fold increase in fund- specialists in industry should be involved in dis-
ing support. Infectious disease research (other than cussions on the problems of emerging antibiotic
AIDS and TB) received a 1.97-fold increase and resistance (8). In addition, as cost can drive pre-
TB research increased from $35 million (1993) to scription use, the national and regional health care
$86.8 million (2001, estimated), or a 2.48-fold providers/payers should be involved in the consid-
increase in the research funding. Although the TB eration of use of antibiotics, balancing the use of
research budget represents a disproportionate in- antibiotics and risk of emergence of resistance
crease in funding, it is in turn disproportionately against cost in the selection of appropriate type and
less than that for AIDS research (82,83). From the use of antibiotics. In exchange for the rational mar-
1995 CISET report (7), funding of work related ket-support approach for selling products, indus-
to infectious diseases other than AIDS or TB was try should help support national efforts for the
c.5% of total research funding; the Centers for prudent use of antibiotics (8). In addition, the po-
Disease Control and Prevention (CDC) dedicated tential association of infectious diseases (including
c.95% of its budget for prevention and control of bacterial infection) with chronic diseases needs to
infectious diseases to AIDS, TB, sexually transmit- be better understood (82), and this will require an
58
immense, long-term, research investment. Overall, reaching the market, the perception of lack-of-
research has been found to be ‘cost effective’ (11). effort is apparent.
This section contains a synthesis of the many
suggestions and recommendations for product de- TABLE 1
velopment that came from the reports cited in the
references. A summary is given at the end of the Company Research area(s)
section. Abbott Labs Antibacterials/genomics
Astra-Zeneca Antibacterials/antifungals/genomics
Industry engagement
Bristol-Myers Squibb Antibacterials/antifungals/genomics
Industrial infectious disease research remains a puz-
Cubist Pharmaceuticals Antibacterials/genomics
zle. Clearly in the 1970s and 1980s major compa-
nies decreased support for their infectious disease Eli Lilly Antibacterials/antifungals
efforts (84,85), especially antibacterials, with the Glaxo-Wellcome1 Antibacterials/antifungals/genomics
understanding that the antibacterial needs were
Johnson & Johnson Antibacterials/antifungals
diminished, but the reality is that pharmaceutical
companies have continued to support to some de- Merck Antibacterials/antifungals
gree infectious disease, moving towards antiviral and Microcide Pharmaceuticals Antibacterials/antifungals/genomics
in some cases antifungal research efforts, but not
to the same extent as the increases in non-infec- Pfizer Pharmaceuticals2 Antibacterials/antifungals/genomics
tious disease research areas such as cardiovascular, Schering-Plough Antibacterials/antifungals/genomics

CNS, lipid disorders, oncology, dermatology, etc.
SmithKline-Beecham Antibacterials/genomics
The success rate for antibacterial discovery and
1
development, much diminished since the ‘hey days’ Now one research unit.
2
Through strategic external aliances
of the 1960s–1970s, continues to pose a “value risk”
for industry (21). There is, however, no shortage
of good ideas (84,86,87). The decrease in industrial support may be re-
The UK Standing Medical Advisory Commit- vealed by the number of commercial Investigational
tee (SMAC) report (19) notes that: “It is also rec- New Drug (IND) submissions in infectious dis-
ognized that over recent years the pharmaceutical eases from 1991 to 1999, dropping from 327
industry has developed vastly more efficient sys- (1991) to 265 (1995) to 52 (1999) (82,83). At the
tems for seeking new antimicrobial agents. These equivalent interval of 9 years (but shifted backwards
strategies will, hopefully, yield new generations of in real time due to unavailability of more current
antimicrobial agents by the end of the next dec- data), overall funding for research (all therapeutic
ade.” According to the report (19), development areas) by industry increased at a rate more than 50%
of a new antimicrobial agent costs about $500 mil- higher than that of government funding for re-
lion (£350 million), over an estimated 7–10 year search, with industry support rising from $6.19
period (within a 17–20 year window of patent life, billion (1986) to $18.65 billion (1995) (82,83).
depending on country of filing). The costs, together However, this increase does not reflect a commit-
with an understanding that these agents will be used ment to infectious disease, but rather an increase
for a relatively short period of time in a therapeutic in funding in the chronic disease areas, with an
area subject to the development of resistance and emphasis on non-infectious disease research.
high competition, it is easy to see why pharmaceu- As most INDs submitted for infectious diseases
tical companies may elect to invest in research in are not for individual, novel chemical entities, an
other therapeutic areas (84,85). examination of the serious downtrend in industrial
A survey of the public domain reports (see support for infectious diseases can be seen in the
Table 1), databases and literature by this author comparison of New Molecular Entity (NME) sub-
indicates major efforts by large pharmaceutical com- missions in the FDA Division of Anti-Infective
panies, start-up biotechnology-based pharmaceu- Drug Products, indicating a decreasing trend in the
tical companies, and many smaller start-up deliverability of novel agents (82,83). The NME
initiatives, directed towards antibacterial resistance approvals in the years from 1991 to 1999 are sum-
problems. But with success being harder to come marized in Table 2. NMEs dropped from 4–6 per
by and with very few new antimicrobial agents year in the early 1990s to just 1 per year in the late
59
TABLE 2
1991 1992 1993 1994 1995 1996 1997 1998 1999
# NMEs 5 6 4 NR 2 8 1 NR 1
Average NME 27.4 21.1 24.9 — 25.6 14.3 15.0 — 7.8

Approval Time mo. mo. mo. mo. mo. mo. mo.
NR = none reported
1990s (although there was a single-year spurt of inhibitors (Mupirocin™), magainin-like peptides,
agents in 1996 with 8 NMEs). This may represent antisense agents, quorum-sensing agent inhibitors,
an under-reporting of agents in the late 1990s with and efflux pump inhibitors may provide novel
the shifting of some approvals to the FDA Divi- approaches to combat resistance. These and others
sion of Special Pathogens and Investigational Drug are summarized in Table 3.
Products, but even with these numbers factored in,
the NMEs have dropped more than 2-fold in the TABLE 3. SPECIFIC AREAS IDENTIFIED (6) WHICH MIGHT
10-year period ending with the turn of the millen- YIELD PROMISING PRODUCTS WITH ACTIVITY
AGAINST ANTIBIOTIC RESISTANT BACTERIA
nium (82,83). INCLUDED:
Virtually all antibacterial agents over the past
18–20 years, up to the approval/launch of the first Streptogramins
oxazolidinone in 1999 (Linezolid™, Pharmacia- Tetracycline analogues
Upjohn), have been against ‘old’ targets, i.e.,
Dual-action cephalosporins
targets subject to the emergence of resistance. Even
Synercid™ (Rhone-Poulenc Rorer) is a new ana- Newer vancomycin analogues or vancomycin-like glycopeptides
logue of the virginiamycins used for many years in Macrolides
animal husbandry in the UK, with pre-existing
Catalytic antibodies
resistance in the gene pool. Numerous problems
have delayed or denied support, development, or Oligosaccharide-derived antibacterials
approval of novel antibacterial agents, among them: Antibiotic peptides
toxicological problems with novel chemotypes;
development of resistance, even among the quino- Bacterial/permeability increasing peptides
lones; concern for restricted use of new antibacte- Magainins, cecropins, defensin-like molecules
rial agents; and loss of gram-negative activity in the
Steroid antibiotics
newer agents in development.
Lactoferrin-based antibiotics
Development of new antimicrobials Anti-sense nucleotides
Wise and colleagues (71,72) provide an overview

of the development of new antimicrobial agents, New strategies in antimicrobial development
categorizing research strategies into three groups: may afford unprecedented opportunities for new,
novel antibacterial agents (88). The development
1. improvement of existing agents;
of three major technologies have provided hope:
2. vaccine developments; and
• the use of genomics to identify novel targets;
3. genomic approaches.
• the use of combinatorial chemistry, including
Existing classes (β-lactams, cephalosporins, and parallel synthesis, providing a new level of high-
carbapenems) have been a rich source of agents in throughput medicinal chemistry synthesis of
the past, but limited novelty opportunities and compounds; and
emerging resistance have diminished these agents’
• advancements in screening technologies have
value. Older agents used solely in animal health,
increased daily throughput by over 100-fold,
such as orthosomycins and avilamycins, may
which use much smaller amounts of compounds,
provide novel chemotypes for human drug devel-
and screen up to 20,000 compounds per day
opment. Everninomycins, virginiamycins (strepto-
(19).
gramins), oxazolidinones, t-RNA synthase
60
Partnerships and incentives for development of new • Choice in industrialized versus developing world
antimicrobials vaccine targets;
The Office of Technology Assessment (OTA) re- • Delivery of a vaccination programme to devel-
port (6), concerning research and development and oping world needs.
its impact on antimicrobial resistance, suggested
Also vaccination against a pathogen that is also
several options for encouraging the development
a member of the normal commensal flora (e.g.,
of new antibiotics; among them was a common-
Escherichia coli, enterococci, etc.) may be problem-
theme found in many of the other reports i.e., the
atic or deleterious for the host.
need for cooperative research among the govern-
Worldwide medical needs for bacterial vaccines
ment regulatory bodies, academia, and industry (6).
are summarised in Table 4 (6,21).
In the SMAC report (19), the following incen-
tive recommendation is made to increase the phar-
maceutical company support in a competitive and TABLE 4
profit-limited ‘competitive’ market: “One possible
Bacteria Infection
way forward, balancing the need for continued in-
novation with that of drug conservation, lies in the Neisseria meningitidis Meningococcal infection
(serotype B)
trade-off between extended patent life and increased
restriction.” Mycobacterium tuberculosis Tuberculosis
Streptoccoccus pneumoniae Pneumonia for children under

Vaccines 12 years of age
“Vaccination is one of the safest and most cost- MRSA Systemic infections; endocarditis
effective ways of preventing disease” (19). Vancomycin-resistant Systemic infections; endocarditis
Vaccines may represent the best chance for tar- enterococci
geted coverage of a pathogen, although “resistance” Neisseria gonorrhoeae STDs
to a vaccine may also be unavoidable if variants of
the pathogen emerge which are not covered by the Staphylococcus species Skin and soft tissue infections; Upper
respiratory, including sinusitus
vaccine. McKeller et al. (89) suggest that the use of
vaccines rather than prophylactic use of antibiotics Helicobacter pylori GI diseases (ulcer)
should be the norm in infection management in Group A streptococci Pharyngitis
animal health.
Clostridium difficile Colitis
Vaccines may pose the most straightforward
option for long-term solutions to the resistance Shigella flexneri Gastrointestinal dysentery
problem e.g., for meningitis (pneumococcal,
Pseudomonas aeruginosa Respiratory (cystis fibrosis);
Haemophilus influenzae or Neisseria) (6,21,90). burn wounds
However, scientific feasibility, production capacity,
Chlamydia STDs; coronary artery disease
delivery infrastructure, social compliance, political
pressures, and cost constraints are not always easily
managed in industrial countries, let alone develop- The National Institute for Biological Standards
ing countries (6,21,90).There are a number of and Controls cited in (21) suggested that much
important issues to deal with in developing a vac- more needs to be done about vaccine research and
cine i.e.: development, especially aspects of research in im-
• Selection of disease states, microorganisms to munology, microbial genetics, epidemiology, and
target (geographical, patient population differ- pathogenesis. In addition, issues surrounding the
ences such as age, gender, culture); formulation and delivery of vaccines are in need of
major initiatives worldwide.
• Risk versus benefit;
• Efficacy (different efficacies and length of pro- Diagnostics
tection);
The delay in the diagnosis of a specific pathogen in
• Antigenic variation of pathogens (that reduce the an infectious state may be the major reason for so-
efficacy of the vaccine); called “empirical use” of antibiotics and increases
• Use of therapeutic vaccines; the risk of inappropriate use. As the typical anti-
61
microbial susceptibility testing takes ≥48 hours, the at the first site of pathogen attack, the epithelial
overall process from first contact with medical care surface. Study of the intrinsic resistance of oral-
to delivery of a specific diagnostic report (21) may nasal-pulmonary sites, gastrointestinal sites, and
be longer. genitourinary sites may provide opportunities for
Among the new technology detection systems host-facilitated resistance to microbial invaders. The
for rapid diagnosis of bacterial pathogens and re- link of pathogenesis and immunological response
sistance are (6): to microbial insult is a new field of study (beyond
the many years of vaccine development), and may
• DNA probe assays.
provide an “immunoprotective” approach to com-
• Target amplification methods. bating antimicrobial resistance (22).
• Enzymatic tests for specifically detecting resist-

ance (i.e., β-lactamases). Summary of recommendations for
research and development
• Tests based on indicator dyes or light-produc-
ing enzymes. The generalized strategies from the USAID Report
(39) with five key recommendations, the Epilogue
• DNA-based methods for testing antibiotic re- from the Task Force on “Antimicrobial Use and
sistance. Resistance Worldwide” (1) with eleven recommen-
dations, and the 1999 WHO report (50) with
Whereas rapid and reproducible bacterial iden-
eleven key recommendations, and the recommen-
tification in the clinic may become reality in the
dations of other expert groups can be summarized
future, the estimates are minimally 5–10 years out,
and focused towards industrialized and developing
and most probably much longer when one consid-
countries as follows:
ers the standardization issues, technology limita-
tions, scale-up issues, cost constraints, politics, and
legal issues (risk of putative action for making the Industrialized countries
wrong call). Genotypic testing, in which polymerase • Fund basic and applied research in academia,
chain reaction (PCR) technology is used to amplify government and industry to better understand
as little as a single bacterium’s DNA (in vitro), may be all relevant aspects of antimicrobial resistance
technically feasible but the scale-up and application (genetic, epidemiological, mechanisms, transfer
in the clinic will be a major undertaking. Most im- of genetic material, etc.) and to ascertain short-
portantly, the identification of a microorganism by term gains to combat the ongoing threat of anti-
this technique in the patient may not always signal microbial resistance. Support surveillance of
a causal relationship to the infection. antimicrobial resistance as a research tool, and
link the data from surveillance to action in
Novel interventions response to the data (i.e., update old product
labelling for pathogen/indication coverage for
Levy (91) encourages the prudent use of antibiot-
older antimicrobial agents that may be contrib-
ics and for us to stop trying “…to sterilize our en-
uting to antimicrobial resistance by inappropri-
vironment.” Levy argues that we need to review
ate use).
how antibiotics are used and where resistant strains
reside, since resistance is mobile from country to • Provide incentives to industry to address unmet
country. We need to examine the “ecology” of the medical needs and provide new antibacterials to
resistance, as this may tell us where the future re- combat antimicrobial resistance worldwide in
sistance may occur from selective pressures. Lastly, the short term, while encouraging partnerships
the indiscriminate use of disinfectants designed to between industry, academia and government to
“…indiscriminately destroy bacteria…” rather than better exploit existing and new technologies to
reserving the arsenal for a defensive approach, combat antimicrobial resistance (drugs, vaccines,
diminishes our capacity and capability to act when diagnostics). Remove ‘anti-trust’ risk of having
human health is threatened by multidrug-resistant industry collaborate on antimicrobial resistance.
pathogens (91). Provide intellectual property protection rights
A new approach to combating antimicrobial and enforcement to encourage industry to in-
resistance has emerged in which relevant human vest in antibiotic research and development in
host factors are identified and stimulated, especially developing countries.
62
• Where industrial concerns elect to “pass” on in- — Address the use of antibiotics in agricultural
fectious disease opportunities, provide a mecha- and animal husbandry/feed (growth promot-
nism for a government or not-for-profit ers) and act appropriately on the basis of
leadership/risk in development of an essential definitive data/conclusions.
infectious disease therapy product (such as
• Ramp-up basic research to provide for the ex-
vaccine or drug or diagnostic test); in a reverse
ploitation of new technologies to capitalize on
strategy of industry licensing-in from academia,
the genomic revolution. Exploit genomic infor-
rather establish the option for the reverse proc-
mation in its basic form to turn ‘data’ into
ess (license from the industrial concerns) to
‘knowledge’ and extract information for new
occur.
targets, new opportunities for vaccines, new
• Ramp-up applied research, pairing pre-clinical opportunities for diagnostics, new insights into
and clinical research to better assess the correla- molecular mechanisms of antimicrobial resist-
tion between in vitro antimicrobial resistance and ance, and to identify up-and-coming antimicro-
clinical efficacy of drugs, and the links between bial resistance problems
the bacterial infectious state and chronic diseases.
• Provide sound experimental support for the Developing countries
rational and prudent use of antibiotics, in par- • Identify and implement plans to identify solu-
ticular: tions to major impact diseases in developing
— Engage in clinical data-proven epidemiologi- countries providing new therapeutic interven-
cal outcomes research to determine meth- tion options.
odology to decrease antimicrobial resistance • Fund basic and applied research in academia,
by improvement in best practices for antibi- government and industry to better understand
otic use. all relevant aspects of antimicrobial resistance in
— Demonstrate proof of concept of using the the developing world and provide research and
most active (and safe) appropriate anti- development support for successful delivery of
bacterial regardless of cost, rather than the treatment regimens to developing countries that
historical or least expensive agent; do not have the infrastructure to do so them-
— Explore clinical usage of ‘resistance suppres- selves by innovative approaches to treatment
sive’ agents (agents with decreased resistance options.
development) such as the new quinolone
antibacterial agents with the C8-methoxy • Invest in improving the quality of life and health
substituent, and other chemotype anti- overall, thus decreasing the risk of spreading in-
bacterials or anti-resistance agents if clinical fectious disease. Invest in local research and de-
data supports in-vitro data; velopment to specifically address antimicrobial
— Explore the use of adjunct therapy with resistance problems and solutions.
“non-antibiotics”, similar to β-lactamase in- • Invest in education about the appropriate treat-
hibitors, to control or reverse antimicrobial ment regimen (preventative measures, drug
resistance (e.g., efflux inhibitors); therapy, vaccines); provide support to invest in
— Stop using ‘old’ antibacterials with poor developing world diseases (even developments
activity and efficacy and adopt more appro- without industrial country ‘value’); assist in im-
priate therapeutic agents (regardless of cost). plementation of preventive strategies through
This can be accomplished by the use of sur- improving social infrastructure, sanitation, and
veillance of antimicrobial resistance to guide water supply systems. Provide education about
appropriate therapeutic decisions; the relevance of surveillance that may be em-
— Examine pharmacokinetics, pharmacody- ployed to implement appropriate antibiotic
namics, and dosage regimens of antibiotics treatment regimens. Invest in education to pro-
in relationship to resistance emergence prob- vide a framework for future research and devel-
ability; opment in developing countries themselves.
— Recognize that the “prudent use of antibiot-
• Help provide developing countries the same
ics” is not synonymous with “restriction of
opportunity to build a quality infrastructure to
antibiotic use” in man.
address health needs in the long term, includ-
63
ing self-investment in research and development, Conclusion

through sharing of resources with developing The need for basic and applied research and for
countries. new product development is recognized through-
• Invest in a vaccine strategy to combat antimi- out the literature reviewed. The introduction of new
crobial resistance by preventing infectious dis- technologies in drug discovery provide hope for the
eases in man from vaccine-preventable diseases future but the lack of research support for non-
worldwide. Consider combining genetically-en- AIDS infectious disease research, especially TB re-
gineered vaccines and food stuffs as a delivery search and other unmet medical needs in the
system for both food and vaccines (i.e., engi- developing world, remains a serious limitation to
neer specific antigens into the potato or rice global solutions of antimicrobial research. The re-
plant). fusal to recognize antimicrobial resistance in the
clinic as a serious, relevant, real problem compro-
• Remove governmental control/blockage from
mises world health.
efforts to address antimicrobial resistance world-
wide.
64
CHAPTER V
Improve antibiotic use in animals

Scott A. McEwen
Abstract Introduction
Expert scientific panels from all over the world have The human health impact of non-human uses of
reviewed the evidence for resistance selection in antimicrobials is an exceedingly controversial part
food animals and resultant human disease. Reports of the overall resistance problem, and a part that is
of several of the most recent expert deliberations not very well understood. Antimicrobials have for
are reviewed here, some of them devoted wholly to years been used in food animals, pets, and farmed
the subject of non-human antimicrobial use. While fish for treatment of disease and in some cases for
many uncertainties remain, recent studies have growth promotion and disease prophylaxis; they
shown that agricultural uses of antimicrobials do have even been used to prevent bacterial infections
have an impact. There is consensus among the in fruit. Humans do not live in a bubble; we share
documents reviewed that antimicrobial use in ani- the environment with animals and plants. Bacteria
mals selects for resistance in zoonotic pathogens and that are around us and within us can move rela-
commensal bacteria, and these resistant bacteria can tively freely throughout the ecosystem in food,
be transmitted to humans through contact with water, air, and the soil. Most of the attention on
animals or food, and that they can infect humans non-human use has focused on animal agriculture
and cause disease which can be more severe or because of the large volumes used there: as much
longer lasting than non-resistant infections. Fur- as 50% of total antimicrobial production by weight.
thermore, there is increasing concern about the res-
ervoir of resistance that is building in enteric
Important findings from the
commensals of animals (e.g., Escherichia coli, Ente- literature review
rococcus faecium) which may be transferred to
related, or even completely unrelated human Most of the documents reviewed made at least some
commensals and pathogens through exchange of reference to the public health problems of antimi-
genetic material. crobial resistance from antimicrobial use in animals,
A number of strategies have been recommended plants, and aquaculture. A few documents
to reduce human health impacts from non-human (9,18,24,25,92–95) were wholly devoted to the
uses of antimicrobials, the most important being subject. Some mentioned concerns about using re-
to increase surveillance of resistance and antimi- sistance genes as markers in genetically-engineered
crobial use, to implement good regulation to con- plants. While there is uncertainty about the envi-
trol antimicrobial use in animals in light of ronmental impact of resistance marker genes, it is
resistance concerns, and to take steps to ensure the believed that the probability of their transfer to
prudent use of antimicrobials in animals, especially microorganisms leading to health problems is ex-
by reducing exposure of animals to low doses of tremely low (95).
antimicrobials for long periods of time (i.e., growth Antimicrobials are used therapeutically to treat
promoters and prophylactics) if such uses select for food animals (cattle, sheep, poultry, fish, etc.) and
resistance to drugs used in human medicine. Other pets for bacterial infections (9,20,25,93). Some
strategies include educational programmes for animals are treated individually, although food ani-
veterinarians, food animal producers, and dispens- mals may be treated in groups through medicated
ers of antimicrobials for non-human uses, reduc- feed or water if individual animal administration is
ing the need for antimicrobials through alternative not feasible (e.g., poultry, fish) or is less efficient.
treatments and infection control, and research. Therapeutic doses are administered for varying
periods of time, ranging from one to several days,
depending upon the drug and approved applica-
tion as indicated on product labels. In some cases,
65
veterinarians prescribe antimicrobials in an extra- tities of food. Other reports contend that this in-
label manner (e.g., increased dose or duration of tensification of food animal production is at least
treatment), either because labeled drugs are un- partially responsible for antimicrobial resistance
available for the condition, or they are considered problems in agriculture, by increasing the need for
no longer effective. antimicrobial use. Aside from growth promoter use,
Food animals, especially those raised intensively, which is more common under intensive animal rear-
may also be administered antimicrobials (usually, ing conditions than in extensive, or pasture-based
but not always under veterinary prescription) for husbandry, intensive rearing can increase the need
prophylactic purposes during especially high-risk for treatment by fostering the spread and clinical
periods for infectious disease (e.g., after weaning expression of infectious diseases of animals, and by
or transport) or when one or more animals in the enhancing the spread of resistant foodborne patho-
group are observed with clinical disease and more gens and other bacteria among animals.
cases can be expected. Fruit may also be treated Antimicrobial use data are sparse and most docu-
with antimicrobials (e.g., tetracycline and strepto- ments cite the difficulty in obtaining accurate, up-
mycin) in some countries to prevent certain bacte- to-date consumption figures by species and
rial infections, for example, Erwinia amylovora intended use. It has, however, been estimated that
(19,21). as much as 50% of total antibiotic production (by
Most controversially, food animals may also be weight) is used in animals and plants, with 50–80%
administered antimicrobials for growth promotion used in some countries for growth promotion or
or performance enhancement purposes (e.g., feed disease prophylaxis and the rest used for therapeu-
efficiency). In some cases, the distinction between tic purposes (9,20,21). Usage patterns vary tremen-
prophylaxis and growth promotion is unclear be- dously, but in some countries, a majority of food
cause certain drugs may be approved for both pur- animals receive antibiotics at some point in their
poses, and growth promoters may have disease lives, and many for extended periods of time at
prophylaxis benefits. Growth promoters are usu- subtherapeutic doses.
ally administered in relatively low concentrations, Many antimicrobials are administered to animals
ranging from 2.5–5 mg/kg (ppm) depending on under veterinary prescription, but in some coun-
the drug and to some extent the species treated (93). tries, they may also be available for veterinary use
Despite the fact that these drugs have been used without a prescription. These drugs are frequently
extensively in agriculture for over three decades available over the counter in feed stores and pet
(21), scientists are not sure exactly how they im- shops and may be included in purchased feeds with-
prove growth efficiencies. It is believed, however, out veterinary prescription. Financial incentives
that in addition to dampening the effects of sub- exist for the production and distribution of veteri-
clinical disease on growth, the drugs may suppress nary drugs, just as they do for human anti-
certain susceptible bacteria that compete for nutri- microbials. Pharmaceutical companies, importers,
ents with the host animal. It has been pointed out pharmacies and other retailers may all profit from
that the benefits are greater under poor hygiene the sale of antimicrobials to animal owners.
conditions, and their current efficacy is questioned Veterinarians may also profit from the sale of
because other means of controlling disease (e.g., antimicrobials to food animal producers, and it has
biosecurity, vaccination) have been introduced more been reported that as much as 40% of their income
widely into intensive animal husbandry. It is be- can come from this source (50).
lieved that efficiencies of 1–11% can be realized Most of the classes of drugs used in human medi-
(21,93). Another purported benefit of growth pro- cine are also used in veterinary medicine, although
moters is a reduction of total nitrogen and fecal there is considerable variability within and between
output per animal marketed, which has environ- countries in the range of drugs approved for use in
mental impact implications. One expert panel (25) various animal species. Some examples of anti-
went so far as to state that antimicrobials, in par- microbials approved (as of 1999) in the United
ticular at sub-therapeutic doses (as in growth pro- States are presented in the Table.
motion and disease prophylaxis), had an important Very little attention was given to antimicrobial
positive role in facilitating the intensification of use in pets in the documents reviewed, although
food animal agriculture that is characteristic of this area will probably receive more attention in
many industrialized and some developing countries, the future. Pets are frequently in close contact with
thereby enabling the production of abundant quan- their owners and when ill they are often treated
66
TABLE. EXAMPLES OF ANTIMICROBIALS APPROVED FOR USE IN THE UNITED STATES (ADAPTED FROM 25)
Antibiotics approved in the United States for various species
Purpose Cattle Swine Poultry Fish
Treatment of various Amoxicillin Amoxicillin Erythromycin Ormetoprim

infections Cephapirin Ampicillin Fluoroquinolone Sulfadimethoxine
Erythromycin Chlortetracycline Gentamycin Oxytetracycline
Gentamycin Erythromycin Neomycin
Novobiocin Gentamycin Penicillin
Penicillin Lincomycin Spectinomycin
Sulfonamides Sulfamethazine Tetracyclines
Tilmicosin Tiamulin Tylosin
Tylosin Tylosin Virginiamycin
Growth and feed efficiency Ampicillin Arsenilic acid Bambermycin

Bacitracin Bacitracin Bacitracin
Chlortetracylcine Bambermycin Chlortetracycline
Lasalocid Chlortetracycline Penicillin
Monensin Penicillin Tylosin
Oxytetracylcine Tiamulin Virginiamycin
Tylosin
Virginiamycin
with the same drugs used in human medicine. treatments, administered at higher doses for shorter
Regulatory approval for use of antimicrobials in periods of time to individuals or groups of animals,
animals and plants, when it is accompanied by can also select for resistance. Enteric bacteria of food
human health risk assessment by competent animals are especially exposed to selection pressure
national regulatory authorities, may not include because many drugs are administered in food or
considerations of microbial safety (especially resist- water but bacteria in other anatomic locations may
ance). In fact, until recently only a small number also be exposed because many drugs are absorbed
of countries considered resistance at all in the vet- from the gut and others are administered parenter-
erinary drug approval process (93). Traditionally, ally. In addition, many drugs are excreted in active
human health safety determinations of veterinary form in urine or faeces and peresist in the environ-
antimicrobials focused on the effects of antimicro- ment for prolonged periods of time, where they
bial residues in foods of animal origin. The United may exert selection pressure on environmental bac-
States (18) required pharmaceutical companies to teria. In fish farming, for example, it has been esti-
compile and report microbial safety data in their mated that as much as 70–80% of antimicrobials
pre-approval submissions to regulatory authorities administered may end up in the sediment of the
for drugs intended for long-term prophylactic or body of water (96). In general, the implications of
growth promotion use in feeds. Even in recent years this environmental exposure are poorly understood.
when antimicrobial resistance issues have been in Antimicrobial resistance occurs in the target
the forefront, some countries approved important species of organisms (animal pathogens in the case
drugs (e.g., fluoroquinolones) in light of epidemio- of veterinary drugs) and in a variety of non-target
logical evidence from other countries of resistance species in the gut or in other sites. Resistance in
emergence in foodborne pathogens (19). This sug- the animal pathogens of most importance to ani-
gests that antimicrobial resistance concerns were not mal health is often of little direct human health
addressed in the approvals, or any human health significance. While there are many bacterial infec-
risks that were identified were insufficient to over- tions of animals that can cause disease in humans
ride other considerations. (zoonoses), few of these (Salmonella is a notable
There is consensus among the documents re- exception) are important causes of clinical disease
viewed that treatment of animals and plants with in food animals or pets. There are a variety of ways,
antimicrobials leads to resistance in bacteria. The however, that antimicrobial resistance arising in ag-
selection pressure of antimicrobial usage is thought riculture can have a negative impact on public
to be greatest during low-dose, long-term exposure, health. The first two were most frequently men-
which is characteristic of growth promoters and tioned in the reviewed documents:
some disease prophylaxis. However, therapeutic
67
1. Treatment of animals with antimicrobials im- their virulence. In this instance, resistant patho-
portant in human medicine, or drugs of the same gens may cause more severe or longer-lasting
family or class, can select for resistance to these disease in people than comparable susceptible
drugs in zoonotic pathogens (e.g., Salmonella, pathogens.
Campylobacter). Resistant zoonotic pathogens
6. Antimicrobial use in food animals may, in some
can be transmitted from animals to humans
cases, lead to an increase in the shedding of
through direct contact or indirectly through food
zoonotic pathogens (e.g., Salmonella) in animal
or water, and cause illness which does not re-
faeces and thereby available for human exposure,
spond to treatment. Exposure of animals to
whether or not the pathogen is resistant. This is
drugs not used in humans (or no longer used in
a phenomenon called “pathogen load”, and it
humans) can also select for resistance to drugs
could occur through a number of complex and
important in human medicine if the resistance
poorly understood mechanisms whereby anti-
determinants are genetically linked. For this rea-
microbial use in animals results, for example, in
son, the linkage of two or more resistance genes
an increase in the duration of faecal shedding of
on transmissible elements such as plasmids is of
foodborne pathogens, or an increase in the con-
increasing concern. This phenomenon also
centration of pathogens in faeces which may then
makes the separation of antibiotics into “animal”
contaminate food or water.
and “human” use categories less tenable from a
resistance point of view. 7. There is some concern that antibiotic residues
eliminated in animal faeces and urine may exert
2. Genetic determinants of resistance in commen-
resistance selective pressure on bacteria in soil
sals of animals (e.g., Escherichia coli, enterococci)
and water. Treated animals and humans may ex-
may be shared by exchanging plasmids, trans-
crete considerable quantities of active drug or
posons or other transferable elements with
metabolite and many of these residues are slow
related or even unrelated human pathogens dur-
to degrade in the environment.
ing transient colonization of the gut of humans
after ingestion of contaminated food or water. Most of the documents acknowledge that the
public health impacts of antimicrobial use in ani-
Some of the documents drew attention to other mals and plants are complex and poorly understood.
potential human health impacts: These issues have been the subject of considerable
3. Extending the principle in (2) above, resistant controversy and scientific debate for decades. There
bacteria from animals or plants are part of a larger is consensus, however, that resistance does occur in
antimicrobial resistance ecosystem, and their zoonotic pathogens and commensals when animals
resistance genes could find their way through a are treated, that humans are occasionally exposed
variety of poorly understood, indirect pathways to these bacteria through contaminated food and
to human pathogens. These pathways could water, and that illness, and sometimes treatment
involve transfer of resistance genes through in- failure, does occur due to these resistant zoonotic
termediary environmental organisms. Concern infections. There is also consensus, however, that
in some quarters has been expressed about much uncertainty remains about the frequency with
inclusion of resistance markers in genetically- which these events occur, and the overall magni-
modified plants, however the documents re- tude (numbers of people affected, severity of out-
viewed do not consider this as an important issue come, economic impact, etc.) of the public health
(93,21). impact of resistance arising in agriculture.
Some of the uncertainties were reconciled in
4. As a consequence of taking an antimicrobial for recent years through a number of well-conducted
some other reason (e.g., ear infection or pneu-
epidemiological studies, carried out principally in
monia), people become more susceptible to dis-
Europe and the United States. The results of these
ease when exposed through food or other source
studies are summarized later in the chapter. How-
to a pathogen from animals that happens to be
ever, the reviewed documents were virtually unani-
resistant to that drug (e.g., multi-resistant
mous in recommending more research and
Salmonella spp.).
enhanced surveillance to better understand resist-
5. Resistance may be linked with other genetic ance in both medical and veterinary medicine. Sur-
determinants which render pathogens more veillance of antimicrobial resistance among zoonotic
capable of causing disease, and thereby increase pathogens and commensals in food animals, food
68
products, and foodborne infections of humans, as produced a large number of documents; many of
well as monitoring non-human uses of antimi- those are reviewed here. One of the most cited of
crobials is thought to be the best way to identify these was the UK Swann Report of 1969 (97). This
and quantify the effects of non-human antimicro- report is remembered as one of the first recom-
bial use on resistance throughout the food chain. mending that antimicrobial growth promoters and
“Only quantitative data, obtained through appli- other drugs used without prescription in animal
cation of standardized laboratory methods, will feeds should be restricted to antimicrobials that have
allow for meaningful epidemiological analysis and little or no application as therapeutic agents in hu-
evaluation” (9). mans or animals, and will not impair the efficacy
Antimicrobial resistance from agriculture is in of a prescribed therapeutic drug through develop-
many ways a food and water safety issue (8). Over ment of resistance. Secondly, the Swann Report
the past couple of decades, food and waterborne recommended that therapeutic antimicrobials for
diseases appear to have increased in incidence in a animals should only be available under a veterinary
number of countries. A number of factors are prob- prescription. These principles have been endorsed
ably responsible for this, including a greater bur- by most subsequent expert panels and task forces
den of pathogens (resistant and susceptible) that is and lay a foundation for modern recommendations.
transmitted through the food chain from animal The British government later implemented the
populations and plant products to humans. No Swann recommendations, and some credit was
doubt myriad factors are responsible for the emer- given to a reduction in antimicrobial-resistant
gence and dissemination of the wide range of these Salmonella infections. Some have claimed, however,
food and waterborne infections that are major pub- that the measures recommended by Swann were
lic health problems for both industrialized and not effective because total antimicrobial consump-
developing countries. These same factors may be tion in UK agriculture did not decline, and further
important in promoting the spread of resistant outbreaks of antimicrobial resistant salmonellosis
zoonotic pathogens and commensals, as well as eventually occurred. In reality, it is difficult to de-
environmental bacteria, to humans. By the same termine the effects on resistance and total use be-
token, steps that are being taken throughout the cause there was no comprehensive surveillance
food chain to reduce the impact of food and system in place at the time. The US Food and Drug
waterborne infections in which resistance is not yet Administration (FDA) proposed in the 1970s to
recognized to be a problem (e.g., E. coli O157:H7, stop the sub-therapeutic (growth promotion and
Salmonella enteritidis) may also reduce the public prophylactic) use of penicillin and tetracycline in
health burden of resistance. Some of these steps animal feeds but was criticized because there was
include Hazard Analysis, Critical Control Point inadequate evidence of adverse human health
(HACCP) programmes, quality assurance pro- effects and the proposal was unsuccessful (6,24).
grammes, irradiation and pasteurization (19,92). In 1986, Sweden banned the use of growth pro-
The most important strategies that were recom- moters in animal production (21). Unfortunately,
mended specifically to reduce the public health at the time the Swedish government did not have a
impact of antimicrobial use in agriculture fell into resistance surveillance system in place with which
the following major categories (9,25,50,53,92–95): to measure the effects of the ban on resistance in
government regulation; education and prudent or animals, foods, and humans. However, the quanti-
judicious antimicrobial use guidelines; monitoring ties of antimicrobials sold for use in animals were
of antimicrobial use; surveillance of resistance; re- monitored. Animal health statistics show that in
ducing the need for antimicrobials through alter- the early stages after the rather abruptly introduced
native treatments and infection control; and ban, increases in morbidity and mortality were
research. observed (e.g., post-weaning diarrhoea in piglets
and necrotic enteritis in chickens). To counteract
this, antimicrobials used earlier for growth promo-
Effective and non-effective strategies tion were prescribed for prophylaxis during high-
The human health impact of antimicrobial use in risk periods. Efforts were made to improve
agriculture has been the subject of debate, discus- management, feed, and hygiene in order to adapt
sion, analysis, expert panel deliberation, and quali- to non-routine use of antimicrobials. In the early
tative risk assessment for decades. National and 1990s, zinc oxide replaced antibiotics as prophy-
international expert panels and committees have laxis for piglets. Since 1998, zinc oxide is only avail-
69
able in Sweden on prescription and use has declined Avoparcin is a glycopeptide antimicrobial in the
to less than 10% of its maximum. Total sales of all same family as vancomycin. It was approved for
antimicrobials for animals decreased fairly substan- use in many European countries as a growth pro-
tially (by approximately 60%) (98). moter. At the time since vancomycin was not widely
In the 1990s, public health surveillance in the used, there was little reason to be concerned about
UK and elsewhere in Europe identified some new resistance problems in humans. Things changed,
resistance issues that once again heightened con- however, when vancomycin became critical in
cerns about agricultural use of antimicrobials. human medicine for treatment of methicillin-
Among these issues were the increase in Salmonella resistant Staphylococcus aureus (MRSA) and other
typhimurium DT104 infection in humans and ani- serious infections. Resistance to vancomycin, espe-
mals, the appearance of fluoroquinolone-resistant cially among enterococci (VRE) became an impor-
Campylobacter jejuni infections in humans and tant public health problem in many countries.
poultry, and the occurrence of vancomycin-resist- Researchers identified VRE in food animals exposed
ant enterococci (VRE) in pigs and poultry. to avoparcin, where they were not found in ani-
Salmonella typhimurium DT 104 was first iden- mals in countries where avoparcin was not used as
tified in the UK but has since been found in many a growth promoter. Furthermore, the prevalence
countries throughout the world where it is an im- of VRE among non-hospitalized people in the com-
portant cause of disease in humans, cattle, pigs, munity was much higher in countries that used
poultry, and other animals. Salmonella strains avoparcin. There is evidence that VRE in food
appear to come and go in “waves” every few years animals may have been a reservoir for resistance in
(epidemics of DT29, DT204, DT193 and DT104 humans, perhaps through exchange of genetic
strains were observed in the UK (21) but DT104 material between animal and human strains, or
was particularly concerning to public and animal through transient colonization of the human gut
health officials because of its pathogenicity and the by animal strains.
fact that most isolates were resistant to at least five It is worth reiterating that prior to identifica-
antimicrobials (pentaresistance). While the role of tion of the link between avoparcin use and VRE in
agricultural antimicrobial use in the genesis and food animals, the drug was thought to be an
spread of Salmonella typhimurium DT104 is un- appropriate choice for a growth promoter. This is a
known, there is good evidence that antimicrobial good example of a major problem confronting the
use in animals was associated with development of animal and pharmaceutical industries and those
reduced susceptibility to fluoroquinolones among charged with drug regulation. Growth promoter
some isolates of this organism. This evidence rests drugs that are seemingly safe today because they
mainly on the temporal relationship between ap- are not used in people and do not select for resist-
proval of fluoroquinolones for use in food animals ance in people may not be in the same position
and identification of resistant (reduced susceptibil- tomorrow, if the same or related drugs become
ity) strains. Shortly after fluoroquinolones were important in human medicine. Some older fami-
licensed as therapeutic agents for food animals in lies of pharmaceuticals, previously not considered
the UK, public health laboratories began to iden- necessary or desirable for human medicine, are “re-
tify isolates with decreased susceptibility to trieved” in order to combat new resistance prob-
quinolone drugs. This was particularly alarming lems (e.g., vancomycin for MRSA). More recently,
because fluoroquinolones are very valuable drugs the same sort of thing has happened with
for treating humans for a variety of infections, in- virginiamycin, which is a streptogramin antimicro-
cluding invasive salmonellosis. bial that has been used for many years in agricul-
Similarly, investigators in other European coun- ture, principally as a growth promoter in poultry
tries, (e.g., the Netherlands, Spain) where and pigs but also in some cases for disease prophy-
fluoroquinolones were approved for therapeutic laxis. There is now evidence that virginiamycin use
treatment of poultry, identified substantial increases selected for streptogramin resistance in enterococci
in the prevalence of fluoroquinolone resistance and there is considerable concern that this could
among poultry and human isolates of Campylo- compromise the usefulness of related streptogramin
bacter jejuni. This type of resistance was remark- drugs (e.g., pristinamycin and quinupristin-
able in the rapidity with which it appeared and dalfopristin), which have been recently introduced
increased in prevalence (21,92). Other countries for treatment of vancomycin-resistant enterococci
have reported similar findings. and other bacterial infections in humans.
70
Growth promoters do not necessarily cause re- in some countries (e.g., Australia) the drug has been
sistance problems in humans. For example, withdrawn voluntarily. Fortunately, some countries
ionophores are a group of antimicrobials used have monitored VRE prevalence in animals, food
widely in veterinary medicine for growth promo- and humans and there are reports that the preva-
tion in a variety of species, and for treatment and lence in food animals (initially in poultry) has
prevention of coccidiosis in poultry. Resistance has decreased in Denmark and Germany since the with-
so far not been identified as a problem in animals drawal (4). Although immediate decreases were not
and there are no indications that the family of drugs seen in pigs in Denmark, recent data suggest that
will become useful in humans, perhaps because of the prevalence of VRE in pigs is decreasing, and
toxicity concerns. that levels may have been maintained, at least in
It is important to point out that these examples part, by cross-resistance with macrolides (e.g.,
of recent resistance concerns involve both growth tylosin). Reduction in tylosin use has been accom-
promoters (avoparcin, virginiamycin) and therapeu- panied by a decrease in VRE prevalence (99).
tic drugs (fluoroquinolones). Strategies to address In 1999, four drugs (tylosin, virginiamycin,
these concerns are likely to be somewhat different; spiramicin, and bacitracin) were banned as growth
with the former, regulatory measures (i.e., decision promoters on the basis of the precautionary prin-
to permit their use or not) are most important; with ciple that they or related drugs are used in human
the latter, assurance of prudent use is very impor- medicine, or select for resistance to drugs used in
tant in minimizing concerns. human medicine. This action was also consistent
Collectively, public health concerns arising from with recommendations from the Swann Report and
Salmonella typhimurium DT104, quinolone resist- WHO. While this action was mentioned in the
ance in Campylobacter jejuni and Salmonella, and reviewed documents, the ban is so recent that there
glycopeptide and streptogramin resistance in ente- were no data available on its effects in terms of
rococci substantially raised the profile of antimi- resistance trends among zoonotic or commensal
crobial resistance as a public health issue in the bacteria, trends in antimicrobial usage in animals,
veterinary, agricultural and food industries. Some or in terms of effects on the health of animals or
strategies have been implemented to reduce the indices of production (e.g., feed conversion, days
public health impact, or to improve understand- to market, etc.). It is too early to tell what these
ing of the type and magnitude of the impacts and effects will be; nevertheless, there are some recently
these are discussed below. published data from Denmark where reductions
began a little sooner than in the rest of Europe (99).
Danish farmers had actually decided voluntarily in
Government regulation
1998 to stop feeding growth promoters to food
Mention has already been made about the meas- animals and phase out their use by 2000. The
ures taken in UK after the Swann Report of 1969 DANMAP 99 report (Danish Integrated Antimi-
(97) to restrict the use of growth promoters to drugs crobial Resistance and Research Program) describes
not used in human medicine, and about the sug- drug use patterns in the country in 1998, after the
gestions in the literature that these measures were reductions were in place (99). The early stages of
not effective in reducing total antimicrobial use in reduction in growth promoters were not accompa-
animals. There may, however, have been benefits nied by an increase in consumption of therapeutic
in reducing incidence of resistant Salmonella. drugs, but between 1998 and 1999 there was an
Although not discussed in the reports reviewed, it increase in tetracycline use for treatment of enteric
has been pointed out in the literature that any re- disease in swine.Time will tell whether additional
duction in usage achieved through restrictions on positive or negative effects on therapeutic drug use
growth promoters was compensated by increases will be seen in Denmark.
in prescription drug use. This underscores the need The effects of the European ban of 4 growth
in any overall strategy to carefully monitor all uses promoters on resistance in zoonotic bacteria and
of antimicrobials and take appropriate control commensals are also largely unknown because the
action if excesses are detected, and to reduce the ban is so recent. DANMAP reported that sampling-
need for antimicrobials by making improvements related problems made the Danish Salmonella
in animal management, hygiene, and health. results from 1998 difficult to interpret, because
Many countries, most notably in Europe, have many isolates from both animals and humans were
banned the use of avoparcin in animal feeds, and linked epidemiologically. Resistance in Campylo-
71
bacter coli to erythromycin dropped by almost 50% ant bacteria will be transmitted to humans through
in 1998, and this was attributed to withdrawal of foods or other sources, and the likelihood that this
tylosin (another macrolide) as a growth promoter. transfer will result in the loss of treatment options.
Among enterococci of pigs and poultry, reduction Categorization would include consideration of drug
in resistance to vancomycin, virginiamycin, and attributes (e.g., mechanism and rate of resistance
erythromycin were observed after the ban. Among or cross-resistance induction), the expected prod-
E. coli, the proportion of isolates resistant to one uct use patterns (e.g., duration of treatment, spe-
or more antimicrobials decreased over the same pe- cies, number, and type of animals treated), and
riod, but changes in prevalence of resistance to spe- potential human contact (e.g., bacteria of concern,
cific banned growth promoters were not observed environmental and food contamination, food
(99). processing effects). Examples that were given in-
Another important regulatory development that clude: a growth promoter used in multiple species
has taken place in some, but not all countries, is and inducing resistance to an antimicrobial used
the inclusion of antimicrobial resistance considera- in human medicine would be placed in the high
tions in the drug approval process. In the United potential human exposure category; a drug used
States, a great deal of attention has been given to for entire herd therapy during outbreaks of disease
the so-called “Framework Document” (Proposed which occur in a small fraction of herds would be
Framework For Evaluating And Assuring The placed in the medium category; and a drug used
Human Safety Of The Microbial Effects Of Anti- for individual animal treatment of only occasional
microbial New Animal Drugs Intended For Use In animals in herds, for a short duration, would be
Food-Producing Animals), developed within the placed in the low category.
Food and Drug Administration and published in Another very important feature of the Frame-
1998 (24). The Framework is “intended to pro- work in a regulatory sense is the notion of estab-
vide a mechanism for evaluating and ensuring the lishing safe resistance threshold levels for
human safety of antibiotics and other antimicrobials antimicrobials. Conceptually, the threshold level
used in food animals, including those used for could be set at the level of resistance that carries
growth promotion” (24). The Framework is a con- with it insignificant likelihood of transfer to
ceptual risk-based process with the stated goal of humans, if it were possible to accurately determine
preserving the effectiveness of drugs which are im- such a level. There is also provision for establishing
portant in human medicine while enabling the safe levels for Category I drugs to be used in post-
use of antimicrobials in food animals. It provides approval monitoring of resistance and which could
for categorization of antimicrobials on the basis of serve as an early warning system indicating that
an assessment of their importance to human medi- resistance was reaching a level of concern. The docu-
cine. Category I drugs (or members of a class of ment acknowledges that the usefulness of such
drugs) are essential for treatment of life-threaten- thresholds depends upon the ability to demonstrate
ing diseases of humans, or are important for treat- that they are sufficiently protective of public health,
ment of foodborne diseases of humans, or are and that there is a capability of detecting when such
members of a unique class of drugs used in levels are reached.
humans. Examples include quinolones, vancomy- The Framework document also makes provision
cin, and quinupristin-dalfopristin. Category II for requiring pharmaceutical companies to conduct
drugs are important for treatment of potentially pre-approval studies of drugs in order to character-
serious human diseases, but for which suitable al- ize the type and rate of resistance development.
ternatives exist (e.g., ampicillin, erythromycin). Post-approval monitoring studies may also be
Category III drugs have little or no use in human required of certain drugs in order to identify emer-
medicine or are not the drug of first choice for gence of resistance of sufficient concern to public
human infections. health to trigger intervention and mitigation strat-
Importantly, the Framework strategy would also egies. Finally, there is provision for requiring sub-
categorize, into high, medium and low, the likeli- mission by pharmaceutical companies of detailed
hood of human exposure of resistant human patho- drug sales information by species, state, dosage
gens arising from the use of drugs in food animals. form, year, and estimate of active units sold.
This is an attempt to use in the characterization of Another important initiative undertaken by
risk information on the ability of the drug to select FDA in 1999 was preparation and public presen-
for resistance in bacteria, the likelihood that resist- tation of a “Draft Risk Assessment on the Human
72
Health Impact of Fluoroquinolone Resistant titative risk assessment is used in a number of fields
Campylobacter Associated with the Consumption to assist risk management decision-making when
of Chicken”. This effort could be a milestone in the magnitude of health impacts is clouded by com-
evidence-based regulatory decision-making in the plexity and uncertainty. This is certainly the case
area of antimicrobial resistance in agriculture. The with estimating the human health impacts of anti-
risk assessment is a highly focused, structured as- microbial use in agriculture. The FDA assessment
sembly of scientific and public health information is also a good example of the use of available sur-
from a variety of relevant sources, including the veillance data to estimate quantitatively the human
scientific literature, public health surveillance health impact. Quantitative risk assessment is be-
databases, and expert opinion. The assessment is ing used increasingly in other microbial food safety
an attempt to estimate in quantitative terms the issues, and experience and confidence in the proc-
public health risk in one year from resistant food- ess are growing. An important next step for regula-
borne pathogens due to the use of antimicrobials tors is to identify the public health risks from
in food producing animals. Within the assessment, resistance that are “acceptable” to society. A gener-
a mathematical model was developed which related ally acceptable level of cancer risk from environ-
the prevalence of fluoroquinolone-resistant mental chemicals is one per million in the
Campylobacter infections in humans to the preva- population over a lifetime of exposure. It remains
lence of fluoroquinolone-resistant Campylobacter in to be seen whether acceptable levels for microbial
chickens (a major source of Campylobacter jejuni risks can be agreed upon internationally. If such
infection in the United States). Fluoroquinolone levels (or “risk standards”) can be agreed upon,
resistance in Campylobacter was selected because quantitative risk assessment could be used to iden-
campylobacteriosis is the most commonly reported tify resistance thresholds, beyond which public
bacterial foodborne disease in the United States, health impacts become unacceptable. This will no
fluoroquinolones are important drugs in human doubt prove to be a difficult, but important task.
medicine which are sometimes used to treat people
sick with this disease, and fluoroquinolones are
Education and prudent use of antimicrobials
approved for use as therapeutic agents in poultry.
As previously mentioned, fluoroquinolone resist- None of the documents reviewed educational or
ance has been identified as a problem in Campylo- prudent antimicrobial use strategies which have
bacter jejuni in a variety of other countries where been shown to be effective in reducing resistance
these drugs are used to treat poultry. risks, nor was evidence presented that any have
Using data from epidemiological studies and the actually been implemented. There are anecdotal
FOODNET surveillance system in the United reports in the scientific literature that a number of
States, the model estimated the most likely and es- national and international organizations (e.g., pro-
timated range of cases of fluoroquinolone-resistant fessional veterinary associations) have begun to
Campylobacter jejuni infections that occur in one develop prudent or judicious use guidelines for
year in the United States, and which are treated antimicrobials in animals, and in some cases, codes
with fluoroquinolones by physicians. The risk as- of antimicrobial prescription in veterinary practice.
sessment clearly describes the assumptions that are There are also some reports of attempts to draw
made in construction of the model and identifies attention to the issue in the minds of veterinarians
the various uncertainties that arise from lack of and food animal producers, many of whom still
knowledge or variability in data inputs. As an believe that the only public health concerns that
example of one outcome from this model, the esti- arise from antimicrobial use in food animals are
mated mean number of people with fluoro- residues of drugs in edible tissues.
quinolone-resistant Campylobacter infection from Although not mentioned in the documents,
chicken who received fluoroquinolone in 1998 was Denmark has recently put significant limits on the
5065 (with a 90% confidence interval of 2585, ability of veterinarians to profit from the sale of
8595). antimicrobials in food animal production. The
This risk assessment is important for a number effects of this measure on antimicrobial sales and
of reasons. Many stakeholders in the veterinary, consumption are not yet known.
animal production, and pharmaceutical sectors have
for years been asking for a risk-based regulatory
decision-making process on antimicrobials. Quan-
73
Monitoring of antimicrobial use potential bias. This programme is able to document

Some of the documents mentioned that some coun- the effectiveness of some of the strategies that have
tries (notably in Scandinavia) have been assembling been used in Denmark to curtail resistance from
national antimicrobial consumption data, or have food animals, most notably the ban on growth pro-
recently instituted the assembly of these data. moters.
Sweden was able to document the effects of their In the United States, NARMS (National Anti-
growth promoter ban on consumption of microbial Resistance Monitoring System) Enteric
antimicrobials for prophylactic and therapeutic Bacteria Program tests antimicrobial resistance re-
purposes because they had an antimicrobial use lated to agriculture (22,24). It began in 1996 as a
monitoring system in place. As described above, joint effort by the Centers for Disease Control and
the United States has declared plans to require the Prevention (CDC), FDA and US Department of
submission of antimicrobial sales data to the FDA, Agriculture. Isolates (initially Salmonella, with ad-
which can be used to monitor trends in consump- dition of Campylobacter in 1997) are obtained from
tion, and in epidemiological and risk assessment human clinical specimens, animal clinical speci-
studies addressing the associations between anti- mens, normal animals, and carcasses at slaughter
microbial use and resistance in animals and humans. from across the United States. Data from NARMS
Although not specifically mentioned in the docu- were used in the FDA’s quantitative risk assessment
ments reviewed, Denmark has instituted an anti- of fluoroquinolone-resistant Campylobacter from
microbial use monitoring system (DANMAP) to chicken (described above) and have been presented
accompany its resistance monitoring. in a variety of scientific venues.
Surveillance of resistance Alternative treatments and infection control

Calls for resistance surveillance systems figure As mentioned above, Sweden reported that farm-
prominently in nearly all reviewed documents. It ers eventually adapted to the ban on growth pro-
is generally hoped that these systems will provide moters by a number of means, including the
descriptive data on resistance, which will enable the implementing improved husbandry practices and
identification of temporal trends, emerging issues, increased use of zinc oxide (which has been criti-
and the extent of resistance in human and animal cized on environmental grounds (21), but now
populations and food products. appears to be under control (98). While this is evi-
Many countries have for some time had elements dence that antimicrobial needs were reduced, there
of national resistance surveillance in place. It was was no resistance monitoring in place that could
surveillance of resistance data assembled by the measure the effect of management changes on
Public Health Laboratory Service in the UK which resistance.
identified the emergence of decreased susceptibil-
ity to fluoroquinolones among Salmonella
typhimurium DT104 isolates (21). Public health
Barriers to action
scientists in other countries have made similar con- There are many disincentives and barriers to the
tributions to our understanding of resistance issues. further implementation of resistance risk reduction
Two comparatively new antimicrobial resistance strategies. These include a general lack of accept-
surveillance programmes are the previously men- ance among veterinarians and food animal produc-
tioned DANMAP in Denmark, and NARMS in ers that a resistance problem exists in agriculture; a
the United States. DANMAP is run by the Danish lack of scientific information on the extent and
Veterinary Laboratory (22,99). DANMAP reports magnitude of public health risks; conflicting eco-
are issued annually and describe antimicrobial con- nomic interests; the costs of implementing alter-
sumption data in animals and humans, resistance natives; lack of regulatory will and capability; lack
in zoonotic bacteria (e.g., Salmonella, Campylo- of efficacious and economical alternatives to
bacter), resistance in indicator bacteria (e.g., E. coli, antimicrobials; and lack of resources to develop and
enterococci), and resistance in bacteria from diag- implement strategies.
nostic submissions from humans and animals. Sum- A major barrier is the lack of acceptance that
maries are included which include interpretation agriculture and veterinary medicine are significant
of observed trends, relationships between antimi- contributors to the human health impacts of re-
crobial use patterns and resistance, and sources of sistance. Large numbers of veterinarians, other sci-
74
entists involved in agriculture, and food animal antibiotic use in humans, strong financial reasons
producers simply do not believe that antimicrobial exist for continued use of antibiotics in food-
use in food animals has substantial negative health producing animals for food animal producers,
effect on humans. This is not simply a lack of aware- veterinarians, and pharmaceutical companies.
ness due to inadequate or insufficient education or If society as a whole is not prepared to accept
training, but has to do with the relative lack (until some risk from the non-human use of anti-
recently) of concrete examples clearly document- microbials then all uses would be banned from
ing the impacts. Unlike physicians, who see patients agriculture. Few people subscribe to this extreme
with disease caused by resistant bacteria, and who view. This implies that some level of risk, however
can see that resistance in hospital and community- small, is acceptable in exchange for the perceived
derived pathogens is related to use of antimicrobials benefits of treating sick animals (alleviation of ani-
in those settings, veterinarians and producers do mal suffering) or reducing losses due to disease in
not see these cases. Until recently, few well- animals. The difficulty comes in identifying the line
documented examples of human illness from of demarcation between acceptable and unaccept-
resistant pathogens originating on the farm have able risk. The general feeling among the veterinary
been described, (e.g., the recently-described case and animal production communities is that the
of ceftriaxone resistant salmonellosis in a child benefits of antimicrobial use in treating and pre-
apparently infected on a farm) (100). The tremen- venting infectious disease in animals far outweigh
dous complexity of the food production, process- the risks associated with their use in animals. As
ing, distribution and food service system in long as this feeling prevails, it will be a major
industrialized countries makes it extremely diffi- barrier to implementing the strategies intended to
cult to trace infections and resistance genes. If reduce any risks that are indeed present.
people do not believe that their practices and be- There is a strong perception in some quarters
haviours create public health risks, it is more diffi- that more drugs are needed in veterinary medicine
cult to get them to change these behaviours. so that food animal production can continue to be
The lack of scientific information presents a efficient and sick animals can be treated. The ma-
further barrier to obtaining general agreement, even jority of bacterial infections of animals are not
among people without a financial stake in the zoonotic and most veterinarians and producers feel
issue, when intervention strategies are warranted. that resistance among these pathogens is purely an
Almost intuitively, many stakeholders in food animal health concern. Historically, the response
animal industry and veterinary medicine call for a to problems of resistance in veterinary medicine
“science-based” or “risk-based” regulatory decision- has been to reach into the cabinet for another new
making process on resistance issues. Many govern- drug. Notably, an antimicrobial resistance crisis has
ment agencies themselves call for more evidence not been perceived in veterinary medicine, as is the
before implementing interventions (24). There is a case in human medicine. Hence, some groups call
conflict between those who believe that enough for more regulatory approvals of new drug applica-
evidence exists to warrant risk-reduction actions, tions without acknowledging in any substantial way
and those who believe there is a need for more evi- the need for stewardship of available antimicrobials
dence of the nature and extent of the problem be- in agriculture (25). There does not appear to be an
fore attempting to fix it. appreciation of the animal health costs of antimi-
Balancing the risks of resistance against the ben- crobial resistance and that there are good animal
efits of antimicrobial use in agriculture is also a health reasons to preserve the currently available
barrier to action. One of the reasons for this is that drugs. Perhaps in the past, new drugs were so read-
the risks and benefits are borne by different groups. ily available that this was unnecessary, or pharma-
The food animal producer might save the life of an ceutical companies were sufficiently successful in
animal (and therefore his investment) by treating marketing their new products that veterinarians and
it; he realizes directly the benefit of treatment. Any producers looked to new drugs rather than preserv-
resistance risks arising from that treatment would ing the existing ones. In many ways, the effective-
most likely be realized by someone exposed to the ness of drugs that have been available for therapy
resistant bacteria, far down the food chain. Con- in veterinary medicine (e.g., penicillin, tetracycline)
versely, if the producer reduces antibiotic use on has in some countries been squandered by their
his farm, he may not realize any direct benefit. excessive use as prophylactic agents or growth pro-
Just as there are some financial incentives for moters.
75
Another barrier is the financial interest of vari- non-human than human uses of drugs) there are a
ous participants in food animal and plant produc- number of barriers to implementation. There may
tion. These are not simply the interest in be a lack of regulatory will in some countries be-
minimizing losses due to bacterial disease, or the cause the subject is so controversial and rife with
financial interests of the pharmaceutical industries, uncertainty, and effective political lobbying may
which are essentially the same as those encountered be conducted by those in opposition to resistance
in human medicine. Unlike physicians in most in- control measures. Many countries lack the resources
dustrialized countries, antimicrobial sales are often to conduct risk assessments to support regulatory
an important source of income for veterinarians. change, and resources to implement surveillance
Many include charges for other services (health programmes. There may also be reluctance or
management advice, for example) within the mark- inability to regulate prescribing practices of
up for drugs, and this source of income helps sus- veterinarians at the national level.
tain rural veterinary practice, which can be difficult
in many areas. Most professional organizations and
Recommended strategies
individual veterinarians would recoil at the sugges-
tion that profit was a motive for prescribing A recent WHO document (94) relevant to use of
antimicrobials, and few if any data are available to antimicrobials in animals has been produced which
support the contention. It would nevertheless be contains specific recommendations on a number
desirable to remove such financial incentives. of these strategies. This document is the most com-
Many food animal producers operate on very plete and recent set of recommendations pertain-
narrow profit margins, and to stay in business they ing to animal use and the interested reader should
need to be as efficient and economical as possible. refer to the original in its entirety.
The costs of implementing animal husbandry or The document entitled “A Public Health Action
other management changes that could decrease Plan To Combat Antimicrobial Resistance” con-
resistance risks are a barrier. Many food animal in- tains many action items for the implementation of
dustries have made major investments in control strategies to address antimicrobial resistance within
of infectious diseases for the simple reason that it the United States (53). These are presented at a level
was in their interest (and in their animals’ inter- of detail not found in most of the other documents
ests) to eliminate or substantially reduce the im- making mention of non-human uses of anti-
pact of infectious diseases on their operations. microbials and the interested reader should also to
Measures that reduce clinical disease in animals will the original document for details.
decrease the need for antimicrobial treatment, Many of the documents reviewed mentioned
which could reduce human health resistance risk. that antimicrobial resistance is a global issue and
Some, perhaps many, of these changes (e.g., steps are needed to control the international spread
biosecurity measures) may also reduce transfer and of resistance through movement of humans, ani-
dissemination of resistant zoonotic agents and mals and food products (7). One major document
commensals. However, few of the commonly used relating to the animal area was much more con-
biosecurity measures or vaccination programmes are servative than the others in its recommendations
aimed specifically at foodborne zoonotic pathogens pertaining to resistance from agriculture (25). This
or commensals (with the exception of Salmonella document was prepared by a committee that was
programmes in some species), because they are much more heavily representative of veterinary and
normally not important causes of clinical disease pharmaceutical company interests than was the case
in animals. with the other reviewed documents. It did not in-
The lack of suitable, economically attractive, clude in any of its major recommendations a call
alternatives to antimicrobials is also a barrier to for the abolition or withdrawal of growth promot-
change. The experience of major changes instituted ers of a similar class to drugs used in human medi-
in some countries (e.g., Sweden, Denmark) is hav- cine, or which select for resistance to these drugs.
ing an impact in other countries, but it would help Nor did it recommend greater efforts to ensure the
greatly to have local examples of alternatives in place prudent use of antimicrobials. The other documents
on typical farms in many or most countries, rel- called for these actions.
evant to the agricultural systems of those countries. The general strategies are presented below in
From a regulatory standpoint (which is argu- abbreviated form from the original documents
ably more important to resistance containment for (7,9,25,50, 53,92–95), and in descending order of
76
priority. The main headings are given in order of good reasons to modify their behaviour and these
priority (e.g., “surveillance of resistance” first), then should be provided to them.
specific strategies under each heading are prioritized
by this author. In general, the most important strat-
Surveillance of resistance
egies are to increase surveillance of resistance and
antimicrobial use, to implement good regulation • Identify the components of a national post-
to control antimicrobial use in animals in light of approval resistance surveillance plan including
resistance concerns, and to take steps to ensure the organisms (zoonotic pathogens, enteric
prudent use of antimicrobials in animals, especially commensals from animals, food, humans),
by reducing exposure of animals to low doses of standards and methodologies, and core capacity
antimicrobials for long periods of time (i.e., growth (laboratory, etc);
promoters and prophylactics) if such uses select for • Undertake regular monitoring for resistant bac-
resistance to drugs used in human medicine. terial pathogens and commensals in food-
The top priority strategy is to improve surveil- producing animal populations and animal-based
lance of resistance arising in agriculture. Increased food products;
surveillance of resistance in foodborne pathogens,
commensals of animals and humans, and moni- • Resistance monitoring in food animals should
toring of drug use is essential for the assembly of allow for correlation with similar data from
data that can be used to identify the important humans;
human (and animal) health impacts of resistance, • Data generated from surveillance of resistance
and how these impacts relate to actual drug use in and antimicrobial use should play a key role in
animals. This information is vital to good policy- the development of national policies;
making, and to convince people where the prob-
• Closely monitor the use of antimicrobials in
lems exist. To date, only a few countries have been
animal surveillance programmes. Post-approval
able to construct reasonably comprehensive surveil-
surveillance is essential and should be able to
lance systems and none has a perfect programme
detect resistance in time to take corrective meas-
in place. Other industrialized countries should be
ures;
able to implement surveillance systems within 2–3
years. Developing countries in particular will have • The threshold levels of resistance that are of
difficulties with this strategy, given the financial, public health concern must be defined; these
human and other resource demands required for levels should be low enough that any interven-
implementation. International cooperation is tions they may trigger can still be efficacious;
needed to disseminate the results of surveillance
• If resistance increases above levels of concern,
among all countries, so that even those without the
then incremental interventions up to withdrawal
infrastructure can use the results to conduct risk
of the drug from the market should be consid-
assessment, make policy, and manage risk.
ered;
Secondly, good regulation at the national level
is urgently needed in all countries to control anti- • Evaluate the usefulness of monitoring sentinel
microbial use. Since many countries have not even human populations (e.g., farm and abattoir
considered resistance issues when developing workers) and people in the community for in-
current policies, these need to be revised appropri- fection with resistant bacteria;
ately. Most countries will not have the resources to • Incorporate antimicrobial resistance explicitly in
undertake elaborate risk assessments of all drugs food safety monitoring of imported foods.
used, however, examples of regulation and policy with
supporting data should be made available through
WHO to countries that can make use of it. Monitoring of antimicrobial use
Third, encouraging prudent use of anti-
• Monitor closely the use of antimicrobials in
microbials in all aspects of animal and plant
animal surveillance programmes;
production is essential. Veterinarians and animal
owners in particular must be made aware of the • Post-approval surveillance is essential and should
facts of the impact of resistance on humans, and of be able to detect resistance in time to take
the costs of resistance to themselves, their families corrective measures.
and animals, and to the public. People need to have
77
Government regulation use should be regularly assessed for effectiveness

• Enforcement policies should be designed to and need;
ensure compliance with laws and regulations • Establish codes of practice for veterinarians that
pertaining to the authorization, distribution, reflect antimicrobial resistance concerns;
sale, and the use of antimicrobials in food-
• Locally derived treatment guidelines should in-
producing animals;
clude a list of antimicrobials for conditions com-
• Licensing of veterinary antimicrobial products monly presented in various species and offer a
should include consideration of safety issues re- rational treatment choice based on scientific
lated to the human health impact of resistance data;
developing in food animals;
• Treatment records should be kept and veteri-
• Abolish the use of antimicrobials that are of a narians should continuously evaluate their
similar class to those used for treating humans prescribing practices;
as growth promoters in animals;
• Evaluate the impact of making all systemic
• A single, multidisciplinary government commit- veterinary antimicrobials available by prescrip-
tee should oversee the regulation of antimi- tion only;
crobials in both human and non-human fields;
• Support demonstration projects to evaluate pro-
• Threshold levels of resistance for post-approval grammes which use multiple interventions to
surveillance should be defined and provision promote judicious drug use and reduce infec-
should be made to modify or suspend the mar- tion rates;
keting of antimicrobials if thresholds are
• If sufficient evidence exists that profit from sales
surpassed;
negatively impacts on prescribing, appropriate
• Governments should assess the risks and ben- countermeasures should be taken;
efits of antimicrobial use in agriculture; a risk-
• Advertising and promotion of animal health
based evaluation of human health effects of all
products should comply with national guidelines
antimicrobials should be conducted, including
and codes of practice.
currently registered products;
• Registration decisions should include considera-
tion of the potential rate of resistance in the Education
pre-approval evaluation. • Conduct education programmes for veteri-
narians and farmers on the prudent use of
antimicrobials (including the potential risks to
Prudent or judicious use
human health of emerging resistance);
• Encourage the prudent use of antimicrobials in
• Veterinary undergraduate, postgraduate and con-
animals, in accordance with similar strategies for
tinuing education should be evaluated to ensure
humans; recommended dosages should be opti-
that prudent antimicrobial use and resistance are
mal for therapy and minimize the development
given high priority;
of resistance;
• Convey information to involved parties (e.g.,
• Develop and implement standards of practice
veterinarians, farmers and dispensers) that
to ensure that antimicrobials are not used as sub-
facilitates understanding of the human health
stitute for good farm hygiene;
impacts of resistance;
• Ensure that animal producers employ produc-
• Expand the understanding of the ecology of
tion systems that promote animal health/
antimicrobial resistance among involved parties;
welfare such that the use of antimicrobial agents
is part of, not a replacement for, an integrated • Support public health education campaigns on
animal health programme; food safety and the merits of irradiation for
reducing foodborne infections.
• Prophylactic use of antimicrobials can only be
justified when it can be shown that a particular
disease is present or likely to occur, and such
78
Research • Assess the impact on household contacts of

• Evaluate the nature and magnitude of impacts antimicrobial use in pets;
of antimicrobial growth promoters and use the • Conduct pilot studies to assess the extent of
information to assist in risk-benefit assessments environmental contamination by antimicrobial
of each use; residues and resistant organisms that enter the
• Seek alternatives (including vaccines) to anti- soil or water from human and animal waste;
microbials for food animals; • Gather information on the relationship between
• Conduct research to define the effects of anti- antimicrobial pesticides and emergence of resist-
microbials in veterinary use and used in plants ance.
on the emergence of resistant bacteria;
• Evaluate the effect of current food processing Alternatives to antimicrobials
and distribution methods on the emergence and
• Streamline the regulatory process for drugs and
spread of resistant organisms;
products that are not likely to cause antimicro-
• Conduct research to better understand the bial resistance;
molecular epidemiology and mechanisms of
• Seek alternatives to antimicrobial growth pro-
gene transfer, and the population biology and
moters (vaccines, nutrition, etc).
epidemiology of resistance;
79
Conclusion
Stuart B. Levy
The year 2000 was a banner year for the recogni- mark’s success. By eliciting support from research
tion of antibiotic resistance as a priority public scientists, health care providers, educators, and
health problem around the world. The World policy-makers, the resistance problem can be con-
Health Organization provided leadership in devel- trolled in each country.
oping a global strategy for addressing antibiotic Because infectious disease seriously threatens the
resistance (26). United States governmental organi- health and economy of each country, preserving
zations developed a detailed interagency plan with the power of antibiotics should become a national
specific agency assignments (53). In addition, the priority. The WHO global strategy (26) provides
United Kingdom, Sweden, Canada, and others an excellent framework for action by all country.
began strong public awareness campaigns to im- Industrialized countries can take the lead in com-
prove antibiotic use. Even more remarkable is the mitting resources for more basic, clinical and
commitment of countries with limited resources applied research, and related interventions to curb
which have instituted national regulations to pro- antibiotic resistance. In all countries, government,
tect the potency of existing antimicrobial agents in non-governmental organizations, professional so-
their region. Of note, Chile, Panama and Costa cieties and clinical leaders at appropriate levels of
Rica have recently established national regulations jurisdiction must develop feasible approaches that
for the sale and prescription of antibiotics. To build are tailored to local conditions and available re-
on this momentum, a commitment from each sources. In some instances, a simple hand washing
country and institution is needed to roll back anti- or “antibiotic use improvement programme” will
biotic resistance on a global basis. make an enormous difference (20). It is the com-
bined efforts of these individual interventions that
will become the global solution.
Optimism for the future
Nations and local institutions must work together
to preserve the power of antibiotics. Each country
needs to act as a steward of antibiotics to pass them
on to the next generation. Individual countries
should maximize accessibility to ap-
propriate antibiotics and minimize FREQUENCY OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA) IN DENMARK
their misuse in order to extend their
life in the country. The literature now 20
documents that national and institu-
tional initiatives can dramatically re-
15
Percent resistant strains
duce the prevalence of antibiotic

resistance (14,20). The strict enforce-
ment of antibiotic use policies in hos- 10
pitals has helped Denmark achieve a
drastic reduction in the incidence of
methicillin-resistant Staphylococcus 5
aureus (see graph, 101). Compliance
with infection control procedures
0
and the inclusion of clinical
1960 1965 1970 1975 1980 1985
microbiologists in the prescribing
process have also contributed to Den- Source: V.T. Rosdahl, and A.M. Knudson (101). Reprinted with permission from SLACK, Inc.
81
References
1. Levy SB, Burke JP, Wallace CK, editors. Antibiotic immediate threat to the nation’s health. The role of
use and antibiotic resistance worldwide: report of a research. 1997.
study sponsored by the Fogarty International Center
12. Royal Society of Medicine. Resistant Organisms:
of the National Institutes of Health, 1983–1986.
Global impact on continuum of care. Proceedings
Rev Infect Dis 1987; 9(suppl3):231–316.
of a conference sponsored by 3M Health Care and
2. Public Health Service USA. Healthy People 2000: Regent Medical, London, September 27, 1996.
National Health Promotion and Disease Prevention.
13. Shlaes DM, Gerding DN, John JF, Craig WA,
Full report with Commentary, 1990.
Bornstein DL, Duncan RA, et al. Society for
3. Lederberg J, Shope RE, Oats SC, editors. Emerging Healthcare Epidemiology of America and Infectious
infections: microbial threats to health in the United Diseases Society of America Joint Committee on the
States. Report from the Institute of Medicine Com- prevention of microbial resistance: guidelines for the
mittee on Emerging Microbial Threats to Health. prevention of antimicrobial resistance in hospitals.
Washington, DC: National Academy Press; 1992. Infect Control Hosp Epidemiol 1997;18:275–291.
4. Centers for Disease Control and Prevention. 14. Chadwick D, Goode J, editors. Antibiotic resistance:
Addressing emerging infectious disease threats: a origins, evolution, selection and spread. Proceedings
prevention strategy for the United States. 1994. from a Ciba Foundation Syposium, London July 16–
18, 1996.John Wiley & Sons, Inc. 1997.
5. World Health Organization. Proceedings of the
WHO Scientific Working Group on Monitoring and 15. World Health Organization. The current status of
Management of Bacterial Resistance to Antimicro- antimicrobial resistance surveillance in Europe. Re-
bial Agents; 1994 Nov 29–Dec 2; Geneva, Switzer- port of a World Health Organization workshop in
land. Geneva Switzerland: World Health collaboration with the Italian Associazone Culturale
Organization; 1995. Microbiologia Medica; 1997 Dec 12; Verona, Italy.
Geneva, World Health Organization, Geneva 1998.
6. Office of Technology Assessment, US Congress.
WHO/EMC/BAC/98.1.
Impacts of antibiotic-resistant bacteria. Washington,
DC: US Government Printing Office; 1995. 16. Proceedings of the international conference on
emerging infectious diseases, Atlanta, March 1998.
7. National Science and Technology Council, US. In-
Emerging Infectious Diseases, special issue.
fectious disease—a global health threat. Report of
the National Science and Technology Council Com- 17. Centers for Disease Control and Prevention. Pre-
mittee on International Science, Engineering, and venting emerging infectious diseases: a strategy for
Technology Working Group on Emerging and Re- the 21st century, 1998.
emerging Infectious Diseases. Washington DC: US
18. Food and Drug Administration. Antibacterial drugs
Government Printing Office; 1995.
in animal feeds. Human health safety criteria guide-
8. American Society for Microbiology. Report of the line 18, 1998.
ASM taskforce on antibiotic resistance. Proceedings
19. Department of Health, UK. The path of least resist-
of the American Society for Microbiology; 1994 Jul
ance. Main report of the Standing Medical Advi-
6; Washington, DC. Washington DC: Office of
sory Committee, Sub-Group on Antimicrobial
Public Affairs, American Society for Microbiology;
Resistance. London, UK: Department of Health;
1995.
1998.
9. World Health Organization. The medical impact of
20. Antimicrobial resistance. Br Med J 1998 Sep;
the use of antimicrobials in food animals. Report
317:609–690.
and proceedings of a WHO meeting, Berlin, Ger-
many, 13–17 October 1997. WHO/EMC/ZOO/ 21. House of Lords, UK. Resistance to antibiotics and
97.4. other antimicrobial agents. Seventh Report of the
House of Lords’ Select Committee on Science and
10. Institute of Medicine. America’s vital interest in
Technology; 1997–98. London, UK: The Station-
global health, report of a workshop, November 1995.
ary Office; 1998.
11. American Society for Microbiology. New and
reemerging infectious doseases: a global crisis and
83
22. Harrison PF, Lederberg J, editors. Antimicrobial re- 35. Avorn, J, et al. Information and education as deter-
sistance: issues and options, workshop report. Pro- minants of antibiotic use: report of task force 5. Rev
ceedings of the Forum on Emerging Infections of Infect Dis 1987;9:S286–S296.
the Division of Health Sciences Policy, Institute of
36. Wilson AA, Crane LA, Barrett PH, Gonzales R.
Medicine; 1997 Jul. Washington DC: National
Public beliefs and use of antibiotics for acute respi-
Academy Press; 1998.
ratory illness. J Gen Intern Med 1999;14:658–662.
23. Centers for Science in the Public Interest. Protect-
37. Watson RL et al. Antimicrobial use for pediatric
ing the crown jewels of medicine: a strategic plan to
upper respiratory infections: reported practice,
preserve the effectiveness of antibiotics. 1998.
actual practice, and parent beliefs. Pediatrics 1999;
24. General Accounting Office. The agricultural use of 104:1251–1257.
antibiotics and its implications for human health.
38. Bell RA, Kravitz RL, Wilkes MS. Direct-to-
1999.
consumer prescription drug advertising and the pub-
25. National Research Council. The use of drugs in food lic. J Gen Intern Med 1999;14:651–657.
animals: benefits and risks.1999.
39. US Agency for International Development. Reduc-
26. WHO Global Strategy for the Containment of Anti- ing the threat of infectious diseases of major public
microbial Resistance. World Health Organization health importance: USAID’s initiative to prevent and
2001. WHO/CDS/CSR/DRS/2001.2. control infectious diseases. Manuscript; 1998.
27. World Health Organization. WHO international 40. Davis DA, Thomson MA, Oxman AD, Haynes RB.
collaborative study of antibiotic sensitivity testing, Changing physician performance. A systematic re-
1968–1970. In: ACTA et Microbiologia Scandina- view of the effects of continuing medical education
via. Suppl 217; Sec B; 1971. strategies. JAMA 1995;274:700–705.
28. World Health Organization. WHO scientific work- 41. Soumerai SB, Avorn J. Economic and policy analy-
ing group on microbial resistance. Proceeds from a sis of university-based drug “detailing.” Med Care
working group; 1981 Nov 23–27; Geneva, Switzer- 1986;24:313–331.
land. Geneva, Switzerland: World Health Organi-
42. Green LW and Kreuter MW. Health Promotion
zation; 1982.
Planning: an Educational and Environmental
29. World Health Organization. WHO consultation Approach. Mountain View, Calif.: Mayfield Publish-
group for surveillance of antimicrobial resistance. ing Co., 1991.
Proceedings from a conference of the World Health
43. Prochaska JO, DiClemente CC, Norcross JC. In
Organization; 1982 Nov 22–26; Geneva, Switzer-
search of how people change. American Psychologist
land. Geneva, Switzerland: World Health Organi-
1992;47:1102–1114.
zation; 1982.
44. Ross-Degnan D, Laing R, Santoso B, Ofori-Adjei
30. American Academy of Microbiology. Report from
D, Diwan V, Lamoureux C, Hogerzeil H. Improv-
the American Academy of Microbiology: antimicro-
ing pharmaceutical use in primary care in develop-
bial resistance, an ecological perspective. Washing-
ing countries: a critical review of experience and lack
ton DC: American Society of Microbiology; 1999.
of experience. Prepared for the International Con-
31. US Interagency Task Force on Antimicrobial Resist- ference on Improving Use of Medications; 1997;
ance. Draft public health action plan to combat an- Chaing Mai, Thailand.
timicrobial resistance. Proceeds from a task force
45. Pestonik SL, Classen DC, Evans RS, Burke JP.
co-chaired by the Centers for Disease Control and
Implementing antibiotic practice guidelines through
Prevention, the Food and Drug Administration, and
computer-assisted decision support: clinical and
the National Institutes of Health; 1999. Draft for
financial outcomes. Ann Intern Med 1996;124:884–
comment; 2000.
890.
32. Avorn JL, Solomon DH. Cultural and economic
46. Pestonik SL et al. Therapeutic antibiotic monitor-
factors that (mis)shape antibiotic use: the non-
ing: surveillance using a computerized expert
pharmacologic basis of therapeutics. Ann Intern Med
system. Am J Med 1990;88:43–48.
2000;133:128–135.
47. Shojania KG et al. Reducing vancomycin use utiliz-
33. Metlay JP, Stafford RS, Singer DE. National trends
ing a computer guideline: results of a randomized
in the use of antibiotics by primary care physicians
controlled trial. J Amer Med Inform Assoc 1998;
for adult patients with cough. Arch Intern Med
5:554–562.
1998;158:1813–1818.
48. Gonzales R et al. Decreasing antibiotic use in
34. Gonzales R, Steiner JF, Sande MA. Antibiotic pre-
ambulatory practice: impact of a multidimensional
scribing for adults with colds, upper respiratory tract
intervention on the treatment of uncomplicated
infections, and bronchitis by ambulatory care phy-
acute bronchitis in adults. JAMA 1999;281:1512–
sicians. JAMA 1997;278:901–904.
1519.
84
49. Overcoming antimicrobial resistance. World Health 67. Levy SB. Antibiotic resistance: an ecological imbal-
Organization, Geneva, Switzerland 2000. ance. Ciba Found Symp 1997;207:1–9.
50. World Health Organization. Containing antimicro- 68. Postier RG. Antibiotic-resistant organism infection.
bial resistance: review of the literature and report of Am Surg 2000;66:112–116.
a WHO workshop on the development of a global
69. Lipsitch M, Bergstrom CT, Levin BR. The epide-
strategy for the containment of antimicrobial resist-
miology of antibiotic resistance in hospitals: para-
ance. Proceedings of a WHO workshop; 1999 Feb
doxes and prescriptions. PNAS 2000;97:1938–1943.
4–5; Geneva, Switzerland. Geneva, Switzerland:
World Health Organization; 1999. WHO/CDS/ 70. Institute of Medicine. Emerging infections: micro-
CSR/DRS/99.2. bial threats to health in the United States. Washing-
ton, DC: National Academy Press; 1992.
51. Fidler DP. Legal issues associated with antimicro-
bial drug resistance. Emerg Infect Dis 1998;4:169– 71. Wise R et al. Antimicrobial resistance is a major
177. threat to public health. BMJ 1998;317:609–610.
52. Codex Alimentarius. FAD/WHO Standards. Codex 72. Wise R. The development of new antimicrobial
Committee on residues of veterinary drugs in foods. agents. BMJ 1998;317:643–644.
Discussion paper on antimicrobial resistance. Draft-
73. Huovinen P, Cars O. Control of antimicrobial re-
ing group meeting, May 15–16, 2001.
sistance: time for action. The essentials of control
53. Centers for Disease Control and Prevention. Public are already known. BMJ 1998;317:613–614.
health action plan to combat antimicrobial resist-
74. Eandi M, Zara GP. Economic impact of resistance
ance. Atlanta, GA: Centers for Disease Control and
in the community. J Clin Pract 1998;95(Jun
Prevention; draft manuscript; 2000.
Suppl):27–38.
54. Cohen ML. Changing patterns of infectious diseases.
75. Nathwani D, Malek M. Cost considerations in the
Nature 2000;406:762–767.
evaluation of new therapies for Gram-positive
55. Dougherty TJ et al. Antimicrobial resistance-why do bacteria. Int J Antimicrob Agents 1999;13:71–78.
we have it and what can we do about it? Exp Opin
76. Wright GD. Resisting resistance: new chemical strat-
Invest Drugs 2000;9:1707–9.
egies for battling superbugs. Chem Biol 2000;
56. Bjorkman J, Anderson DJ. The cost of antibiotic 7:R127–132.
resistance from a bacterial perspective. Drug Resist-
77. Urassa W, Lyamuya E, Mhalu F. Recent trends on
ance Update 2000;3:327–345.
bacterial resistance to antibiotics. East Afr Med J
57. Mazel D, Davies J. Antibiotic resistance: the big pic- 1997;74:129–133.
ture. Adv Exp Med Biol 1998;456:1–6.
78. Fauci AS. New and reemerging diseases: the impor-
58. Liu HH. Antibiotic resistance in bacteria: a current tance of biomedical research. Emerg Infect Dis
and future problem. Adv Exp Med Biol. 1999; 1998;4:374–378.
455:387–396.
79. Relman DA. Detection and identification of previ-
59. Guillemot D. Antibiotic use in humans and bacte- ously unrecognized microbial pathogens. Emerg
rial resistance. Curr Opin Microbiol 1999;2:494–498. Infect Dis 1998;4:382–389.
60. Barker KF. Antibiotic resistance: a current perspec- 80. Sentry: http://www.ewi.med.uu.nl/enare/sentry_
tive. Br J Clin Pharmacol 1999;48:109–124. antimicrobial_surveillance.html
61. Phillips I. The subtleties of antibiotic resistance. 81. Alexander project : http://www.nearchus.com
J Antimicrob Chemother 1998;42:5–12.
82. NIH funding data; public domain through web
62. Levy SB. Antimicrobial resistance: bacteria on the searching.
defense. Resistance stems from misguided efforts to
83. Parexels Pharmaceutical R&D Statistical Source-
sterilize our environment. BMJ 1998;217:612–613.
book. 2000.
63. Rao GG. Risk factors for the spread of antibiotic-
84. Bax R. Antibiotic resistance: a view from the phar-
resistant bacteria. Drugs 1998;55:323–330.
maceutical industry. Clin Inf Dis 1997;24:S151–
64. Bergogne-Berezin E. Who or what is the source of S153.
antibiotic resistance? J Med Microbiol 1997;46:461–
85. Culotta E. Funding crunch hobbles antibiotic
464.
resistance research. Science 1994;264:362–363.
65. Kumar A. Microbial resistance to drugs—a univer-
86. Walsh C. Molecular mechanisms that confer anti-
sal problem in urgent need of a comprehensive
bacterial drug resistance. Nature 2000;406:775–781.
approach. Natl Med J India 1997;10:221–224.
87. Kessler RE. Perspective on chemotherapeutic
66. Baquero F, Nergi MC. Strategies to minimize the
approaches to antibiotic-resistant bacteria. Clin Inf
development of antibiotic resistance. J Chemother
Dis 1997;24(Suppl 1):S146–S147.
1997;9(suppl3):29–37.
85
88. Kotra LP, Vakuleno S, Mobashery S. From genes to 96. Health, Education, and Human Services Division,
sequences to antibiotics: prospects for future devel- USA General Accounting Office. Antimicrobial
opment of microbial genomics. Microbes Infect resistance: data to assess public health threat from
2000;2:651–658. resistant bacteria are limited. Washington, DC:
USA General Accounting Office; 1999.
89. McKeller QA. Antimicrobial resistance: a veterinary
perspective. Antimicrobials are important for ani- 97. Report of the Jt. Committee on the use of Antibi-
mal welfare but need to be used prudently. BMJ otics in Animal Husbandry and Veterinary Medi-
1998;317:610–611. cine. Chairman Professor M. Swann, Cmnd 4190.
The Stationary Office, London UK, 1969.
90. Mawle AC. Vaccine-preventable diseases. Emerg
Infect Dis 1998;4:404. 98. Greko C. Sweden and the European Union: what
is happening in relation to antibiotics in feed. In:
91. Levy SB. The challenge of antibiotic resistance. Sci
Annual conference proceedings of Australian
Amer 1998;278(3):46–53.
veterinarians in industry and Australian veteri-
92. Advisory Committee on the Microbiological Safety natrians in public health. Proceedings of Austral-
of Food, UK. Report on Microbial Antibiotic ian Veterinarian Association Annual Conference;
Resistance in Relation to Food Safety. London, UK: 2000 June 26–30; Perth, Australia. 2000. p. 18–
The Stationery Office; 1999. 22.
93. Joint Expert Advisory Committee on Antibiotic 99. Bager F, editor. DANMAP99. Danish Zoonosis
Resistance (JETACAR). The use of antibiotics in Centre, Danish Veterinary Laboratory, bulowsvej
food-producing animals: antibiotic resistant bacte- 27 DK-1790 Copenhagen V, Denmark. (http://
ria in animals and humans. Australia: Common- www.svs.dk).
wealth Department of Health and Aged Care,
100. Fey PD et al. Ceftriaxone-resistant Salmonella in-
Commonwealth Department of Agriculture, Fish-
fection acquired by a child from cattle. N Engl J
eries and Forestry; 1999.
Med 2000; Apr 27;342:1242–1249.
94. World Health Organization. WHO global princi-
101. Rosdahl VT, Knudson AM. The decline of methi-
ples for the containment of antimicrobial resistance
cillin resistance among Danish Staphylococcus
in animals intended for food. report of a WHO con-
aureus strains. Infect Control Hosp Epidemiol 1991;
sultation 5–9 June 2000.Geneva, Switzerland.
12:83–88.
WHO/CDS/CSR/APH/2000.4.
102. Thomas M, editor. Guidelines to antibiotic policy.
95. European Commission, Scientific Steering Commit-
Proceedings from a workshop of the World Health
tee. Opinion of the Scientific Steering Committee
Organization in collaboration with the Christian
on antimicrobial resistance. Brussels: European
Medical College; 1998 Jan 22–23; Vellore, India.
Commission, Directorate-General DGXXIV; 1999.
Emppee Graphics;1998.
86
Some useful web sites
■ Alliance for the Prudent Use of Antibiotics

www.apua.org
■ BUBL Catalog of Internet Resources—Infectious Diseases
http://bubl.ac.uk/link/i/infectiousdiseases.htm
■ Canadian Committee on Antibiotic Resistance
http://www.ccar-ccra.org
■ Center for Adaptation Genetics and Drug Resistance
http://www.healthsci.tufts.edu/labs/Sblevy/home.html
■ Center for Complex Infectious Diseases
http://www.ccid.org/
■ Centers for Disease Control and Prevention
www.cdc.gov
■ Eurosurveillance
http://www.eurosurv.org/
■ Global Polio Eradication Initiative
http://www.polioeradication.org
■ National Institute of Allergy and Infectious Diseases
www.niaid.nih.gov/factsheets/antimicro.htm
■ Infectious Disease News
http://www.slackinc.com/general/idn/idnhome.htm
■ Infectious Diseases Society of America
www.journals.uchicago.edu/IDSA/guide/SE39_584.pdf
■ International Society for Infectious Diseases
http://www.isid.org
■ Johns Hopkins University—Infectious Diseases
http://www.hopkins-id.edu/index_id_links. html
■ Karolinska Institut, Sweden
http://micf.mic.ki.se/Diseases/
■ National Foundation for Infectious Diseases, USA
http://www.nfid.org/
■ Project Icare: Intensive Care Antimicrobial Resistance Epidemiology
http://www.sph.emory.edu/ICARE/
■ Roll Back Malaria
http://www.rbm.who.int/
■ TDR (Special Programme for Tropical Disease and Research)
http://www.who.int/tdr
87
■ The Copenhagen Recommendations. http://www.sum.dk/publika/micro98

These recommendations are a report from a conference on “The Microbial Threat,” which promotes
collection of data concerning the supply and sales of antimicrobials from individual nations to be shared
internationally.
■ The Epic Project: Developing National Evidence-Based Guidelines for Preventing Health-care-Associ-
ated Infection.
http://www.epic.tvu.ac.uk/
■ The Hot Zone: Emerging Infectious Diseases Reports and Web Sites
http://www.qis.net/~edwardmc/eid.htm
■ The HELICS project: (Hospitals in Europe Link for Infection Control Through Surveillance).
http://helics.univ-lyon1.fr
■ The MIKSTRA Programme
http://www.stakes.fi/mikstra/e/
■ The Scottish Intercollegiate Guideline Network (SIGN) Guideline on Antibiotic Prophylaxis in Surgery.
http://www.show.scot.nhs.uk/sign/home.htm.
This has national guidelines on antibiotic prophylaxis in surgery which addresses the benefits and risks
involved in using antibiotics to prevent surgical site infections.
■ The Swedish Strategic Program for the Rational Use of Antimicrobial Agents and Surveillance of Resist-
ance
http://www.strama.org
■ UK Public Health Laboratory
http://www.phls.co.uk/
■ UK Public Health Laboratory Service’s Management of Infection Guidance for Primary Care.
http://www.phls.co.uk/advice/antibiotic/old/phls%20antibiotic%20guides%20refs% 2009.01.01.rtf
The guidance template found on the website is designed so that the antibiotics and advice given may be
changed to suit local circumstances, for example to reflect laboratory resistance data and cost.
■ USA National Center for Infectious Diseases
http://www.cdc.gov/ncidod
■ Washington University Infectious Disease Division
http://www.id.wustl.edu/
■ World Health Organization
http://www.who.int/
■ WHO Antimicrobial Resistance InfoBank
http://oms2.b3e.jussieu.fr/arinfobank/
■ WHO Communicable Diseases home page
http://www.who.int/health-topics/idindex.htm
88
APPENDIX A
Summaries of reports by expert policy groups

(1987–2000)
(1) *Task Force Reports on Antibiotic Use • Support for and expansion of WHO’s surveil-
and Resistance Worldwide (Fogarty lance program for the global prevalence of anti-
Report) bacterial resistance.
Organization: National Institutes of Health, Fogarty • Studies on the mechanics of antibiotic resistance
Center on the level of genetic elements, in order to
devise plans on how to contain and reduce re-
Year published: 1987 sistance.
• Research studies on antibacterial regulation that
Selected key findings include the following:
• Antibiotic use varies greatly from country to — Long-term, multicountry studies to deter-
country; surveillance data on antibiotic use, mine whether or not regulation of antibi-
emergence of resistant strains, and availability otic use and the enforcement of such rules
to consumers were difficult or impossible to have any effect on the development of anti-
obtain. biotic resistance.
• Practitioner knowledge, drug availability, and — Studies of the consequences of implement-
drug price are the three key factors that influ- ing restrictive regulations and enforcement,
ence a prescriber’s choice of antibiotics. Where including the need to train health care per-
antibiotics are available without a prescription, sonnel and possible economic impacts.
the same factors influence the choice of the — Studies that specifically examine the effects
consumer. that regulations and enforcement have on
• The task force did not find enough evidence to children.
prove that the implementation of firmer — Investigation of the potential consequences
regulations regarding antibiotic use, or stricter to human health that would arise from
enforcement of or better compliance with such restrictions on antibacterial use in food
regulations, slows the development or spread of production and animal husbandry.
resistance. — Studies that examine how national, regional,
• Medical students in developing countries often and institutional antibiotic use policies in-
receive inadequate training in basic bacteriology, fluence the training and education of physi-
infectious diseases diagnosis, and antimicrobial cians and other health care workers.
use. Theories of antimicrobial therapy are not • Improved communications between the regula-
always integrated with practical experience. tory agencies that govern antibacterial use, and
• There are almost no regulated requirements for the people responsible for prescribing and using
health care providers to continue their educa- such agents.
tion in pharmacological developments beyond • Research studies on antibacterial use in devel-
their formal training. This lack is evident in both oping countries that include the following:
developing and industrialized countries. — Studies that determine the efficacy of
national formulary schemes, including drug
Key recommendations costs, availability, as well as research and de-
• Uniform data-collection systems at the national velopment of new agents.
level. — Studies on the effects that having access to
microbiology laboratory tests has on antibi-
otic prescription and use.
* The number in parenthesis refers to the citation listed in • Redesign of the curricula of medical schools in
References. developing countries to provide more thorough
89
education on diagnosing and managing infec- nomic determinants of antibiotic usage for
tious diseases. particular geographic areas and demographic
• Creation of systems which will disseminate groups.”
information on patterns of antibiotic use and
development of antibiotic resistance to hospital Conclusions
staff. “The importance of social and behavioral charac-
• Research studies on the effects of education and teristics of individuals receiving antimicrobial
information on determining antibiotic use, therapy (as well as the supply and variety of antibi-
including: cultural and social reasons behind otics available) was noted in plenary discussions as
patient demand; the quality of physician educa- influencing courses of antibiotic therapy. Studies
tion on the use of antibiotics, both during the of such variables are needed in order to answer
course of study and after graduation; and the questions related to under- or overutilization of
effects of pharmaceutical marketing campaigns antibiotics.”
on physicians’ prescriptions of antibiotics. “There was the consensus that there is consider-
• Evaluation of current policies on the use of able suboptimal antibiotic use in the developing
antibiotics to determine what effects they have countries, where there is a tendency...for higher lev-
on the pharmaceutical industry’s incentives to els of microbial resistance... The developing nations
research, develop, and market new antibiotics. have environmental conditions, infectious disease
burdens, and associated needs and factors affecting
Implementation suggestions antibiotic use and resistance patterns that differ
• To achieve standardized data on antibiotic use, from those in the developed nations. The partici-
institute “a standard index for measuring drug pants in this project stressed the importance of rec-
use in each country by using the same system of ognizing and addressing these distinctions.”
drug classification, the same unit of measure- “Better data on utilization of antimicrobial
ment (e.g., DDDs/1,000 population per day or agents in the developing world are needed. This
grams/1,000 population per day), and the same would include information from studies on the
point in the distribution channel in each coun- magnitude of inadequate doses resulting in the
try [and] by obtaining access to data of this type failure to achieve bactericidal concentrations, on
that are currently collected by private compa- improper duration of therapy...and on the use of a
nies (i.e., International Medical Statistics) but single capsule or a limited number of capsules...for
are not made publicly available.” cultural, financial, or idiosyncratic reasons (associ-
• WHO, USA Public Health Service, and minis- ated with a transient sense of well-being).”
tries of health in other countries “should sup- “Projects focusing on improving our understand-
port research studies proposed by the task force, ing of the observed correlation between antibiotic
assist countries in establishing or improving their use and subsequent resistance should be carried
systems of drug regulation, facilitate collabora- out... Multiple parameters should be assessed:
tive research among investigators in different microbiologic susceptibility patterns of the organ-
countries, and improve cooperation among regu- isms principally involved; the kinds of diagnostic
latory agencies, physicians and other health tests being performed; demographic patterns and
workers, and drug companies.” associated social and behavioral characteristics;
• Regional and international centers for the study policies affecting antibiotic utilization; and the
of antibiotic resistance should be established in quantity and cost of antibiotics used. Such data
Asia, Africa and Latin America by WHO, NIH, assembled in one system have heretofore not been
and CDC/USA Public Health Service/USA available.”
Department of Health and Human Services, in “What is lacking, and of fundamental impor-
collaboration with ministries of health and other tance, is detailed information on the distribution
relevant agencies. over time of specific antimicrobial resistance genes
• “Establishment of field surveillance teams and plasmids in the global bacterial ecosystem.
located in representative regions in developing Geographic information on individual compo-
nations. Such teams would gather information nents... is needed to trace and understand better
on actual antibiotic use, develop affordable strat- the emerging patterns of such resistance.”
egies for preventing or curing infectious diseases, “Some unified way to follow the incidence and
and determine the social, behavioral, and eco- prevalence of microbial resistance on a global scale
90
is required; however, it is not yet clear how best to R. Lee, Alan H. Linton, Helen Levens Lipton, Robert
proceed... It is, therefore, recommended that a H. Liss, Hubert Loncin, Per Knut Lunde, Edgar J.
workshop be convened to help elucidate the direc- Martin, R. Russel Martin, Ramiro Martines-Silva,
tion in which future surveillance studies should Charles Medawar, Dianna Melrose, Arnold S. Monto,
proceed, as well as to work out the details of a uni- Stuart L. Nightingale, Richard Norton, Thomas F.
form methodology for collection and comparison O’Brien, Ronald W. O’Connor, Makoto Ohashi, Jorge
of data.” Olarte, Nancy Olins, Peng Wen Wei, Maria Eugenia
“Fundamental studies at the cellular level con- Pinto, Philip A. Pizzo, Richard J. Plumridge, Wayne
cerning the cell’s impressive capacity over time to Ray, J.P Revill, Ahmed Rhazaoui, Frederick C.
defend itself against foreign agents should be sup- Robbins, O.P.W. Robinson, Heonir Rocha, Vidal
ported and extended, particularly studies involv- Rodriguez-Lemoine, Bernard Rowe, T. Donald
ing genetics and mechanisms for gene amplification Rucker, Theodore Sacks, Jay P. Sanford, William
and gene exchange leading to multidrug resistance.” Schaffner, William E. Scheckler, Roy Shaffer, K.B.
“New diagnostic tools, simplified, appropriate, Sharma, Richard P. Silver, Harold J. Simon, Ewe Hui
and more accurate and sensitive than tests currently Sng, Stephen B. Soumerai, Visanu Thamlikitkul, John
available, are coming into use. The utilization of F. Timoney, A. Tognoni, Luiz R. Trabulsi, Themlma
these newer techniques at the central surveillance Tupasi, John R. Virts, V. Vymola, Craig K. Wallace
level needs to be encouraged. These central surveil- (Guest Editor), Wang Fu, Bernd Wiedemann, Sidney
lance systems, particularly those focusing on Wolfe
selected and important infectious disease in the
developing nations...and on specific etiology agents Type of publication: Supplement to Reviews of Infec-
...should be expanded.” tious Diseases; Volume 9, Supplement 3, May–June
“Vaccine development and newer, more rapid 1987
diagnostic tests should provide additional means
Pages: 89
to combat the problem. Economic conditions and
a climate favorable for the continued progress and Intended audience: International; policy-makers, gov-
expansion of medical therapeutics, as well as the ernment, health care providers
widespread utilization of new antimicrobial agents, Study timeframe: The Task Forces met between fall
remain important factors in considering antibiotic of 1983 and spring of 1986.
use and antibiotic resistance worldwide.”
Study process: Six task forces were assembled, com-
Authors: Task Force participants: Stuart B. Levy (Gen- prised of representatives from different disciplines
eral Chairperson and Guest Editor), Jacques F. Acar, and countries. Each Task Force focused on a dif-
Gianni Acocella, Jerry Avorn, Ingebjorg Baksaas, ferent aspect of antibiotic resistance; they developed
Fernando Baquero, Gilles Bardelay, F. Ralph Batchelor, their sections of the report over a year and a half of
Karen Bell, Ulf Bergman, Enriquetta Bond, Kenneth meetings and revisions.
Bridbord, James J. Burchall, John P. Burke (Guest Type of organization: Professional society
Editor), Felipe C. Cabello, Charles C.J. Carpenter III,
Languages (published in): English
Georges Y. Causse, Leighton E. Cluff, Mitchell Cohen,
Nananda F. Col, John V. Copeland, George Curlin,
Key contact
Joseph T. Curti, I. Damansjah, F. Daschner, Irving P.
Ordering information: International Studies
Delappe, M.N.G. Dukes, John M. Eisenberg, Tamara
Branch, Fogarty International Center, Bethesda,
Erickson, Enrique Feffer, Susan E. Feinman, Peter I.
MD 20892
Folb, Ernst Freese, Ryochi Fujii, Aleksander Goic, Julio
Content: Stuart Levy, General Chairperson for the
Gonzales-Molina, Joseph E. Grady, Richard L.
Task Force
Guerrant, Richard Gustafson, Ken Harvey, Andrew
Herxheimer, Scott D. Holmberg, M. Imdadul Huq,
Hu Zhen, N. Islam, John E. Jefferis, Amir Jivani, Bengt
Jönsson, William S. Jordan, Jr., Edward H. Kass,
Dianne Kennedy, Thomas Kereselidze, H.H.
Kleeberg, Dieter Koch-Weser, Goran Kronvall, Calvin
M. Kunin, Yankel M. Kupersztoch, Louis Lasagna,
Norman W. Lavy, Donald Le Blanc, David Lee, Philip
91
(2) Healthy People 2000: National Health prevention of these diseases; and for research to
Promotion and Disease Prevention. Full improve immunizations, diagnostic methods, and
report, with commentary therapeutic modalities.”
Organization: Public Health Service; USA Depart- Authors: Principal staff/editors: James A. Herrell, Lynn
ment of Health and Human Services M. Artz, Ashley Files, David Baker. Project Coordination
Year published: 1990 and Development: Barbara Anderson, John Bailar, Am-
ber Barnato, Sandra Buesking, Mary Jo Deering,
Selected key findings Christopher DeGraw, Olga Emgushov, Martha G.
• Patients in hospital Intensive Care Units account Grazier, Toni M. Goodwin, Linda M. Harris, Doug-
for about 15% of hospital admissions, but at las B. Kamero, Thomas Kim, Loretta M. Logan,
least 50% of nosocomial infections (data from Patricia Lynch, Caroline McNeil, Linda D. Meyers,
1990). Diane Rittenhouse, Marilyn K. Schulenberg, Sara L.
• Approximately 40,000 people die each year from White, Jennifer Woods, Christina Wypijewski,
complications arising from pneumococcal Michael Yao, Daniel Yarano
disease. Type of publication: Report
Key recommendations Pages: 692

By the year 2000: Intended audience: United States; citizens, policy-
• “Reduce by at least 10 % the incidence of surgi- makers
cal wound infections and nosocomial infections
Study timeframe: N/A
in intensive care patients;
• Reduce acute middle ear infections among chil- Study process: The report is the result of a collabora-
dren aged 4 and younger, as measured by days tion of 22 expert working groups, a consortium
of restricted activity or school absenteeism, to including almost 300 national organizations and
no more than 105 days per 100 children; all state health departments, and the Institute of
• Increase to at least 90 % the proportion of pub- Medicine of the National Academy of Sciences. The
lic health departments that provide adult IOM and the USA Public Health Service held
immunization for influenza, pneumococcal regional and national hearings and gathered testi-
disease, hepatitis B, tetanus, and diphtheria; mony from over 750 individuals and organizations.
• Develop a set of health status indicators appro- More than 10,000 people participated in the pub-
priate for Federal, State, and local health agencies lic review, after which the objectives were revised
and establish use of the set in at least 40 states.” and refined.
Type of organization: United States Federal Govern-
Implementation suggestions
ment
Reduction of nosocomial infections to be achieved
through collaboration of hospital epidemiologists, Languages (published in): English
infection control practitioners, the Association of Key contact
Practitioners in Infection Control, Society of Hos- Ordering Information: Superintendent of Docu-
pital Epidemiologists of America, Surgical Infec- ments, Government Printing Office, Washington,
tion Society, American Hospital Association, Joint DC 20402-9325; tel.: (202) 783-3238; fax:
Commission on the Accreditation of Health Care (202)275-0019.
Organizations, and the Health Care Financing
Administration.
(3) Emerging Infections: Microbial Threats
Conclusions/Executive Summary
to Health in the United States
“In addition to application of specific measures, Organization: Institute of Medicine
such as immunization and regulation of food,
Year published: 1992
water, and sewage disposal, there is a need for con-
tinued public education about basic hygienic
Selected key findings
practices, in home, school, and occupational set-
The Committee focused on factors that contribute
tings; for continued education of health care
to the emergence and re-emergence of infectious
students and workers about the epidemiology and
diseases, including:
92
• Human demographics and behavior. Contribut- — Strive to make NNISS member hospitals
ing factors are movement of the ever-growing more representative of all USA hospitals.
global population into urban areas, with corre- — Evaluate the sensitivity and specificity of
sponding crowded conditions, poor hygiene and nosocomial infection surveillance activities
sanitation, and lack of clean water supplies; in- performed in NNISS member hospitals.
creasing numbers of people with suppressed — Determine the reliability of antimicrobial
immune systems, including the elderly and susceptibility testing performed in NNISS
people infected with HIV; and the transmission member hospitals.”
of disease through sexual activity and substance • “The committee recommends that the USA
abuse. Public Health Service develop a comprehensive,
• Technology and industry. Hospitals are increas- computerized infectious disease database.”
ingly implicated as sources of infection; many • “The committee recommends that international
nosocomial infections have developed resistance infectious disease surveillance activities of USA
to antibiotics thanks to the combination of a government agencies be coordinated by the
population very susceptible to infection, and the Centers for Disease Control (CDC). Alterna-
widespread therapeutic and prophylactic use of tively, a federal coordinating body could be
antibiotics. assigned the coordinating function. Implemen-
• Microbial adaptation and change. The evolution- tation of surveillance activities, however, should
ary mechanisms of microbial pathogens allow remain with the appropriate federal agencies
them to adapt to new host cells or host species, (e.g., the CDC, Department of Defense,
produce “new” toxins, bypass or suppress inflam- National Institutions of Health, USA Depart-
matory and immune responses, and develop ment of Agriculture).”
resistance to drugs and antibodies. • “The committee recommends that the United
• Breakdown of public health measures. Inadequate States take the lead in promoting the develop-
sanitation, complacency on the part of medical ment and implementation of a comprehensive
officials, physicians, researchers and other pub- global infectious disease surveillance system.
lic health workers, war, economic hardship, and Such an effort could be undertaken through the
natural disasters may all undermine any progress USA representatives to the World Health
made by advances in science and technology. Assembly.”
• “The committee recommends the expansion and
Key recommendations coordination of National Institutes of Health-
• “The committee recommends the development supported research on the agent, host, vector,
and implementation of strategies that would and environmental factors that lead to emer-
strengthen state and federal efforts in USA sur- gence of infectious diseases. Such research should
veillance. Strategy development could be a func- include studies on the agents and their biology,
tion of the Centers for Disease Control (CDC). pathogenesis, and evolution; vectors and their
Alternatively, the strategy development and co- control; vaccines; and antimicrobial drugs. One
ordination functions could be assigned to a fed- approach might be to issue a request for pro-
eral coordinating body (e.g., a subcommittee of posals (RFP) to address specific factors related
the Federal Coordinating Council for Science, to infectious disease emergence.”
Engineering, and Technology’s Committee on • “The committee recommends increased research
Life Sciences and Health), specifically consti- on surveillance methods and applied control
tuted to address this issue.” strategies; on the costs and benefits of preven-
• “The committee recommends that additional tion, control, and treatment of infectious dis-
resources be allocated to the to the Centers for ease; and on the development and evaluation of
Disease Control to enhance the National Noso- diagnostic tests for infectious diseases. Reinstat-
comial Infections Surveillance System in the ing and expanding (both in size and scope) the
following ways: extramural grant program at the Centers for
— Include data on antiviral drug resistance. Disease Control, which ceased in 1973, would
— Include information on morbidity and mor- be one important step in this direction. Simi-
tality from nosocomial infections. larly, the Food and Drug Administration’s (FDA)
— Increase the number of NNISS member extramural grant program should be expanded
hospitals. to place greater emphasis on the development
93
of improved laboratory tests for detecting emerg- break, and estimate the magnitude of the problem.
ing pathogens in food.” It can also help to describe the natural history of a
• “The committee recommends the domestic and disease, identify factors responsible for emergence,
global expansion of the CDC’s Epidemic Intel- facilitate laboratory and epidemiological research,
ligence Service program and continued support and assess the success of specific intervention ef-
for Centers for Disease Control’s (CDC) role in forts. The importance of surveillance to the detec-
the Field Epidemiology Training Program.” tion and control of emerging microbial threats
• “The committee recommends continued cannot be overemphasized. Effective intervention
support, at a minimum at their current level of against [emerging] diseases necessitates coordinated
funding, of Department of Defense overseas in- efforts by a variety of individuals, government agen-
fectious disease laboratories.” cies, and private organizations. The committee
• “The committee recommends that Congress believes that the current USA capability for re-
consider legislation to fund a program, modeled sponding to microbial threats to health lacks
on the National Health Service Corps, for train- organization and resources. Vaccines and antimi-
ing in public health and related disciplines, such crobial drugs have led to significant improvements
as epidemiology, infectious diseases, and medi- in public health in the United States and in many
cal entomology.” other nations during the latter half of this century.
• “The committee recommends that clinicians, the Despite this encouraging history, the committee is
research and development community, and the concerned that many of the vaccines and drugs
USA government introduce measures to ensure available today are the same ones that have been
the availability and usefulness of antimicrobials used for decades. It believes that there is a need to
and to prevent the emergence of resistance. These review the present vaccine and drug armamentaria
measures should include the education of health with a view toward improving availability and
care personnel, veterinarians, and users in the capacity, as well as safety and efficacy.”
agricultural sector regarding the importance of
Authors: Edited by: Joshua Lederberg, Robert E. Shope,
rational use of antimicrobials (to preclude their
and Barry R. Bloom. Task Force Members: Robert L.
unwarranted use), a peer review process to moni-
Buchanan, John R. David, Ciro A. De Quadros,
tor the use of antimicrobials, and surveillance
Patricia N. Fultz, John J. Holland, Dean T. Jamison,
of newly resistant organisms. Where required,
Edwin D. Kilbourne, Adel A.F. Mahmoud, Gerald
there should be a commitment to publicly
L. Mandell, Stephen S. Morse, June E. Osborn,
financed rapid development and expedited
William C. Reeves, Philip K. Russell, Alexis Shelokov,
approval of new antimicrobials.”
P. Frederick Sparling, Andrew Spielman. Project Staff:
• “The committee recommends that the National
Ruth Ellen Bulger, Polly F. Harrison, Stanley C. Oaks,
Institutes of Health give increased priority to
Jr., Elizabeth E. Meyer, Nancy Diener, Greg W.
research on personal and community health
Pearson.
practices relevant to disease transmission. Atten-
tion should also be focused on developing more Type of publication: Report
effective ways to use education to enhance the Pages: 294
health-promoting behavior of diverse target
groups.” Intended audience: Primarily the United States; policy-
makers, lay public, government, scientists, physi-
Implementation suggestions cians
Responsibilities delegated to various government Study timeframe: February 1991 to July 1992
agencies and departments of the United States,
Study process: 19-member multidisciplinary commit-
primarily CDC and NIH.
tee convened to identify significant emerging in-
fectious diseases, develop plans on how to deal with
them, and make recommendations on how to
“The key to recognizing new or emerging infec-
approach similar threats in the future. The full com-
tious diseases, and to tracking the prevalence of
mittee met four times during the 18-month study.
more established ones, is surveillance. A well-
Four task forces and subcommittees also formed
designed, well-implemented surveillance program
according to specialties, and met to address more
can detect unusual clusters of disease, document
specific topics.
the geographic and demographic spread of an out-
94
Type of organization: Non-profit public health and tification to ensure early detection of antimicro-
advisory organization; advisor to Federal Govern- bial resistance;
ment on issues of public health • Strengthen and integrate programs to monitor
and prevent emerging infections associated with
food/water, new technology, and environmen-
Key contact tal forces;
Ordering information: National Academy Press, • Strengthen and integrate programs to monitor,
www.nap.edu control, and prevent emerging vector-borne and
Content: Joshua Lederberg and Robert E. Shope, zoonotic diseases;
Committee Co-chairs • Expand epidemiologic and prevention effective-
ness research;
(4) Addressing Emerging Infectious • Improve laboratory and epidemiologic tech-
Disease Threats.A Prevention Strategy niques for the rapid identification of new patho-
for the United States gens and syndromes;
• Ensure timely development, appropriate use, and
Organization: Centers for Disease Control and Pre-
availability of diagnostic tests and reagents;
vention; National Center for Infectious Diseases
• Use diverse communication methods for wider
Year published: 1994 and more effective delivery of critical public
health messages;
Selected key findings • Establish the mechanisms and partnerships needed
Surveillance is the key to tracking the development to ensure the rapid and effective development and
and spread of infectious diseases, reservoirs of dis- implementation of prevention measures;
ease, and antimicrobial drug resistance. • Ensure the ready availability of the professional
One weakness in the United States’ strategy to expertise and support personnel needed to bet-
control infectious diseases is the lack of multi- ter understand, monitor, and control emerging
disciplinary approaches. The USA needs stronger infections;
connections between laboratory science and pub- • Make available state-of-the-art physical resources
lic health practices, as well as economic analyses of (laboratory space, training facilities, equipment)
the impacts of both infectious diseases and the in- needed to safely and effectively support the
terventions proposed to stop them. preceding goals and objectives.”
Most federal government funds dedicated to
surveillance of infectious diseases at the state level Implementation suggestions
go towards only four categories of disease: tuber- “Between 1994 and 1996, CDC intended to im-
culosis, HIV/AIDS, sexually transmitted diseases, plement its recommendations by establishing
and certain vaccine-preventable diseases. This leaves priority goals in the four areas of Surveillance,
a large number of other emerging infectious dis- Applied Research, Prevention and Control, and
eases under-funded and under-observed. Infrastructure. They include the following:
The current approach to public health in the • Strengthen notifiable disease surveillance at the
United States (i.e., the focus on treatment rather state and local levels;
than prevention; reactive rather than proactive poli- • Establish two physician-based Sentinel Surveil-
cies; and general complacency) leads to the emer- lance Networks to detect and monitor emerg-
gence and spread of infectious diseases that ought ing diseases;
to be preventable. • Establish four population-based Emerging In-
fections Epidemiology and Prevention Centers
Key recommendations to conduct focused epidemiology/prevention
• “Expand and coordinate surveillance systems for projects emphasizing foodborne and waterborne
the early detection, tracking, and evaluation of infectious diseases and potentially vaccine pre-
emerging infections in the United States; ventable diseases;
• Develop more effective international surveillance • Strengthen and link four existing sites for a
networks for the anticipation, recognition, global consortium to promote the detection,
control, and prevention of emerging infectious monitoring, and investigation of infections
diseases; emerging internationally that could affect the
• Improve surveillance and rapid laboratory iden- health of Americans;
95
• Reestablish an extramural program to support tions; private industry; and international partners,
emerging infectious disease prevention and including WHO and international service organi-
control activities, such as evaluating the role of zations and foundations. Each of these partners will
prescribing practices in the development of play an integral role in the cooperative efforts re-
antimicrobial drug-resistant pathogens; quired to safeguard the public’s health from emerg-
• Initiate prevention effectiveness studies to assess ing infectious disease threats.”
the impact of food preparation guidelines on the
Authors: Emerging Infections Working Group:
incidence of foodborne infections such as E. coli
Ralph T. Bryan, M.D., Robert W. Pinner, M.D.,
O157:H7 and Salmonella enteritidis;
Robert P. Gaynes, M.D., C.J. Peters, M.D.,
• Develop additional means to deliver laboratory
Meredith A. Hickson, M.P.H., Judith R. Aguilar
and public health information informing health
professionals about emerging infections and Type of publication: Report
antimicrobial drug resistance; Pages: 46
• Develop and implement guidelines for the
prevention of opportunistic infections in Study timeframe: The Advisory Committee consid-
immunosuppressed persons; ered scientific literature from 1976 to 1993.
• Provide state-of-the-art training in diagnostic Study process: The plan was developed by the CDC
evaluation and testing for medical laboratory in partnership with representatives from state and
personnel to ensure the diagnosis and surveil- local public health organizations, other federal agen-
lance of emerging infection; cies, health care professionals, members of medical
• Establish a public health laboratory fellowship and public health professional associations, infec-
in infectious diseases that will train medical tious disease experts, and public service organiza-
microbiologists in public health approaches to tions. Committee members met several times to
diagnosis and molecular epidemiology.” discuss the plan and gather additional input
between December 1992 and June 1993.
Conclusions
Type of organization: Federal Government
“As the United States moves towards comprehen-
sive health care reform, it is crucial that emerging Intended audience: United States; physicians and other
infectious disease threats be addressed and that the health care providers, policy-makers
basic tenets of prevention-oriented public health
policy form an internal component of plans for
health care reform. Key contact
Strengthened efforts in the prevention and con- Ordering Information: Centers for Disease Con-
trol of emerging infectious diseases will comple- trol and Prevention, National Center for Infectious
ment and improve the effectiveness of current Diseases, Office of Program Resources EP, Mailstop
efforts in HIV/AIDS, TB, STDs, and immuniza- C-14, 1600 Clifton Road, Atlanta, GA 30333
tions as well as other important infectious diseases.
To provide the vigilance and rapid response required (5) WHO Scientific Working Group on
to effectively address emerging infectious diseases, Monitoring and Management of
significant improvements in public health policy, Bacterial Resistance to Antimicrobial
program design, and infrastructure are needed. A Agents
far-reaching and comprehensive strategy, carefully
Organization: World Health Organization, Division
integrated with broader plans for health care re-
of Bacterial, Viral Diseases and Immunology.
form is required.
Effective public health policy results from in- Year published: 1994
teraction, cooperation, and coordination among a
wide range of public and private organizations and Selected key findings
individuals. Particularly critical to this process are • There is a lack of data on the economic conse-
CDC’s partnerships with state and territorial health quences of antibiotic resistance and of commu-
departments; other federal agencies; professional nity-acquired infections.
organizations; academic institutions; private health • It may be useful to reconsider older alternatives
care providers; health maintenance organizations to antibiotics, including bacterial interference,
and health alliances; local community organiza- serum therapy, and bacteriophages.
96
• The approach of the pharmaceutical industry to personnel; and linkage between hospital infec-
the development and spread of antimicrobial tion control programs to quality assurance
resistance includes: continued chemical modifi- efforts at the national and local levels.
cation of existing agent classes; interference with • Transmission of resistant organisms in the com-
resistance mechanisms to increase target access; munity would be decreased through promotion
and searching for agents with novel mechanisms of community hygiene standards for safe water
of action. and food and support of programs for improved
access to treatment.
Key recommendations • The emergence and spread of resistant organ-
Recommendations for WHO: isms in veterinary medicine and the environment
• “Communicate the importance of the problem would be decreased by ensuring that only quali-
of antimicrobial resistance to developed and fied veterinary personnel be permitted to pre-
developing countries and other international scribe antimicrobial agents for the treatment of
health agencies; infections in animals; prohibiting the use of
• Improve systems for surveillance of antimicro- antimicrobial agents for growth promotion that
bial resistance; are also used in human medicine; and by dis-
• Develop recommendations to improve clinical couraging “the unnecessary use of therapeutic
use of antimicrobial agents and decrease selec- antimicrobials for prophylaxis in food animals.”
tion of resistant bacteria;
• Develop strategies to decrease the selection and Conclusions/Executive Summary
transmission of resistant microorganisms in “Antimicrobial resistance represents a crisis at the
medical centers; present time. It stems from a wide range of prob-
• Develop strategies to decrease transmission of lems, but there are a number of key factors. A
resistant microorganisms in the community and primary one is the heavy usage of antimicrobial
plans for responding to outbreaks of bacterial agents. The intense selective pressure resulting from
pathogens; antimicrobial overuse has been an important
• Develop strategies to decrease the emergence and factor in the rapid emergence of resistance. The dis-
dissemination of resistant organisms in veteri- semination of resistant strains in hospitals and other
nary medicine and the environment; institutional settings is largely attributable to
• Support the development and evaluation of new person-to-person transmission, due to the incon-
preventive and curative modalities.” sistent application of basic infection control tech-
niques and treatment of patients not guided by
Implementation suggestions susceptibility testing. Meanwhile, environmental
• Communication would be improved through contamination with antimicrobial-resistant patho-
distribution of newsletters and bulletins (i.e., gens adds another dimension to the problem of
Weekly Epidemiological Record, WHO Drug prevention and control. In addition, in some coun-
Information Bulletin); facilitation of interaction tries, availability of antimicrobial agents without
among government agencies, academic institu- prescription is a major factor in their misuse. Else-
tions and the pharmaceutical industry; and data where, the use of antimicrobial agents in animal
sharing and surveillance system linkage. husbandry, particularly for growth promotion and
• Improvement of surveillance systems would be prophylaxis of infection, provides an additional
achieved by helping national laboratories to selective pressure which encourages the emergence
determine their current status and needs to suc- of drug-resistant organisms. Addressing the many
cessfully identify bacterial pathogens and test challenges posed by emerging antimicrobial resist-
them for susceptibility; distribute and help to ance requires a strategy at institutional, commu-
install WHONET software in laboratories; help nity, regional, national, and international levels.
laboratories to develop quality control and Partners in the development and implementation
assurance programs. of such a strategy should include representatives
• Reduction of antibacterial resistance in medical from clinical and veterinary medicine, public
centers would be achieved by developing edu- health, microbiology, animal husbandry, the phar-
cational programs and hygienic standards in maceutical, agriculture and aquaculture industries,
daycare centers and long-term care facilities; in- as well as the behavioral sciences.”
fection control training programs for hospital
97
Authors: Participants: Dr. Y.Z. Abou, Dr. J.F. Acar, Dr. (6) Impacts of Antibiotic-Resistant
G.A.J. Ayliffe, Dr. N. Citri, Dr. B. Cookson, Dr. Wang Bacteria
Fu, Dr. D.A. Goldmann, Dr. D. Grossklaus, Dr. M. Organization: Office of Technology Assessment; Con-
Guzman, Dr. R.E.W. Hancock, Dr. R. Helmuth, Dr. gress of the United States
P. Huovinen, Dr. J.M. Hughes, Dr. W. Johnson, Dr.
E.L. Kaplan, Dr. T.S. Kereselidze, Dr. P. Kriz, Dr. G. Year published: 1995
Kronvall, Dr. A. Kucers, Dr. M.K. Lalitha, Dr. R.
Leclercq, Dr. B. Levin, Dr. I. Lind, Dr. A. Marton, Selected key findings
Dr. A. Medeiros, Dr. G.H. Miller, Dr. T.F. O’Brien, • Inappropriate antibiotic use contributes to the
Dr. G. Orefici, Dr. K. Rahal, Dr. B. Tasmussen, Dr. increase of selection pressure for the selection
B. Rowe, Dr. R. Bradley Sack, Dr. J. Schindler, Dr. and spread of antibiotic resistance. It is possible
N.A. Semina, Dr. J. Stelling, Dr. F. Tenover, Dr. A. that as much as 50% of antibiotic use is inap-
Tomasz. Observers: Dr. R. Bax, Dr. D.H. Bouanchaud, propriate.
Dr. E. Bozkurg, Dr. I. Carugo, Dr. R. Charnas, Ms. • Although only one-third to one-half of the 24.5
M. Cone, Dr. H. Dekoning-Gans, Dr. R. Kessler, Dr. million otitis media cases that occur each year
C. Krasemann, Dr. H. Locher, Dr. J.S. Mantell, Dr. benefit from antibiotics, physicians often pre-
O. Morin, Dr. G. Mosely, Dr. D. Pontani, Dr. A. scribe them. Parental pressure and time con-
Roos, Dr. C.D. Rothermel. WHO Secretariat: Dr. M. straints that keep physicians from testing for viral
Couper, Dr. D. Cohn, Dr. Svein-Erik Ekeid, Dr. sources of the disease are common reasons for
M.M. El-Nageh, Mrs. K. Esteves, Dr. E. Griffiths, resorting to potentially ineffective antibiotic
Dr. C.-C. Heuck, Dr. J.W. LeDuc, Dr. L.J. Martinex, prescriptions.
Dr. N. Pearce, Dr. A. Pio, Dr. J. Perriens, Dr. M. • At any given time, 25% to 35% of all hospital-
Raviglione, Dr. K.B. Sharma, Dr. Hulian Sima, Dr. ized patients are receiving antibiotic treatment,
A. Sow, Dr. K. Tankari, Dr. E. Tikhomirov, Dr. G. whether therapeutic or prophylactic. The result
Torrigiani, Dr. P.I. Trigg of such heavy use among a very vulnerable popu-
lation often leads to the emergence and spread
Type of publication: Meeting report of antibiotic-resistant bacteria.
Pages: 33
Key recommendations
Intended audience: Global; policy-makers, pharma-
(The Advisory Board presents options, rather than
ceutical industry, health care providers
direct recommendations)
Study timeframe: The working group met from
Surveillance
November 29 to December 2, 1994.
• “Congress could support the establishment of a
Study process: The working group, comprised of national surveillance system, including provid-
professionals from the fields of clinical medicine, ing funding. The features of current, limited
research and public health, met to review the cur- systems can be incorporated and combined to
rent status of the nature and consequences of anti- produce a system of desired size, complexity, and
microbial resistance, and to make recommendations cost. Any system must have a strong advisory
on alleviating the problem. group that includes diagnostic laboratory and
computer experts, clinicians, hospital adminis-
Type of organization: International, non-governmen-
trators, pharmaceutical company researchers,
tal, public health agency
academic scientists, and federal and state regu-
Languages (published in): English latory and health officials.”
Key contact Infection control
Ordering Information: Communicable Disease • “Congress could encourage all states to adopt
Surveillance and Response Documents, World guidelines for the coordination of infection con-
Health Organization, CH-1211 Geneva 27, Swit- trol measures between acute care and long-term
zerland; fax: +41 22 791 4198, attention CSR care facilities and to extend guidelines to include
Documents; email: csr@who.ch, attention Docu- all antibiotic-resistant bacteria.”
ments.
Research funding
• “Congress can make money available for studies
of the development, transfer, and persistence of
98
antibiotic resistance [and] for research into the 1) prolonging the effectiveness of currently avail-
basic biology of bacteria; able antibiotics through infection control and op-
• Congress can make resources available for the timal use of existing antibiotics and 2) developing
study of appropriate use of devices that present new antibiotics to treat resistant bacteria.”
infection risks to hospitalized patients.” “Although all persons are susceptible to illnesses
related to antibiotic-resistant bacteria, some are more
Controlling antibiotic use
than others. The poor, people without adequate
• “Review Medicare and Medicaid reimbursement
health care, the incarcerated, the homeless, mili-
policies for their unanticipated effects on anti-
tary personnel, children in daycare facilities, the
biotic prescription patterns.”
elderly, and the immuno-suppressed are more sus-
Antibiotics in animal husbandry ceptible to these illnesses than the general popula-
• “Collect information about associations between tion. However, because most of the general public
animal husbandry uses of antibiotics and anti- comes in contact with members of these vulner-
biotic-resistant bacteria in humans; able populations daily, the general public is at risk
• Design a study to determine the sources of anti- because the diseases or illnesses can spread from
biotic-resistant bacteria in the human diet; person to person... Therefore, it is crucial that the
• Study the benefits of antibiotic use in animal scientific and medical communities, the pharma-
husbandry. An analysis of written information ceutical industry, and the general public cooperate
could probably determine the costs of the anti- to find solutions that will slow the pace of antibi-
biotics in feeds.” otic resistance and lessen the impact of illness on
Negotiated marketing agreements for antibiotics: public health.”
• “Congress can provide FDA with authority to Authors: Advisory Panel: Gail Cassell, PhD; Anne
negotiate extended market exclusivity to manu- Bolmstrom; Robert J. Bywater, PhD; Barry Eisenstein,
facturers that agree to restrictions on marketing MD; Prabhavathi B. Fernandes, PhD; Winston
of antibiotics.” Frederick, MD; Joshua Lederberg, PhD; Stephen
Development of off-patent compounds as antibiotics Lerner, MD; Stuart Levy, MD; Robert C. Moellering,
• “Congress could authorize FDA to extend Jr., MD; Barbara Murray, MD; Tom O’Brien, MD;
market exclusivity for off-patent antibiotics that Lone Simonsen, PhD; Harry Taber, PhD; Alexander
are shown to be effective against antibiotic- Tomasz, PhD; Richard Wenzel, MD, MSc; Craig
resistant bacteria; Townsend, PhD; Michael Zasloff, MD, PhD
• Congress could establish a federal program to con- Type of publication: Report
duct clinical trials of antibiotics to determine if they
Pages: 183
have uses against antibiotic-resistant bacteria.”
Intended audience: United States; policy-makers,
Implementation suggestions health care providers
The Advisory Panel suggested delegation of respon-
Study timeframe: The Advisory Panel reviewed the
sibilities to various government agencies and de-
scientific literature from 1961 to 1995, with a few
partments of the United States. Increased funding
references from the late 1930s and 1940s.
for the creation of surveillance systems and infec-
tion control guidelines, and for research and devel- Study process: The Advisory panel reviewed scien-
opment would come from Congress. FDA would tific literature, explored biological mechanisms
be responsible for facilitating the development of behind antibiotic resistance, and researched new
new antibiotics, and for helping to determine the antibiotics.
future uses of antibiotics in food animals and plants. Type of organization: Federal Government
Internal hospital surveillance systems should con-
tinue, and should be linked to other hospitals within Languages (published in): English
a geographical area, with the eventual goal of a na- Key contact
tion-wide system overseen by CDC. Ordering information: USA Government Printing
Office, Superintendent of Documents, Mail Stop:
Conclusions/Executive Summary SSOP, Washington, DC 20402-9328
“The problems caused by antibiotic-resistant bac-
teria can be ameliorated through two major routes:
99
(7) Infectious Disease: A Global Health • Rebuilding the USA infectious disease surveil-
Threat lance public health infrastructure at the local,
Organization: National Science and Technology state, and federal levels;
Council; Committee on International Science, • Working with the private and public sectors to
Engineering, and Technology Policy (CISET) improve USA capacity for the emergency pro-
duction of diagnostic tests, drugs, and vaccines;
Year published: 1995 • Strengthening technical training programs in
disciplines related to infectious disease surveil-
Selected key findings lance and response;
• The re-emergence of infectious diseases may be • Establishing an Interagency Task Force to coor-
linked to human behavior (increased travel and dinate the implementation of these recommen-
trade across borders, shifts in population dations;
demographics, the poor quality of public health • Establishing a private sector subcommittee of the
infrastructures) and ecological changes (climate Interagency Task Force that includes representa-
and weather changes, evolution of microorgan- tives of the USA pharmaceutical industry, medi-
isms, disruption of ecosystems due to human cal practitioners and educators, and biomedical
use patterns). scientists.
• The cost of treating antibiotic-resistant bacte-
rial infections in the United States was $4 bil- Implementation suggestions
lion in 1994, and projected to increase. The committee recommends giving greater author-
• The USA response to reports of outbreaks of ity to certain government agencies and departments
infectious disease is often informal, loosely co- to monitor and respond to disease outbreaks. To
ordinated among government agencies, and this end, it recommends the convening of an
hampered by a lack of funding to conduct a com- Interagency Task Force, consisting of Centers for
plete investigation. Disease Control and Prevention, Food and Drug
Administration, National Institutes of Health, the
Key recommendations Department of State, Department of Defense, and
Work in partnership with other countries, with USA Agency for International Development, and
WHO, and with other international organizations others as necessary.
to improve worldwide disease surveillance, report-
ing, and response by: Conclusions
• Establishing regional disease surveillance and The elements of a global network for disease sur-
response networks linking national health min- veillance already exist but need to be strengthened,
istries, WHO regional offices, USA Government linked, and coordinated. For instance, many USA
laboratories and field stations abroad, foreign Government department and agencies maintain or
laboratories and medical centers, and WHO col- support field stations and laboratories in Africa,
laborating centers; Asia, and the Americas that may be electronically
• Ensuring that reliable lines of communication linked to provide an initial framework for a net-
exist between local and national medical centers work for global infectious disease reporting. In part-
and between national and regional or interna- nership with other countries and with WHO, this
tional reference facilities, especially in parts of skeletal surveillance network could be expanded
the world where modern communications are over time to include many international resources,
lacking; including national health ministries, WHO
• Developing a global alert system whereby na- Collaborating Centers, hospitals, and laboratories
tional governments can inform appropriate operated by other nations, and American and for-
worldwide health authorities of outbreaks of in- eign private voluntary organizations.
fectious disease in a timely manner.
Authors: Report generated by members of CISET
Strengthen the USA capacity to combat emerg- and its working group comprised of members from
ing infectious diseases by: 28 government agencies and departments
• Enhancing collaborations among USA agencies
to ensure maximum use of existing resources for Type of publication: Report
domestic and international surveillance and re- Pages: 56
sponse activities;
100
Intended audience: United States; policy-makers [Minimal Inhibitory Concentration]. There

is also a need to monitor food sources such
Study timeframe: Working group convened Decem-
as animal products at the supermarket level
ber 14, 1994
as well as imported fruits, vegetables, and
Study process: Various government agencies and other products that may carry colonizing,
departments contributed input on the role of the drug-resistant bacteria and colonizing fecal
United States in detecting, reporting, and respond- flora in some patient populations. Salmonella
ing to outbreaks of new and re-emerging infectious and Shigella both should be monitored.
diseases. Salmonella gives the best window into the
Type of organization: Government impact of uses of antibiotics in the animal
world, and the fraction of Shigella that is
Languages (published in): English imported gives us an excellent view of the
Key contact impact of antibiotic uses in the developing
Centers for Disease Control and Prevention, world. Monitoring of soil waste in farms
Office of the Director, National Center for Infec- should also be considered;
tious Diseases: (404) 639-2603 — Establish a baseline of antimicrobial in vitro
efficacy to which the following can be com-
pared: earlier data from similar surveillance
(8) Report of the ASM Task Force on studies found in medical literature reviews,
Antibiotic Resistance
especially if these studies utilized compara-
Organization: American Society for Microbiology ble methodologies and surveillance techniques;
Year published: 1995 subsequent surveillance data resulting from
the establishment of a national surveillance
Selected key findings system analyzed in a longitudinal manner;
• Broad spectrum antibiotic use for otitis media non-USA data to assess the international
is selecting for resistance against other more risks of resistance;
dangerous pathogens. — Accumulate concurrent demographic profile
• Physicians contribute to the resistance problem information to assess the relationships
by inadequately diagnosing ailments before pre- between organisms emerging in hospitals of
scribing antibiotics, prescribing antibiotics to various sizes or disease therapy focuses and
treat viral illnesses, inappropriately prescribing pathogens prevalent among ambulatory pa-
broad spectrum antibiotics, and acquiescing to tients in the community and animals housed
patient demand for antibiotic prescriptions when in various environments. The role of drug
their use would be ineffective. use in these environments shall be addressed;
• Nearly one half of antibiotics used in the USA — Establish a mechanism whereby organisms
are used in farm animals (according to 1988 possessing certain phenotypic and genotypic
report by the National Academy of Sciences). resistance patterns will be referred to ad-
• The estimated yearly cost of treating infections equately funded laboratories for detailed study.
in humans that are related to antibiotic-resist- Various molecular typing and investigative
ant organisms in the United States is over $4 procedures can lead to earlier understand-
billion. ing of developing resistance mechanisms and
spread of epidemic clones;
Key recommendations — Allow for the future assessment of the
• Establish a national surveillance system to do the encountered resistant pathogens’ effect on
following: patient outcomes, general community
— “Focus on the most prevalent bacterial and health, and the costs of health care delivery.
fungal pathogens (not viral) that concern Surveillance will target areas for specific in-
human health. This will assess isolates from tensive interventions for prevention (like
clinical disease cases and routine isolates so vaccine campaigns and antimicrobial use re-
that no bias from one center testing only the duction programs). Surveillance will also
“problem” isolate or more resistant isolates identify areas where epidemiologic investi-
compromises the results. Attention will be gations are needed to improve understand-
given to the trend in upward “creep” of MICs ing of spread of drug-resistant strains and to
101
identify ways to interfere with spread; — Monitor demographic profiles of participat-

— Maximize the possibility that data will lead ing hospitals and laboratories with yearly
to significant forms of professional health updates.
care intervention to reduce the probability — Establish testing methods that are of refer-
that resistance to the drug will be spread ence quality and closely follow the docu-
widely and have an adverse impact on the ments published by the NCCLS. Where
national quality of health care outcomes. possible, conduct initial screening using the
Interventions ideally should be focused at the disk diffusion method (MCCLS M2-A5) for
local level but regional and national inter- those pathogen-antimicrobial combinations
ventions could also provide great benefits; that can be accurately tested.”
— Provide expert federal agencies and societies • Strengthen professional and public education in
the information to modify recommendations the area of infectious diseases and antibiotics to
regarding therapy or prophylaxis of disease reduce inappropriate usage of antibiotics.
or regarding testing procedures. These can — “An urgent need exists for more appropriate
be implemented at various levels related to selection and use of antimicrobial drugs. The
patient or institutional demographics or by curriculum of health professional (medical,
geography (local, regional, national); dental, nursing, and veterinary) schools and
— Provide a compatible system in which sub- postgraduate educational programs should
sets of participants could be grouped for be strengthened in the areas of sterilization,
common benefits. Examples include federal disinfection, hazards of inappropriate anti-
hospitals (Veterans Administration [VA], microbial drug use, appropriate diagnosis
military, etc.), animal care facilities (univer- and treatment of infectious diseases, and
sity-based, USA Department of Agriculture antibiotic resistance. These efforts should
[USDA], etc.), recognized HMO-like pro- result in reduction of spread of infectious
grams, and academic institutions such as agents and more prudent use of antibiotics;
university teaching hospitals; — Better guidelines should be established and
— Provide the accumulated data to pharmaceu- enforced to reduce the spread of infectious
tical manufacturers, thus providing the agents and antibiotic resistance in the hos-
validations of contemporary drug spectrums. pital environment, nursing homes, daycare
This will be valuable in establishing mean- facilities, and food production industries;
ingful organism coverage indications in — Educational materials should be developed
antimicrobial agent package inserts; and widely distributed to patients and food
— Provide a system that can be modified to producers. The need for partnerships in im-
address any discovered area of concern related proving antimicrobial use of cost-effective
to the effective therapy of infectious organ- treatment of infections and to preserve the
isms. This could allow expansion to cover effectiveness of antimicrobial drugs for the
fungi, viruses, cell-associated organisms, and future should be emphasized.”
some parasites.” • “There is an urgent need for more basic research
— Monitor bacterial pathogens considered directed toward development of new antimicro-
important in human and animal infections. bial compounds, effective vaccines, and other
Testing schedules of various strains and spe- prevention measures.
cies will vary according to the recommenda- — In FY 1994 allocations to the National In-
tions of the surveillance oversight panel. A stitute of Allergy and Infectious Diseases of
significant number of organisms should be the NIH for funding of non-AIDS infectious
tested, with medical statisticians contribut- disease research were reduced by $20 mil-
ing input to the final list. lion. Increased appropriations are urgently
— Conduct a broad sampling of geographically needed to fund areas of research directly re-
dispersed laboratory isolates, with a focus on lated to new and re-emerging infections and
human pathogens. Criteria for selection of antibiotic resistance;
laboratories will be based on state popula- — More basic research is needed to delineate the
tion density and diversity of demographic genetic and metabolic pathways, including
populations. essential regulatory factors, that determine
virulence as well as antibiotic susceptibility
102
or resistance in pathogens of human and Authors: Task force: Gail H. Cassell, Ph.D., Gordon L.
veterinary importance...; Archer, M.D., Thomas R. Bear, M.D., Mary J.
— More resources should be devoted to the Gilchrist, Ph.D., Donald Goldmann, M.D., David
sequencing of the entire genome of micro- C. Hooper, M.D., Ronald N. Jones, M.D., Stanley
bial pathogens, particularly in closed popu- H. Kleven, D.V.M., Ph.D., Joshua Lederberg, Ph.D.,
lations (i.e., hospitals, child care facilities, Stuart B. Levy, M.D., Donald H. Lein, D.V.M.,
and food production facilities); Ph.D., Robert C. Moellering, M.D., Thomas F.
— More basic research is needed to better un- O’Brien, M.D., Bennie Osburn, D.V.M., Ph.D.,
derstand the genetics of microorganisms and Michael Osterholm, Ph.D., David M. Shlaes, M.D.,
the development of antibiotic resistance, Ph.D., Martin Terry, D.V.M., Sue A. Tolin, Ph.D.,
particularly in fungi and newly described Alexander Tomasz, Ph.D. Government Liasions: Robert
pathogens; F. Breiman, M.D., Jean Cooper, Ph.D., James M.
— Research is needed for development of rapid, Hughes, M.D., John La Motagne, Ph.D., Edward
reliable diagnostic techniques for identify- McSweegan, Ph.D., Albert T. Sheldon, Ph.D., Fred
ing specific infectious causes of illness…; Tenover, Ph.D. Industrial Liasions: Jerry Boscia, M.D.,
— More basic research is needed to facilitate Carl J. Craft, M.D., Susan Froshauer, Ph.D., Michael
development of effective vaccines and other McCabe, D.V.M., Catherine Reese, Ph.D., Ray Testa,
prevention measures.” Ph.D. Office of Technology Assessment: Sean Tunis,
M.D., Justin Latus, M.P.P.
Type of publication: Report
Implementation of the task force’s recommenda-
tions would be conducted by the National Center Pages: 23
for Infectious Diseases of the CDC. Establishment Intended audience: United States; microbiologists
of priorities and implementation of policies would
be carried out by the National Institute of Allergy Study timeframe: N/A
and Infectious Diseases of the National Institutes Study process: Task Force members participated in a
of Health (NIH), the USA Department of Agri- workshop conducted July 6, 1994, and reviewed
culture, the Environmental Protection Agency, and relevant scientific literature.
the Food and Drug Administration.
Type of organization: Non-profit, life science society
Conclusions/Executive Summary Languages (published in): English
“There is an urgent need for effective domestic and
Key contact
global surveillance of antibiotic resistance in ani-
ASM Headquarters, 202-737-3600.
mals and humans. There is also an urgent need for
Available on the web at: http://www.asmusa.org/
more prudent use of antibiotics in both human and
pasrc/pdfs/antibiot.pdf
veterinary medicine, particularly as it relates to food
production. Of equal urgency is the need for bet-
ter hospital infection control and implementation (9) The Medical Impact of the Use of
of guidelines to reduce spread of infection and an- Antimicrobials in Food Animals. Report
tibiotic-resistant pathogens in the hospital environ- of a WHO Meeting.
ment. There is a great need for strengthening the Organization: World Health Organization, Division
curriculum of human and veterinary health care of Emerging and Other Communicable Diseases
professionals in the areas of sterilization and disin- Surveillance and Control.
fection, mechanisms of antibiotic resistance, and
factors contributing to its spread, including inap-
propriate antibiotic usage. There is also a need for
patient education regarding appropriate uses of anti-
• At the time of the report, Salmonella serotypes
biotics. More basic research is needed to more clearly
showing reduced susceptibility to fluoro-
delineate mechanisms of antibiotic resistance and
quinolones in humans had been observed in
to identify new antimicrobial targets. Lastly, greater
France, Germany, Ireland, the Netherlands, Rus-
emphasis must be placed upon research related to
sia, Spain and the United Kingdom.
rapid, reliable diagnostic tests and vaccines for pre-
• There is a lack of quantifiable data on the preva-
vention and control of infectious diseases.”
103
lence and spread of resistance in zoonotic bacte- prevalence of resistant bacteria in food-produc-
ria or indicator agents, including Escherichia coli, ing animal populations and animal-based food
Entereococcus faecium and Enterococcus faecalis. products;
• Prior to the use of fluoroquinolones in poultry • Classes or organisms to be included in national
production, there has been a dramatic rise in monitoring programs should be the important
the incidence of fluoroquinolone-resistant zoonotic foodborne bacteria (with Salmonella as
Campylobacter jejuni in live poultry, poultry meat the primary group of organisms) and key indi-
and from infected humans. cator bacteria… If feasible, programs should
include E. coli and Campylobacter. In addition,
Key recommendations other potential veterinary and human pathogens
• Adherence to the recommendation made by the (e.g., Enterococcus) should be considered, based
WHO advisory group of 1994, specifically: “The on an individual country’s requirements;
use of any antimicrobial agent for growth pro- • National practices of antimicrobial use in ani-
motion in animals should be terminated if it is: mals would be reviewed, and antimicrobial use
used in human therapeutics; or known to select policies be developed to reduce the risks of
for cross-resistance to antimicrobials used in selection and dissemination of antimicrobial
human medicine.” resistance.”
• “National authorities should define threshold
levels of resistance in bacteria and circumstances Implementation suggestions
where mitigation procedures should be insti- • WHO’s Program on Antimicrobial Resistance
gated and, if such procedures are unsuccessful, Monitoring would be responsible for coordinat-
when approval should be withdrawn; ing international efforts to conduct surveillance
• No antimicrobial should be administered to a of resistant bacteria in food animals and food
food animal unless it has been evaluated and from animal sources, and for training personnel
authorized by competent national authorities. in the medical and veterinary sectors on antimi-
This evaluation should include a thorough risk crobial resistance testing and national policy
assessment which includes the development of framework development activities.
resistance that may impact public health; and • An expanded version of the WHONET software
post-market monitoring program to detect emer- would be used to monitor data on bacteria col-
gence of resistance of public health significance. lected from food animals and food of animal
If such emergence is detected, appropriate origin.
action should be taken, which may include the • Collaborations among the medical, veterinary
withdrawal of the antimicrobial in question; and agricultural sectors would be responsible for
• Increased concerns regarding risks to public coordinating surveillance efforts at the local,
health resulting from the use of antimicrobial regional, or national level.
growth promoters indicated that it is essential • WHO and the Food and Agricultural Associa-
to have a systematic approach towards replacing tion of the United Nations would convene
growth-promoting antimicrobials with safer experts to develop international guidelines for
non-antimicrobial alternatives; prudent use of antimicrobials in food animal
• Request the Codex Alimentarius Commission production.
to include issues of antimicrobial resistance
among the terms of reference of the Codex com- Conclusions/Executive Summary
mittee on Residues of Veterinary Drugs in Foods; “Microbiological and clinical evidence is mount-
• National authorities should maintain records of ing that resistant bacteria or resistance determinants
export/import figures of bulk chemicals with might be passed from animals to humans, result-
potential antimicrobial use, as such information ing in infections that are more difficult to treat.
is vital for quantitative assessments of the medi- With an increase in the prevalence and distribu-
cal risks related to the use of antimicrobials in tion of antimicrobial-resistant infections in hospi-
livestock production; tals and the community, the question has been
• WHO should continue to support ongoing raised as to how this escalation of resistance could
efforts to harmonize residue standards interna- have been influenced by the use of antimicrobials
tionally; in livestock production. Timely public health
• Countries should ascertain and monitor the action is needed to control or mitigate any medical
104
problem that might be related to the widespread prepared by those who would be participating in
application of antimicrobials outside the medical or observing the meeting. The experts discussed and
sphere. The most desirable action is the limitation, commented on the material. Presentations were
or more prudent use, of antimicrobials, particu- given and discussed during the first three days of
larly where alternatives are available. In situations the meeting. On the last two days, working groups
where there is evidence of a link to medical prob- drafted reports on medical impacts of antimicro-
lems, appropriate control action is needed. In light bial use in livestock production, surveillance and
of shrinking public resources and the increasing risk management. The reports were discussed and
need to conduct scientifically-substantiated risk adopted during the meeting’s final session.
assessments for prioritizing public health action,
Type of organization: International, non-governmen-
national policies on the use of antimicrobials in
tal, public health agency
animals must balance the possible benefits to live-
stock production against the medical risk and public Languages (published in): English
health consequences deriving from their use.” Key contact
Authors: Participants: Professor J. Acar, Dr. F. Angulo, Ordering Information: Communicable Disease
Dr. D. Bell, Professor T. Blaha, Dr. J. Boisseau, Dr. J. Surveillance and Response Documents, World
Borvendég, Dr. Anne Brisabois, Dr. R. Buchanan, Dr. Health Organization, CH-1211 Geneva 27, Swit-
Celia Carlos, Dr. Paula Fedorka-Cray, Professor A. zerland; fax: +41 22 791 4198, attention CSR
Franklin, Professor C. Friis, Professor H. Goossens, Documents; email: csr@who.ch, attention Docu-
Professor J. Gropp, Dr. R. Helmuth, Dr.A. Hoszowski, ments.
Professor S. Jin, Dr. I.A. Kroetz, Dr. Hilde Kruse, Dr. Available on the web at: http://www.who.int/emc-
J.-P. Lafont, Professor R. LeClerq, Dr. S. Levy, Dr. J. documents/zoonoses/whoemczoo974c.html
MacKinnon, Dr. J.L. Martel, Dr. G. Martin, Dr. S.
McEwen, Dr. S. McOrist, Dr. M.N. Mohd Nordin,
Professor A. Panin, Dr. Laura Piddock, Professor M. (10) America’s Vital Interest in Global
Pugh, Dr. A. Rattan, Professor L. Songkram, Dr. S.
Health: Protecting Our People,
Enhancing Our Economy, and
Sundlof, Dr. W. Thiel, Dr. Linda Tollefson, Dr. H.
Advancing Our International
Trolldenier, Dr. J. Turnidge, Dr. P. Wall, Dr. U. C. Interests
Warsa, Dr. H. Wegener, Professor B. Wiedemann,
Professor M. Wierup, Professor W. Witte, Dr. C. Wray, Organization: Institute of Medicine
Dr. M. Zervos, Dr. Dorothée André, Dr. J. Blancou, Year published: 1997
Dr. J. Paakkanen, Dr. J. Perez-Lanzac, Professor P.
Peters, Dr. Barbara Röstel, Dr. M. Rutter Observers: Selected key findings
Dr. P.P. Bosman, Dr. S. Brown, Dr. R. Bywater, • The United States lacks a coordinated, national
Dr. R. Carnevale, Dr. R. Froyman, Dr. T. Gomez, plan for conducting basic health research and
Dr. S. Lens, Dr. M. Lütoz, Dr. Margaret Miller, Dr. development and applying it towards the im-
K. Morita, Dr. S. Pitlik, Dr. Andrea Sanwidi, Dr. T. provement of global health.
Shyrock, Dr. P. Sundberg, Dr. T. Tselentis, Dr. C. • Prevention is the most cost-effective approach
Verschueren, Dr. L. Vogel WHO Secretariat: Dr. R. to infectious disease, with millions of dollars
Crom, Mr. G. Hartl, Dr. Sudarshan Kumari, Dr. N. saved globally each year once a major disease is
Moran, Dr. A. Reilly, Dr. K. Stöhr, Dr. Rosamund eradicated.
Williams.
Type of publication: Meeting Report Key recommendations
“The USA government should:
Pages: 24 • act to facilitate the development of an effective
Intended audience: Global; policy-makers, agricultural global network for surveillance of infectious
industry diseases, using the full potential of the informa-
tion and communications revolution and
Study timeframe: The meeting was held from the
fostering the capacity of developing countries
13th to the 17th of October, 1997.
in both biomedical surveillance and communi-
Study process: During the four weeks prior to the cations;
meeting, 522 experts received 39 presentations • further develop and extend the network to pro-
105
vide an early warning system for possible bio- Authors: Barry R. Bloom, Harvey V. Fineberg,
logical or chemical attacks; Jacquelyn Campbell, Richard G. A. Feachem, Julio
• take an active role in global efforts to share in- Frenk, Dean Jamison, Eileen T. Kennedy, Arthur
formation between countries on the most effec- Kleinman, William E. Paul, Allan Rosenfield,
tive means of financing and delivering health Patricia L. Rosenfield, Thomas J. Ryan, Susan C.
care in order to maximize efficiency and equity; M. Scrimshaw, June E. Osborn, John H. Bryant,
• increase its investment in research and develop- William H. Foege, David P. Rall
ment in biomedical science related to major
global health problems through expanded part-
nerships and cost-sharing with other govern- Pages: 62
ments and international donors; Intended audience: United States; policy-makers
• continue federal support for the education and
training of health researchers and practitioners Study timeframe: The report considers information
from other countries as an international public from 1985 to 1997.
good toward health leadership that benefits both Study process: Committee members conducted a
our own nation and others; workshop in November of 1995, and solicited in-
• form an Interagency Task Force on Global put from national and international public health
Health within the government to anticipate and and government organizations.
address global health needs and to take advan-
Type of organization: Non-profit public health and
tage of opportunities in a coordinated and stra-
advisory organization; advisor to Federal Govern-
tegic fashion.”
ment on issues of public health
Implementation suggestions Languages (published in): English
The Task Force designates the USA Department of
Key contact
Health and Human Services as the organization
Ordering information: National Academy Press,
most capable of carrying out the recommendations
www.nap.edu
in the report, including setting of priorities and
Content: Barry R. Bloom and Harvey V. Fineberg,
coordinating the efforts of other health agencies
Co-Chairs of the IOM Board on International
around the world.
Health
Greater financial support of the United Nations
by the United States would help to implement more
effective strategies for achieving better global health, (11) New and Re-emerging Infectious
and give the USA more leverage to enact the kinds Diseases: A Global Crisis and
of global policies that it considers to be necessary. Immediate Threat to the Nation’s
Health; the Role of Research
Conclusions/Executive Summary Organization: American Society for Microbiology
“For the United States to engage successfully in glo-
bal health, coordination among the multiple USA
agencies with statutory responsibilities in the area
will be needed, as well as the formation of partner-
• Antibiotic-resistant bacterial infections in the
ships with the USA industrial and academic sec-
United States cost approximately $4 billion in
tors and nongovernmental organizations, other
medical costs annually.
nations, and international organizations. Without
• Infectious diseases were the third leading cause
active USA engagement and coordination, in con-
of death in the United States in 1996.
cert with the complementary efforts of other
• From 1980 to 1996, the death rate from infec-
nations, the struggle to ensure health around the
tious diseases in the United States has increased
globe threatens to fragment or falter, with the likely
more than 50 percent.
outcome that our own national health, economic
viability, and security will suffer. This report out-
Key recommendations
lines the compelling case for America’s active
• Encourage investment in research in the fields
engagement in global health and offers recommen-
of microbiology, immunology and infectious
dations on how this may best be achieved.”
diseases.
106
• Focus research on molecular genetics and the • Resistance is a local problem, dependent on
biochemistry of bacteria, viruses, and fungi. patterns of use within a hospital and on each
hospital’s infection control programs (Levy).
Implementation suggestions • Resistance is an ecological problem; overuse of
Implementation of recommendations can be antibiotics has removed susceptible organisms
achieved by increasing funding to USA government and seen their replacement with resistant ones.
agencies, including the National Institute of Allergy It is possible to reverse the problem through the
and Infectious Diseases and the National Institutes reduction of antibiotic use (Levy).
of Health. • Factors such as sterility and type of instruments,
wound preparation, wound closure, etc. contrib-
Conclusions/Executive Summary ute to the likelihood of infection during surgi-
“Increased research funding is critical to address the cal procedures (Henderson).
current threats from new and re-emerging infec-
tious diseases through the development of better Key recommendations
diagnostic tests, new drugs, and vaccines. In addi- • More accurate diagnosis before prescribing any
tion, increased funding would provide new oppor- medication (Levy; Plotnick).
tunities for making major advances to define the • Resuscitate efforts to identify and monitor the
potential role of infectious agents in chronic emergence and spread of infectious diseases
diseases, such as cancer, that currently have no (Plotnick).
known causes.” • Evaluate different methods of antibiotic use,
including shorter or cyclical courses.
Authors: Not specified
• Improve staff to patient ratios in hospitals, to
Type of publication: Booklet allow for better diagnosis and prescribing (Lee).
Pages: 13 • Modify prescribing practices to eliminate exces-
sive antibiotic prophylaxis before surgery
Intended audience: United States; scientists, policy- (Henderson).
makers
Study timeframe: Report considers scientific litera- Implementation suggestions
ture from 1992 to 1996 Rear Admiral Plotnick and Laura Lee both recom-
mended strategies developed by the CDC (in co-
Study process: Analysis of documents on emerging
operation with a variety of regional, national, and
infectious diseases
international public and private organizations)
Type of organization: Non-profit, Life Sciences Soci- which act on issues of surveillance, research, pre-
ety vention, control, and institutional management.
Key contact The abatement of the problem of antibiotic resist-
American Society for Microbiology, Public Affairs ance can only be achieved through cooperation of
Office, 202-942-9209 prescribers, patients, government, pharmaceutical
Available on the web at: http://www.asmusa.org/pasrc/ and agricultural industries. Surveillance, infection
pdfs/newandre.pdf control, and improved prescribing practices are all
important components of any collaborative effort.
(12) Resistant Organisms: Global Impact on Authors: Jean Davis, Professor S. Michael Emmerson,
Continuum of Care David K. Henderson, MD (co-editor), Laura Lee,
Stuart B. Levy, MD (co-editor), Rear Admiral Julia
Organization: Royal Society of Medicine R. Plotnick
Year published: 1997 Type of publication: Conference proceedings
Selected key findings Pages: 70

• Attitudes of patients and physicians are key Intended audience: United States, United Kingdom;
factors that contribute to the inappropriate pre- health care providers
scribing and use of antibiotics (Levy; Plotnick).
107
Study timeframe: Conference held September 27, for monitoring antimicrobial resistance of both
1996 community and nosocomial isolate on a monthly
basis or at a frequency appropriate to the vol-
Study process: Varies with each presentation
ume of isolates.
Type of organization: Independent professional organi- • It is recommended that hospitals monitor the
zation relationship between antimicrobial use and
Languages (published in): English resistance, and assign responsibility through
practice guidelines or other institutional poli-
Key contact cies.
Ordering information: Royal Society of Medicine • It is recommended that hospitals apply Contact
Press, Lmt., +44 (0) 20 7290 3945; email: kirsty. Precautions to specified patients known or
orriss@roysocmed.ac.uk suspected to be colonized or infected with
epidemiologically important microorganisms
(13) Guidelines for the Prevention of that can be transmitted by direct or indirect con-
Antimicrobial Resistance in Hospitals tact.”
(SHEA Position Paper)
Organization: Society for Healthcare Epidemiology Recommendations for future studies
of America; Infectious Diseases Society of America • “It is recommended that research to define the
mechanism of transfer of bacteria and their
Year published: 1997 resistance determinants among patient popu-
lations and to determine methods to prevent
Selected key findings emergence and transfer of resistance, including
• The authors contend that, contrary to many control of antibiotic usage, be supported with
studies, antibiotic-resistant bacteria are not nec- increases in targeted research funding.
essarily less virulent than their susceptible • The development and testing of protocols for
parents, and that even in cases where the second measuring the effect of a variety of antimicro-
generation bacteria are less virulent, they are no bial usage controls is recommended for use in
less dangerous to vulnerable hospital multiple hospitals to determine the most effec-
populations. tive ways to prevent and reduce antimicrobial
• Making a definite connection between antimi- resistance in specific species to specific antimi-
crobial use and antimicrobial resistance in hos- crobials.
pitals is often confounded by lack of consistency • It is recommended that educational methods,
from hospital to hospital in defining resistance, including those that are interactive and compu-
methodologies used in susceptibility testing, and ter-based, be developed to improve the appro-
other variables. priateness of antimicrobial prescribing.
• The efficacy of various levels of infection
Key recommendations control precautions should be documented by
Recommendations for hospitals controlled trials.
• “Establish a system for monitoring bacterial • Controlled studies of behavior modification,
resistance and antibiotic usage; including novel approaches, to permit the effi-
• Establish practice guidelines and other institu- cient application of recommended guidelines
tional policies to control the use of antibiotics, within hospitals are recommended.
and respond to data from the monitoring • The efficacy of quality improvement approaches
system; to control of resistance should be studied.”
• Adopt the recommendations of the Centers for
Disease Control and Prevention’s (CDC) Guide- Implementation suggestions
lines for Isolation Precautions in Hospitals, as Guidelines developed by the CDC and the National
concerns the isolation of patients colonized or Committee for Clinical Laboratory Standards are
infected with resistant microorganisms.” suggested as ways for microbiologists and physi-
cians to monitor antibiotic prescribing and use.
Recommendations for prevention & reduction of
antimicrobial resistance in hospitals Conclusions/Executive Summary
• “It is recommended that hospitals have a system “There is convincing evidence that we share a
108
single ecosystem globally in terms of resistance. The • In order to determine the extent of antibiotic
selection of resistance in one organism in one part resistance in hospitals, it is necessary to take into
of the world, even within an animal population, account each hospital’s pattern of antibiotic use.
may have long-term, important implications for • A report on the monitoring of antibiotic use in
human health globally. Therefore, management of a hospital in Greece proved the efficacy of a rig-
the problem of antimicrobial resistance within hos- orous program of prescription control. The com-
pitals is a community responsibility, both within bination of prescription monitoring, improved
and outside of the hospital…Good stewardship of hygiene, educational programs and the limita-
antibiotic usage combined with strong infection tion of certain antibiotics resulted in (for exam-
control will be required. To achieve this, all levels ple) ceftazidime-resistant P. aeruginosa levels
of personnel within the hospital must be involved, decreasing from 45% to 8% after three years.
from top administration down to individuals per- (Giamerellou & Antoniadou)
forming services and providing patient care.”
Key recommendations
Authors: David M. Shlaes, MD, PhD; Dale N.
• Increase development of novel antibiotic agents.
Gerding, MD; Joseph F. John, Jr., MD; William A.
• Increase emphasis on infection control and hy-
Craig, MD; Donald L. Bornstein, MD; Robert A.
gienic practices.
Duncan, MD; Mark R. Eckman, MD; William E.
• Enact multidisciplinary approaches to reducing
Farrer, MD; William H. Greene, MD; Victor Lorian,
hospital resistance rates, including cooperation
MD; Stuart Levy, MD; John E. McGowan, Jr., MD;
between pharmacies and diagnostic laboratories,
Sindy M. Paul, MD; Joel Ruskin, MD; Fred C.
and between infectious disease physicians and
Tenover, MD; Chatrchai Watanakunakorn, MD
clinicians.
Type of publication: Position paper
Pages: 17 Implementation suggestions
Not given
Intended audience: United States; scientific commu-
nity Conclusions/Executive Summary
Study timeframe: The authors reviewed scientific “This meeting has put these issues [antibiotic use
literature dating from 1977 to 1996. and mechanisms of resistance] aside in order to
focus on a larger view of the problem, and to
Study process: The authors analyzed existing scien-
define the potential for return to a healthier state
tific literature on antibiotic resistance mechanisms
vis-à-vis susceptible flora. There is a need for new
and spread.
guidelines on more rational utilization of future
Type of organization: Non-profit public health organi- novel antimicrobials within the context of ecology.
zation There is also a cost to discover and develop these.
Thus, we shall want to keep them from succumb-
ing to a similar fate, i.e., encountering resistance.
Key contact In this effort, consumers can join physicians and
Reprint requests: David M. Shlaes, MD, Wyeth- the pharmaceutical industry in maintaining this
Ayerst Research, 401 N. Middletown Rd., Pearl efficacy. Whether antibiotics are available over-the-
River, NY 10965 counter in developing countries or demanded and
stockpiled in the developed countries, they are too
(14) Symposium on Antibiotic Resistance: often in the hands of consumers who use them in-
Origins, Evolution, Selection and correctly.”
Spread Authors: S.B. Levy, J.E. Davies, P. Huovinen, H.
Organization: Ciba Foundation Sepplälä, J. Kataja, T. Klaukka, R. Gaynes, D. Monnet,
W. Witte, H. Giamarellou, A. Antoniadou, F. Baquero,
M.C. Negri, M.I. Morosini, J. Blazquez, M. Lipsitch,
B.R. Levin, R.E. Lenski, K. Bush, R.A. Skurray, N.
Firth, R.M. Hall, M.C. Roberts, M.L. Cohen
• Antibiotic resistance is an ecological problem,
in that the balance between susceptible and re- Type of publication: Report
sistant bacteria has been disrupted. Pages: 250
109
Intended audience: Global; scientists • “Further discussions are necessary, to develop

collaboration between existing antimicrobial
Study timeframe: 3-day symposium in July of 1996.
resistance surveillance programmes.”
Study process: Participating scientists discussed a va-
riety of pre-submitted articles on antibiotic resist- Implementation suggestions
ance. According to participants’ responses to a question-
Type of organization: International scientific and edu- naire circulated before the workshop, implementa-
cational non-profit tion of any recommendations or improvements
depends on adequate funding, standardized meth-
Languages (published in): English odologies of susceptibility testing, improved gov-
Key contact ernment support, a greater number of trained
Ordering: John Wiley & Sons, Ltd., cs-books@ professionals to carry out surveillance efforts, and
wiley.co.uk; telephone: +44 1243 779777 increased awareness of the resistance problem by
Content: Stuart B. Levy, MD, Symposium Chair- health care providers.
man 1996
“The emergence and spread of antimicrobial resist-
(15) The Current Status of Antimicrobial ance is a significant problem to all people in all
Resistance Surveillance in Europe:
countries, both developed and developing. It im-
Report of a WHO Workshop held in
Collaboration with the Italian pacts both patients with infections and clinicians
Associazione Culturale Microbiologia facing growing limitations on their efficacious use
Medica of antimicrobials. It influences a health care sys-
tem’s ability to implement rational drug use poli-
Organization: World Health Organization, Division
cies and efficiently allocate resources. Because the
of Emerging and Other Communicable Diseases
emergence of antimicrobial resistance is a global
Surveillance and Control
problem that affects us all, national and interna-
Year published: 1998 tional efforts are needed to address the problem.
Information and experience, must be shared so that
Selected key findings all can learn and benefit.”
• There is not enough communication between “At present, many groups are attempting to har-
antimicrobial resistance surveillance networks monize local, national and international antimicro-
and the decision makers at the regional and na- bial resistance surveillance methodologies. These
tional levels in Europe. attempts are not necessarily coordinated with one
• Quality assurance standards that evaluate the another, however, and there is a growing percep-
validity of surveillance data vary throughout tion, reinforced by discussions held during this
Europe, making it difficult to make accurate workshop, that a positive role could be played by a
comparisons. pan-European coordinating group. Such a group
• A coordinated effort by the various European could reflect the various national and European-
surveillance systems is necessary to effectively wide interests in antimicrobial resistance surveil-
address the emergence and spread of antimicro- lance. It could be initiated as a study group of the
bial resistance. European Society of Clinical Microbiology and
Infectious Diseases and focus on actively promot-
Key recommendations ing the performance of good-quality local studies
• “The communication chain between antimicro- which generate internationally comparable data.
bial resistance surveillance networks and national Such data could, in turn, be used to facilitate the
and regional decision makers must be strength- accurate interpretation of results between studies
ened and used.” and generate information on the extent of antimi-
• “There is a need to harmonize quality assurance crobial resistance in Europe. An essential compo-
standards throughout Europe.” nent of any group’s success, of course, will be
• “Adequate support for microbiology and epide- adequate funding.” (I. Phillips)
miology training programs, for laboratory
Authors: Participants: Professor Jacques F. Acar, Profes-
infrastructure, and for data analysis and com-
sor Fernando Baquero, Dr. Andre Bryskier, Dr. Otto
munication, is required.”
110
Cars, Dr. Giuseppe Cornaglia, Dr. Patrice Courvalin, (16) Papers presented at the International
Dr. Roberta Fontana, Dr. Herman Goossens, Dr. Conference on Emerging Infectious
Marija Gubina, Dr. Waleria Hryniewicz, Dr. Pentti Diseases in Atlanta, GA, March 1998.
Huovinen, Dr. Vincent Jarlier, Dr. Mark E. Jones, Compiled in Emerging Infectious
Professor Smilja Kalenic, Professor Conor T. Keane, Diseases 4(3): 353–515
Dr. Marianne Konkoly, Dr. Karl G. Kristinsson, Pro- Organization: Centers for Disease Control and Pre-
fessor Herminia de Lencastre, Dr. David Livermore, vention, National Center for Infectious Diseases
Professor Enrico Magliano, Dr. Boyka Markova, Dr.
Anna Marton, Dr. Jolanta Miciuleviciene, Dr. Helmut
Mittermayer, Dr. Kathrin Muelemann, Professor Carl
Erik Nord, Professor Alvaro Pascual, Professor Ian
• The National Institute of Allergy and Infectious
Phillips, Professor Arne C. Rodloff, Professor Jirí
Disease (NIAID) dedicates about 21% of its
Schindler, Dr. Ivonna Selga, Dr. Anatoly Shapiro, Dr.
non-AIDS infectious disease budget to emerg-
Thomas Lund Sørensen, Dr. Marc Sprenger, Dr. Mar-
ing infectious diseases. NIAID’s total emerging
tin Steinbakk, Professor Leonid Stratchounsky, Pro-
diseases budget increased from $39.3 million in
fessor Marc Struelens, Dr. Alkiviadis C. Vatapoulos,
1993 to a projected $85 million in 1999. (Fauci)
Professor Jan Verhoef, Professor Richard Wise. WHO
• Nosocomial infections were estimated to be re-
Secretariat: Dr. Ana Estrela, Dr. Colette Roure, Dr.
sponsible for 88,000 deaths and $4.5 billion in
John Stelling, Dr. Rosamund Williams, Dr. Clara
treatment costs in 1995. Approximately one-
Witt.
third of such diseases are preventable.
Type of publication: Meeting report (Weinstein)
Pages: 80
Key recommendations
Intended audience: Europe; policy-makers, micro- Surveillance
biologists, those who are responsible for surveillance One author recommends “...dramatically strength-
networks ened local surveillance, including both laboratory
Study timeframe: The workshop was held on De- and epidemiologic capacity; commitment on the
cember 12, 1997. part of local governments; and a strong collabora-
tive international research and response system.”
Study process: The participants met to present and (Broome)
discuss the variety of antimicrobial resistance sys-
tems in operation throughout Europe, to highlight Research
the features of successful programs, and to discuss The NIH recommends expanding research on the
how those features may be incorporated into other ecologic and environmental aspects of disease emer-
systems. gence and transmission; expanding research on the
microbial mechanics of disease emergence; support-
Type of organization: International, non-governmen- ing the development of vaccines and other preven-
tal, public health agency tive therapies, especially for diseases that are
Languages (published in): English threatening to emerge or reemerge; and “strength-
ening the current USA research and training infra-
Key contact
structure for detection and responding to outbreaks
Ordering Information: Communicable Disease
of infectious diseases.” (Fauci)
Surveillance and Response Documents, World
Health Organization, CH-1211 Geneva 27, Swit- Nosocomial infections
zerland; fax: +41 22 791 4198, attention CSR Improve national surveillance of nosocomial infec-
Documents; email: csr@who.ch, attention Docu- tions that occur in the hospital and in home health-
ments. care settings; improve the design of devices that are
associated with nosocomial infections; institute
Available on the web at: http://www.who.int/emc-
aggressive antibiotic control programs, perhaps
documents/antimicrobial_resistance/whoemcbac
making them mandatory for hospitals that receive
981c.html
federal reimbursements; and develop new and
microbiologic methods for detecting and investi-
gating outbreaks of multidrug-resistant pathogens.
111
Implementation suggestions Authors: Stephen A. Morse, Donna E. Shalala, Claire

• Continuation and strengthening of Field Epi- Broome, James Hughes, David Heymann, Guenael
demiology Training Programs that respond to Rodier, Joshua Lederberg, D. Peter Drotman,
reports of emerging infections. Use of the Inter- Anthony Fauci, Karen Hein, David Relman, Sir John
net and other communication technologies to Pattison, Bradley Perkins, Thomas Nchinda, Alison
gather and share surveillance information. Mawle, Martin Cetron, Jay Keystone, David Shilm,
(Broome) Robert Steffen, Kenneth Castro, Mary E. Chamber-
• Continued collaboration between the public and land, Jay Epstein, Roger Y.Dodd, David Persing,
private sectors. (Fauci) Robert G.Will, Alfred DeMaria, Jr., Jean C.
• Hospital personnel would be responsible for Emmanuel, Beatrice Pierce, Rima Khabbaz, William
implementing infection control policies, Foege, Donald Hopkins, Robert Weinstein, Jonathan
especially those concerning basic hygiene. Kaplan, Gary Roselle, Kent Sepkowitz, Janet
(Weinstein) McNicholl, Susan Cookson, Ronald Waldman, Brian
Gushulak, Douglas MacPherson, Frederick Burkle,
Conclusions Jr., Christophe Paquet, Erich Kliewer, Patricia Walker,
• “We are better able in 1998 to address the threats Frederick Murphy, Robert G. Webster, Duane Gubler,
of emerging infections, but we are by no means R Colwell, P. Epstein, M. Hall, P. Reiter, J. Shukla,
fully prepared. We must have the capacity to W. Sprigg, E. Takafuji, J. Trtanj, James Childs, Robert
identify new or reemerging threats and to re- E. Shope, Durland Fish, Francois X. Meslin, Clarence
spond successfully. We need to be creative and J. Peters, Karl Johnson, Emilio Debess, David Dennis,
efficient in identifying necessary resources… Suzanne Jenkins, Robert Tauxe, Samantha Yang,
Eradication activities also contribute to health Deborah Deppe, James LeDuc, Robert Pinner, Brad-
capacity development, and the laboratory and ford Kay, Ralph J. Timperi, Stephen S. Morse, David
surveillance capacities created for polio eradica- Forslund, Julie J. McGowan, Tom OíBrien, Lela
tion should also be useful in detection of and Folkers, Maria Teresa Cerqueira, Robert E. Quick,
response to emerging infectious diseases. Many James Kanu, Gauden Galea, EliasAbrutyn, Ann Marie
other creative approaches and collaborations are Kimball, Carrie Horwitch, Patrick OíCarroll,
needed for an effective global response to what- Sumarjati Arjoso, Chaiyos Kunanusont, Ya-Shin Lin,
ever our microbial adversaries may produce.” Clifford Meyer, Laura Schubert, Phillip Dunham,
(Broome) David Bell, Gail Cassell, D. A. Henderson, Joseph
• “The importance of basic research to the con- McDade, David Franz, Stanley Falkow, George
trol of emerging and reemerging diseases can- Alleyne, May C. Chu, Alexandra Levitt, Karl West-
not be overemphasized. Emerging diseases ern
research encompasses many disciplines, and re-
Type of publication: Peer-reviewed journal
search advances that fall under the rubric of
emerging diseases will be relevant not only to Pages: 164
specific diseases being studied but to a broad Intended audience: United States; policy-makers,
range of disciplines such as vaccinology, immu- government agencies, hospital personnel
nology, and drug development.” (Fauci)
• “Several enduring truths characterize the field Study timeframe: Varies
of infection control. Hospitals will become more Study process: Varies
like ICUs, and more routine care will be deliv-
Type of organization: Federal Government
ered on an outpatient basis. Given the choice of
improving technology or improving human Languages (published in): English
behavior, technology is the better choice. The
Key contact
major advances in overall control of infectious
Ordering information: EID Editor, CDC/NCID/
diseases have resulted from immunization and
MS C12, 1600 Clifton Road, NE, Atlanta, GA
improved hygiene, particularly hand washing.
30333
We must work with hospital personnel on bet-
ter implementation of existing infection control Available on the web at: http://www.cdc.gov/ncidod/
technologies so that we will not need to rely eid/vol4no3/contents.htm
solely on technologic advances.” (Weinstein)
112
(17) Preventing Emerging Infectious • Provide training opportunities in infectious dis-

Diseases: A Strategy for the 21st ease epidemiology and diagnosis in the United
Century States and throughout the world.”
Organization: Centers for Disease Control and Pre- Prevention and control
vention, National Center for Infectious Diseases • “Implement, support, and evaluate programs for
Year published: 1998 the prevention and control of emerging infec-
tious diseases;
Selected key findings • Develop, evaluate, and promote strategies to help
• New developments since 1994 that necessitated health care providers and other individuals
an update of Preventing Emerging Infectious Dis- change behaviors that facilitate disease transmis-
eases include: new emerging threats; advanced sion;
scientific findings; new methods of discovering, • Support and promote disease control and pre-
tracking, and communicating outbreaks; vention internationally.”
changes in health care delivery; and increased
public awareness and government response. Implementation suggestions
• Implementation of CDC guidelines on group B Surveillance
streptococcal disease helped to reduce its inci- • “Extend the ELC [Epidemiology and Labora-
dence by over 40% between 1993 and 1995 in tory Capacity] program to all state, territorial,
the communities that followed the guidelines. and large local health departments;
• A combination of improved practices in the food • Strengthen the EIP [Emerging Infections Pro-
industry, surveillance, and public education de- gram] network by increasing its demographic
creased the incidence of invasive listeriosis by and geographic representativeness and enhanc-
44% between 1989 and 1993; the reduction was ing its laboratory and epidemiologic capacity;
maintained through 1996, the last date cited in • Use the existing provider-based sentinel networks
the report. to monitor syndromes and diseases, and estab-
lish at least one additional network;
Key recommendations • Integrate public health information and surveil-
Surveillance lance systems;
• “Strengthen infectious disease surveillance and • Use surveillance data to analyze questions of
response; public health importance;
• Improve methods for gathering and evaluating • Facilitate access to surveillance data that can be
surveillance data; used in clinical practice;
• Ensure the use of surveillance data to improve • Assist global surveillance and response efforts
public health practice and medical treatment; through increased support of CDC-based WHO
• Strengthen global capacity to monitor and re- Collaborating Centers;
spond to emerging infectious diseases.” • Help monitor conditions that favor the emer-
gence or spread of infectious diseases.”
Applied research
• “Develop, evaluate, and disseminate tools for Applied research
identifying and understanding emerging infec- • “Develop, evaluate, and disseminate testing
tious diseases; methods for infectious agents;
• Identify the behaviors, environments, and host • Identify factors that influence the risk of devel-
factors that put people at increased risk for in- oping infectious diseases;
fectious diseases and their sequelae. • Assess the role of infectious agents in causing or
• Enhance epidemiologic and laboratory capacity; exacerbating chronic diseases and syndromes for
• Improve CDC’s ability to communicate elec- which the causative agents are unknown;
tronically with state and local health depart- • In collaboration with other organizations, sup-
ments, USA quarantine stations, health care port research to develop and evaluate new anti-
professionals, and others; microbial drugs and prophylactic agents, as well
• Enhance the nation’s capacity to respond to com- as methods to control disease vectors and reser-
plex infectious disease threats in the United voirs;
States and internationally, including outbreaks • Support research to develop new methods of
that may result from bioterrorism; disinfection;
113
• Support social science and behavioral research lems and rapid implementation of control meas-
to develop better prevention programs.” ures;
• Develop, implement, and evaluate disease pre-
Infrastructure and training
vention guidelines that can be used by the pub-
• “Define core public health functions and capaci-
lic, health care providers, and health care systems;
ties needed for monitoring the spread of
• Work with foreign governments, WHO, the
microbes and responding to infectious disease
USA-European Union Task Force on Commu-
outbreaks, and provide personnel in state and
nicable Disease, other international partners, and
large local health departments with essential
the CISET Emerging Infectious Disease Task
equipment and training;
Force to promote global programs for the pre-
• Strengthen CDC’s capacity to serve as the na-
vention and control of infectious diseases;
tional and international reference laboratory for
• Provide technical assistance and transfer cost-
diagnosis of infectious diseases and for drug-
effective technologies to other countries, using
resistance testing;
governmental and nongovernmental channels;
• Promote the development and production of
• Participate in bilateral and multilateral initiatives
diagnostic and reference reagents for use by pub-
to improve global infectious disease prevention
lic health laboratories;
and control;
• Work with state health departments to stand-
• Work with WHO and other partners to com-
ardize new diagnostic techniques and facilitate
plete the revision of International Health Regu-
their use throughout the United States;
lations;
• Assist other USA agencies, international organi-
• Work with developing countries to sustain health
zations, and other nations in building global
care improvements and surveillance efforts after
capacity for disease surveillance and response;
outbreaks.”
• Enhance national surge capacity for responding
to outbreaks of unusual size, duration, and
severity;
“Achievement of the objectives described in this
• Ensure the continued training of epidemiolo-
plan will improve our ability to understand, de-
gists in problems related to emerging infectious
tect, control, and prevent infectious diseases. The
diseases;
outcome will be a stronger, more flexible USA pub-
• Increase the number of laboratory scientists
lic health infrastructure well-prepared to respond
trained in infectious diseases through the Emerg-
to well-known disease problems and to address the
ing Infectious Diseases (EID) Laboratory
unexpected, whether it is an influenza pandemic, a
Fellowship Program and add a track for inter-
disease caused by an unknown organism, or a
national students;
bioterrorist attack.”
• Expand CDC’s efforts to train counterparts in
developing countries in the use of epidemiologic Authors: Sue Binder, M.D., Alexandra M. Levitt,
and laboratory methods for combating emerg- Ph.D., Judith R. Aguilar, David M. Bell, M.D., Mar-
ing infectious diseases.” tin S. Cetron, M.D., Mary E. Chamberland, M.D.,
Mark L. Eberhard, Ph.D., Duane J. Gubler, Sc.D.,
Prevention and control
Meredith A. Hickson, M.P.H., Jonathan E. Kaplan,
• “Expand existing community-based programs;
M.D., Rima F. Khabbaz, M.D., James W. LeDuc,
• Develop and support new community-based
M.D., Susan A. Maloney, M.D., William J. Martin,
demonstration programs in the target areas.
Ph.D., Alison C. Mawle, Ph.D., Patrick McConnon,
• Evaluate the impact and cost-effectiveness of
M.P.H., Martin I. Meltzer, Ph.D., Siobhan O’Connor,
alternative approaches to reducing infectious
M.D., Alan J. Parkinson, Ph.D., Anne Schuchat,
diseases;
M.D., Steven L. Solomon, M.D., Robert V. Tauxe,
• Increase the use of vaccines to prevent and con-
M.D., Fred C. Tenover, Ph.D., Theodore F. Tsai,
trol emerging infectious diseases;
M.D., Robert B. Wainwright, M.D., Helene D. Gayle,
• Work with health care providers, hospitals, man-
M.D., Walter A. Orenstein, M.D., Barbara R.
aged care organizations, and others to improve
Holloway, M.P.H., James S. Marks, M.D., M.P.H.,
patient outcomes related to infectious diseases;
Edward J. Sondik, Ph.D., Linda Rosenstock, M.D.,
• Work with private industry, government agen-
M.P.H., Walter W. Williams, M.D., M.P.H., Stephen
cies, and others to develop systems that promote
B. Blount, M.D., M.P.H., Karen K. Steinberg, Ph.D.,
prompt identification of infectious disease prob-
Edward L. Baker, M.D., M.P.H.
114
Type of publication: Report • Controlled studies “to determine whether the

Pages: 75 consumption of food produced by animals
receiving antibacterial drugs will result in: a. An
Intended audience: United States; physicians and increase in the intestinal flora of the prevalence
other health care providers; policy-makers of pathogenic bacteria; b. An increase in the
Study timeframe: The Steering Committee reviewed degree and spectrum of resistance of the intesti-
scientific literature from 1982 to 1998, with the nal flora to drugs used in human clinical medi-
bulk of material from the mid- to late-1990s. cine.”
Study process: The Committee evaluated and up- The guideline also recommends the conducting
dated CDC’s plan from 1994, Preventing Emerging of a literature survey, “to determine the incidence
Infectious Diseases. of reports of hypersensitivity resulting from anti-
Type of organization: Federal Government bacterial drugs in food.”
Key contact The criteria are guidelines for implementing the
Ordering information: Office of Health Commu- policies and complying with the regulations man-
nication, National Center for Infectious Diseases, dated by Congress and FDA.
Centers for Disease Control and Prevention,
Mailstop C-14, 1600 Clifton Road, Atlanta, GA Conclusions/Executive Summary
30333. Available online at http://www.cdc.gov/ “The...criteria must be satisfied in order to estab-
ncidod/emergplan lish that the use of low and/or intermediate levels
of an antibacterial drug in animal feeds is a safe
(18) Human Health Safety Criteria. practice from the aspect of human health. In gen-
Guideline 18. eral terms, such drug use should not result in: (1) a
significant adverse effect in the relative quantity,
Organization: Food and Drug Administration, Center
prevalence and shedding of Salmonella organisms
for Veterinary Medicine; USA Department of
in animals, (2) a significant increase of Salmonella
Health and Human Services
organisms resistant to drugs used in human clini-
Year published: Updated on July 28, 2000. cal medicine in the animal, (3) a significant increase
in the resistance of coliforms to antibacterial drugs
Selected key findings used in human clinical medicine provided this re-
No findings are presented. sistance is transferable to bacteria in man, (4) en-
hancement of pathogenicity of bacteria, or (5)
Key recommendations adverse effect to humans due to ingestion of residues
Antibacterial drugs that are used in the treatment of the antibacterial drug, metabolites, or degrada-
of animals and have not been found to transfer tion products.”
resistance to antibacterial drugs that are used in
Authors: Not identified
human clinical medicine must undertake the fol-
lowing studies: Type of publication: One of 98 guidance documents
• Controlled studies to determine whether or not created by the Center for Veterinary Medicine to
the antibacterial drug, given at subtherapeutic clarify the laws made by Congress or the Food and
levels, causes “an increase in the relative quan- Drug Administration that affect regulated indus-
tity or prevalence of Salmonella in animals or tries. They include guidance on testing procedures,
the duration of shedding of these Salmonella as manufacturing processes and scientific protocols.
compared to controls; and/or an increase in the
Pages: 3
proportion of resistant Salmonella, the degree of
resistance, and the resistance spectrum;” Intended audience: United States; regulated animal
• Controlled studies to determine whether or not health/food production industries, FDA employ-
antibacterial drugs administered to animals in- ees responsible for enforcement
crease the number of coliforms that are resistant
Study timeframe: N/A
to antibacterial drugs that are used in human
clinical medicine and may transfer that resist- Study process: N/A
ance to human intestinal tracts; Type of organization: Federal Government
115
Languages (published in): English Key recommendations

The Sub-Group recommends:
Key contact
• The implementation of a two-tiered national
Ordering information: Food and Drug Adminis-
campaign to improve community prescribing of
tration, Center for Veterinary Medicine, Commu-
antibiotics: a Campaign on Antibiotic Treatment
nications Staff, 7500 Standish Place, HFV-12,
for general practitioners, and a National Advice
Rockville, Maryland 20855; Telephone: (301) 594-
to the Public campaign for patients and con-
1755
sumers;
Available on the web at: http://www.fda.gov/cvm/fda/ • “That further support for appropriate prescrib-
TOCs/guideline18.html ing in primary care be provided by developing
Comments and questions to: Policy and Regula- and promulgating evidence-based national
tions, Team (HFV-6), Center for Veterinary Medi- guidelines for the management of certain infec-
cine, Food and Drug Administration, 7500 tions, under the aegis of the National Institute
Standish Place, Rockville, MD, 20855 for Clinical Excellence [and] that such national
guidelines are adapted for local use during the
(19) The Path of Least Resistance development of Health Improvement Plans;
• That [guidelines] should be integrated within
Organization: United Kingdom Department of computerized decision-support systems as soon
Health, Standing Medical Advisory Committee, as possible. These guidelines should also be
Sub-Group on Antimicrobial Resistance promulgated widely through the medical litera-
Year published: 1998 ture;
• That studies be undertaken in selected hospitals
Selected key findings to develop and test one or more prototype deci-
• Although only 20% of prescriptions of anti- sion-supported systems. To be fully effective,
microbials for human use in the UK are for these computer-based advisory systems should
hospital use, they are the site of the greatest re- include information from local antimicrobial
sistance problems. sensitivity profiles. These in turn should feed into
• Of the 50 million antibiotic prescriptions regional and national surveillance databases;
written each year in the UK, about 50% are for • That local prescribing information should,
respiratory tract infections; about 15% are for whenever possible, be harmonized with that in
urinary tract infections. the British National Formulary (BNF) and other
• Incidence of methicillin-resistant Staphylococcus formularies. Guidelines and formularies should
aureus (MRSA) increased dramatically between also take account of the proposed national evi-
1989 and 1997: 1.5% of the organisms were dence-based guidelines to be produced under the
resistant in 1989, compared to 31.7% in 1997. aegis of the National Institute of Clinical Excel-
• There is every reason to anticipate the further lence all such local guidelines should include,
spread of resistance to currently susceptible as a minimum, certain standard items of infor-
organisms. The most likely of these would be mation on the drug, dosage and duration of
vancomycin-intermediate MRSA, quinolone therapy;”
resistant E. coli, and the resistance of gram- • That greater emphasis be placed on the teach-
negative bacteria to carbapenems. The emer- ing of guidelines for antimicrobial prescribing
gence of penicillin resistant Neisseria meningitidis to medical, dental, pharmaceutical, nursing and
and Streptococcus pyogenes are also possible. veterinary students;
• The pressures of time and volume of patients in • “That a strategic system for resistance surveil-
hospital emergency wards often increases the lance of antimicrobial resistance should be de-
likelihood of inappropriate antibiotic prescrip- veloped as swiftly as possible, and that this
tions. should cover the whole of the UK;
• A lack of clinical trials on antibiotic use in long- • That research into antimicrobial resistance
term care facilities, combined with the vulner- should become a high priority for all funding
able nature of the population and inadequate bodies concerned with health care and biomedi-
diagnostic capabilities, have hampered efforts to cal research;”
control antibiotic resistance in such facilities in • That existing guidelines for hospital infection
the UK and the USA. control be more closely adhered to, and that
116
guidelines for infection control in the commu- C. Murphy, Dr. G. Patou, Dr. M. Powell, Dr. P. Wilkie,
nity be developed; Professor R. Wise, Dr. P. Clappison, I. Cooper, Pro-
• “That the use of antibiotics in animals should fessor B.I. Duerden, R. Fenner, Dr. J. Leese, Dr. K.
be guided by the same principles as those for Ridge, Dr. W. Smith, M. Hart, Dr. D.M. Livermore,
prescribing in humans—namely, they should be Dr. J.R. Weinberg
used only for those clinical conditions where
their use is likely to provide a genuine health
benefit; Pages: 152
• That alternative means of animal husbandry be Intended audience: Primarily United Kingdom, but
developed so that the use of antibiotics as growth also implications for global audience; policy-
promoters can be discontinued; makers, prescribers, consumers and patients
• That consideration be given by the appropriate
bodies to finding ways through pricing and other Study timeframe: The Sub-Group reviewed literature
mechanisms of ensuring that investment in the dating from 1969 to 1997, with a few references
development of new antibiotics remains com- from the 1930s and 40s.
mercially viable for the industry; Study process: Review of case-studies, review of the
• That industry should be encouraged to under- basis and impact of resistance, commission of an
take studies of optimum prescribing regimens independent review of evidence
for new antimicrobial agents, for each indica-
Type of organization: Government
tion and in adults and children as appropriate;
• That every effort is made by the Government to Languages (published in): English
raise the profile of antimicrobial resistance as a
Key contact: Available on the web at http://www.
major public halt issue meriting priority action
doh.gov.uk/smac1.htm
from all Member States of the European
Union.” and from: Publications Unit, PHLS, Headquarters
Office, 61 Colindale Avenue, London NW9 5DF;
Implementation suggestions tel: 0181 200 1295
The committee recommends the establishment of
a National Steering Group to institute the first phase (20) Antimicrobial Resistance: A special
of the national strategy to counter the development edition of the British Medical Journal
of antibiotic resistance. The NSG’s mandate is to
Organization: British Medical Journal
form sub-groups consisting of experts who can fo-
cus on particular aspects of the problem, and then Year published: 1998
to report to the Chief Medical Officer within a year.
The CMO in turn may request that the Standing Selected key findings
Medical Advisory Committee reconvene the Anti- • Butler, et al., assessed the attitudes of physicians
microbial Resistance Sub-Group in order to develop and patients in South Wales when prescribing
the strategy’s next phase. or withholding antibiotics for sore throats.
Patient expectations for antibiotics were found
Conclusions/Executive Summary to be a compelling factor for prescription, even
“The recommendations in this Report are directed though the drugs are largely ineffective for the
towards ensuring that best practice in antimicro- condition.
bial prescribing becomes routine practice. This will • Ferranti, et al., demonstrated that amoxycillin
require a willingness, on the part of health care and folate inhibitors are just as effective as newer,
professionals and the public alike, to treat antimi- more expensive broad-spectrum antibiotics in
crobial agents as a valuable and non-renewable the treatment of uncomplicated acute sinusitis.
resource, to be treasured and protected in their own,
Key recommendations
and everyone else’s interest.”
• Increase patient and prescriber education, sur-
Authors: Sub-Group Members: Dr. Diana Walford, A. veillance, and research.
Close, Dr. A. Dearmun, Professor T. Duckworth, A. • For developing countries: improve prescription
Ewing, Dr. J. Gilley, Dr. R. Horne, Professor A. regulation, access to diagnostic tools, surveil-
Johnson, Professor C. Peckham, Dr. S. Willatts, Dr. lance, and education of the public, doctors and
G. Youngs, Dr. A.M. Johnston, Professor P. Littlejohns, veterinarians.
117
• For international organizations: achieve interna- Deenan Pillay, Maria Zambon, Claude Carbon, Ri-
tional consensus standards for resistance surveil- chard P. Bax, A. M. Johnston, Christopher C. Butler,
lance, and create a global repository of Edward A. Belongia, Benjamin Schwartz, Paul Farmer,
information on resistance in key pathogens. Jim Yong Kim
• For hospitals: encourage multidisciplinary
Type of publication: Peer-reviewed journal
cooperation in policy implementation, timely
detection and reporting of antibiotic resistant Pages: 90
strains, and aggressive control of the transmis- Intended audience: Global; physicians, other health
sion of epidemic resistant bacteria. care providers
Implementation suggestions Study timeframe: varies

Developing countries: Not specified. Study process: varies
International organizations: Adoption of resolution Type of organization: Private company
on antimicrobial resistance that was presented at
Languages (published in): English, and local editions
1998 World Health Assembly.
in Belgium, Brazil, China, Greece, Hungary, Latin
Hospitals: Needs and resources vary from hospital America, Middle East, Netherlands, Pakistan,
to hospital; programs for infection control or the Poland, Portugal, Romania, Scandinavia, South
development of policies should be tailored with Africa, South East Asia, Turkey and West Africa
those differences in mind.
Key contact
Editor, Richard Smith: editor@bmj.com;
Telephone: +44 (0) 171 387 4499
“The increasing resistance problems of recent years
are probably related to the use of increasingly broad
spectrum agents (cephalosporins and fluoro- (21) Select Committee on Science and
quinolones) and crowding of the most vulnerable Technology: Resistance to Antibiotics
members of society in daycare centers and nursing and Other Antimicrobial Agents
homes. These problems are compounded by the Organization: House of Lords
worldwide phenomena of pressure on health care
systems for greater efficiency, with higher bed Year published: 1998
occupancies and stretched nursing and medical care.
Added to this are pressures to allow over-the-
• Drug formularies and policies vary widely
counter use of antibiotics in western countries so
throughout the United Kingdom’s hospital sys-
as to reduce health care costs. To effect change much
tem; they are often created without input from
will be required by the medical profession, politi-
junior staff, and new staff are not well informed
cians, the pharmaceutical industry, and not least
of existing policies.
patients.”
• Increased hospital infections may be linked to a
Authors: Richard Wise, Tony Hart, Otto Cars, Reinen decline in hygiene, staffing shortages, and a
Helmuth, Pentti Huovinen, Q. A. McKellar, David National Health Service policy of maximum
M. Livermore, Alasdair P. Macgowan, Martin C. J. occupancy for beds.
Wale, Stef L. A. M. Bronzwaer, Richard Coker, Bjorn- • Reporting of resistance to the Public Health
Erik Kristiansen, Yngvar Tveten, Andrew Jenkins, Laboratory Service is voluntary and informal.
David Wilkinson, S. B. Squire, Paul Garner, Alan P. The PHLS favors mandatory reporting of cer-
Johnson, Marina Warner, Neil Woodford, David C. tain resistances and of any unusual or unexpected
E. Speller, Valerie Schwoebel, Benedicte Decludt, resistance markers in any microorganisms.
Anne-Claire de Benoist, Sylvie Haeghebaert, Gabriela
Torrea, Veronique Vincent, Jacques Grosset, Sarah D. Key recommendations
de Ferranti, John P. A. Ioannidis, Joseph Lau, William • “The Royal Colleges should increase the atten-
V. Anninger, Michael Barza, Christopher C. Butler, tion paid to antimicrobial therapy in their pro-
Stephen Rollnick, Roisin Pill, Frances Maggs-Rapport, grams of postgraduate education and vocational
Nigel Stott, John Turnidge, C. A. Hart, S. Kariuki, R. training.
J. Williams, M. J. Ryan, Marc J. Struelens, Herman • Health authorities should step up their efforts
Goossens, Marc J. W. Sprenger, Peter M. Hawkey, in the areas of prescribing audits, feedback and
118
educational outreach (including communication nisms of resistance and the action of antimicrobials
skills). and, in the clinical sphere, methods of using agents
• The pharmaceutical industry and grant-giving to best advantage.”
bodies should give priority to work on rapid
Authors: Sub-Committee members: Lord Dixon-Smith,
affordable systems for diagnosis and susceptibil-
Lord Gregson, Lord Jenkin of Roding, Baroness
ity testing.
McFarlane of Llandaff, Baroness Masham of Ilton,
• The Medicines Control Agency should consider
Lord Perry of Walton, Baroness Platt of Writtle,
whether the drug licensing system could be used
Lord Porter of Luddenham, Lord Rea, Lord Soulsby
more effectively to encourage prudent use in the
of Swaffham Prior, Lord Walton of Detchant, Lord
interest of public health.
Winston; with Specialist Advisors Professor Harold
• Antibiotic growth promoters, such as virginia-
Lambert and Professor Richard Wise
mycin, which belong to classes of antimicrobial
agent used (or proposed to be used) in man and Type of publication: Report
are therefore most likely to contribute to resist- Pages: 108
ance in human medicine, should be phased out,
preferably by voluntary agreement between the Intended audience: United Kingdom; policy-makers,
professions and industries concerned, but by general public
legislation if necessary. Study timeframe: July 1997 to March 1998
• The UK National Health Service should set it-
Study process: Sub-Committee members conducted
self targets for controlling MRSA in hospitals,
interviews at the Headquarters of the Public Health
and publish its achievements. The NHS should
Laboratory Service, King’s College Hospital, and
also draw up national standards and guidelines
with individual experts in the United States and
for community infection control management.”
United Kingdom. Members also gathered evidence
from the agricultural and pharmaceutical industries,
international and regional health organizations, and
Responsibilities were delegated to various govern-
professional medical and scientific societies.
ment agencies and departments of the United King-
dom. Type of organization: Government
“This enquiry has been an alarming experience, Key contact
which leaves us convinced that resistance to antibi- The Publications Centre: PO Box 276, London
otics and other anti-infective agents constitutes a SW8 5Dt; Tel. +44 0345 58 54 63; fax +44 0170
major threat to public health and ought to be rec- 873 8200; Web site: http://www.hmso.gov.uk/
ognized as such more widely than it is at present.
We commend the current trend towards local anti- (22) Antimicrobial Resistance: Issues and
biotic formularies and evidence-based clinical Options. Workshop Report from the
guidelines, giving professionals agreed definitions Forum on Emerging Infections
of prudent practice in particular situations. But the
Organization: Institute of Medicine
issuing of documents is not enough to turn policy
into practice; it must be followed through in pro- Year published: 1998
fessional education, and continuing professional
development. We do not recommend that GPs Selected key findings
should be required to establish antimicrobial • The global effort to control antibiotic resistance
susceptibility before prescribing. This, we believe, lacks adequate surveillance mechanisms and
would at present be impracticable, and would over- comprehensive databases.
load diagnostic series which are already stretched. • There is a lack of research on the greater im-
But improved access to microbiological testing pacts of antibiotic use in animals, including the
clearly reduces uncertainty in prescribing. Potent transfer of resistance.
agents important to human medicine, such as the • There has been insufficient analysis of the reser-
fluoroquinolones, deserve extreme economy of use voir of antimicrobial drug-resistant genes.
in veterinary practice. There is still much that needs
to be done to increase understanding of the mecha-
119
Key recommendations tive models of the differences that judicious use

Surveillance: would make, to help in policy development,
• “Funding, implementation, assumption, or advocacy, and action;
assignment of leadership, and formation of part- • Designing and implementing research on clini-
nerships for implementing the 1995 American cal outcomes from shorter courses of therapy and
Society of Microbiology’s detailed recommen- different dosing regimens, as the basis for up-
dations for a comprehensive resistance surveil- dating practice guidelines and revising labeling.”
lance program;
Developing new products
• Improving data gathering and analysis, perhaps
• “Conduct studies of gene flow in order to
through national systems that would continu-
understand the diversity and prevalence of re-
ously monitor antimicrobial usage in hospitals,
sistant gene families and to discern the origins
community and farm environments;
of resistant genes and how they spread from one
• Including information about the effects of
organism to another.”
resistance on the outcome of infections in data
collection systems; Legal and regulatory approaches
• Selecting and strengthening the laboratories in • “Exploring whether increased resistance and
a set of sentinel hospitals as bases for global rapid diminution of effectiveness of existing an-
assessment of the prevalence and transmission tibiotics might justify awarding greater author-
of the most critical antibiotic-resistant genes, ity to the CDC to monitor and enforce legal
including training laboratory personnel in sen- duties regarding resistance, and consideration of
tinel hospitals in standardized methodologies; the means by which this might be accomplished;
• Designing categories and pathways for reducing • Developing alternative ways to define efficacy-
data sets into comprehensive packages for use for example, surrogate markers, in vitro tech-
by clinicians and researchers; nologies, and animal models-to address the lack
• Expanding distribution of NCCLS Guidelines of well-defined populations for clinical trials.”
and perhaps increasing the frequency with which
they are updated.” Implementation suggestions
Existing projects of various government agencies
The use of antibiotics in food production
and departments of the United States are cited as
• “Collaborative access to data from veterinary
foundations for implementing the above recom-
reference laboratories;
mendations, including: a surveillance project
• Systematic, collaborative development, by the
being conducted by CDC, USDA and FDA; the
United States Department of Agriculture, the
USDA’s reports on food safety and antibiotic re-
American Veterinary Medical Association, the
sistance; and the EPA’s considerations of the use of
Food and Drug Administration and producer
antibiotic pesticides. The food-production indus-
organizations, of strategies and educational
try is also cited as a potential source of funding,
materials toward expanding ecological under-
research, and the development of guidelines for
standing;
prudent antibiotic use in food-producing animals.
• Developing cost-benefit and cost-effectiveness
models of different on-farm antibiotic usages to
enhance the public health community’s under-
“The evidence and opinions presented at this work-
standing of farmer perspectives.”
shop suggest…that the transition from a histori-
Prolonging antibiotic effectiveness cally generous armamentarium to one at least
• “Implementing a joint project involving all per- temporarily much less lavish could be mitigated by
tinent professional societies in developing uni- wiser policies, both to conserve what remains and
tary guidelines (including checklists for providers to plan for what is to come; policies for the most
to use in clinical settings) for antimicrobial use, cost-effective use of antibiotics; evidence-based
implementing their extensive dissemination, regulation, with transparent balancing of risks and
and, very importantly, updating them periodi- benefits; and as already exemplified in genome
cally based on annual data from longitudinal projects, social investment in the underlying sci-
studies; ence needed to develop new antimicrobial agents.
• Quantifying the risks of injudicious antimicro- Also, because antimicrobial drug resistance is in-
bial use and developing descriptive and predic- creasingly known to be a global problem, it can be
120
addressed only with international cooperation, at (23) Protecting the Crown Jewels of
a minimum in the acquisition and sharing of in- Medicine: A Strategic Plan to Preserve
formation. Whatever frictions might ensue from the Effectiveness of Antibiotics
shaping and implementing such policies would be Organization: Center for Science in the Public Inter-
more than offset by the savings in medical and hos- est
pital costs and, most importantly, by the deaths and
disability avoided.” Year published: 1998
Authors: Editors: Polly F. Harrison and Joshua Selected key findings

Lederberg. Forum Participants: Joshua Lederberg, Vin- No original key findings; report cites findings from
cent I. Ahonkhai, Steven J. Brickner, Gail H. original sources of research.
Cassell, Gordon H. Defriese, Nancy Carter Foster,
Renu Gupta, Margaret A. Hamburg, Dieter Key recommendations
Hinzen, James M. Hughes, J. Stanley Hull, Samuel • Congress should allocate funding for an antibi-
L. Katz, Kenneth W. Kizer, William Kohlbrenner, otic use initiative (including public and profes-
John R. LaMontagne, Carlos Lopez, Stephen S. sional education, national surveillance, research
Morse, Solomon Mowshowitz, Stuart L. Nightin- and development, etc.).
gale, Michael T. Osterholm, David M. Shlaes, John • The Department of Health and Human Services
D. Siegfried, P. Frederick Sparling. Forum Liaisons: should include goals for decreasing inappropri-
Barry R. Bloom, Enriqueta C. Bond, Gary ate use of antibiotics and antibiotic resistance in
Christopherson, Michael Hughes, Stephanie James, its Healthy People 2010 initiative.
C. Michelle Limoli, Stephen M. Ostroff, Gary • The FDA should change its policies on antibi-
Roselle, Fred Tenover. Study Staff: Jonathan R. Davis, otic advertising to curtail inappropriate antibi-
Polly F. Harrison, Gretchen G. Kidder, Christina otic use.
Thacker • The FDA should ban all subtherapeutic uses of
Type of publication: Workshop Report antimicrobial agents that are used in human
medicine or might select for cross resistance to
Pages: 115 antimicrobials used in human medicine.
Intended audience: United States; policy-makers, gov-
ernment Implementation suggestions
• Increased funding from Congress to implement
Study timeframe: Workshop conducted in July of
national education programs and surveillance.
1997
• Government health care facilities should serve
Study process: Workshop discussion, with partici- as models for the prudent use of antibiotics.
pants from government, industry and academia
Type of organization: Non-profit public health and
“Despite antibiotics’ extraordinary value, the over-
advisory organization; advisor to Federal Govern-
use of those miracle drugs in medicine and agricul-
ment on issues of public health
ture endangers their continued effectiveness. The
Languages (published in): English more antibiotics are used, the more likely it is that
Key contact bacteria will develop mechanisms to evade them.
Ordering information: National Academy Press, The development of new antibiotics has not kept
http://www.nap.edu up with the development of antibiotic resistance.
Content: Joshua Lederberg, Chair, Forum on The time has come when public and private insti-
Emerging Infections tutions, as well as the general public, must change
their policies and practices to prevent further in-
creases in antibiotic resistance. Rather than believ-
ing that new drugs continually can be developed
to treat antibiotic-resistant infections, public-health
prevention measures should be adopted.”
Authors: Patricia B. Lieberman, Ph.D., Margo G.
Wootan, D.Sc.
121
Type of publication: Booklet Human Services that creates a framework for evalu-
ating the risks and benefits of the current and
Pages: 27
future uses of antibiotics in agriculture.
Intended audience: United States; general public
Study timeframe: Works cited incorporate research Implementation suggestions
findings from 1972 to 1998. The Departments of Agriculture and Health and
Human Services would create the plan, devising
Study process: Compilation of statistics and infor- the goals and timeframes, and identifying the re-
mation from other sources (USDHHS, CDC, sources necessary to determine the safest uses of
American Society for Microbiology, scientific jour- antibiotics in agriculture. The Departments will also
nal articles, etc.). see to the filling of the existing gaps in data and
Type of organization: Non-profit, public health organi- research.
zation
“Although research has linked the use of antibiot-
Key contact ics in agriculture to antibiotic-resistant strains of
Center for Science in the Public Interest, 202-332- specific foodborne pathogens that affect humans,
9110 agricultural use is only one factor in the emergence
of antibiotic resistance in non-foodborne patho-
gens. Debate exists over whether the role of
(24) The Agricultural Use of Antibiotics
and Its Implications for Human agricultural use in the overall burden of antibiotic-
Health resistant infections of humans warrants further
regulation or restriction. CDC believes the poten-
Organization: United States General Accounting Of- tial human health risks call for action to restrict
fice antibiotics for growth promotion in animals. We
Year published: 1999 first raised concerns in 1977 about the potential
human health risks of this practice. Today, more
Selected key findings than two decades later, federal agencies have not
Experts from the Department of Health and reached agreement on the safe use of antibiotics in
Human Services, CDC and FDA “believe that re- agriculture. In developing a federal response, both
sistant strains of three specific organisms that cause human health concerns and the impact on the ag-
illness or disease in humans—Salmonella, Campylo- riculture industry are factors to consider.”
bacter, and E. coli—are linked to the use of antibi- Authors: Major Contributors: Robert E. Robertson, Erin
otics in animals.” Lansburgh, Stuart Ryba, Natalie Herzog, Jerry
There is only one federal program that specifi- Seigler, Shannon Bondi.
cally tests for antimicrobial resistance related to
agriculture: the National Antimicrobial Resistance Type of publication: Report to Senator Tom Harkin,
Monitoring System’s Enteric Bacteria program. The Ranking Minority Member, Committee on Agri-
program tests samples of Campylobacter and culture, Nutrition, and Forestry.
Salmonella from humans and animals for suscepti- Pages: 33
bility to 17 antibiotics.
“About 95 percent of Salmonella DT-104 strains Intended audience: United States
are resistant to five antimicrobials—ampicillin, Study timeframe: The review was conducted between
chloramphenicol, streptomycin, sulfonamides, and May 1998 and April 1999. It covered material from
tetracycline.” 1969 through 1999.
Between two and four million people each year
Study process: The authors conducted interviews with
contract Campylobacter infections; out of every
representatives from USA government agencies, the
1,000 reported cases, one will develop into Guillain-
agricultural industry, and agricultural associations.
Barré Syndrome, which may result in paralysis.
They also reviewed existing research on the subject
and consulted with experts and officials from CDC,
Key recommendation
FDA, USDA, and others to get their opinions on
Development and implementation of a plan by the
the material.
Secretaries of Agriculture and of Health and
122
Type of organization: Federal Government tive on efficacy and risk assessment to encom-
pass review of data on products already approved
and used elsewhere in the world;
Key contact • To improve drug availability, worldwide harmo-
Ordering information: USA General Accounting nization of requirements for drug development
Office, P.O. Box 30750, Washington, D.C., 20013; and review should be considered and further
tel.: (202) 512-6000; fax: (202) 512-6061 enhanced among the federal agencies that are
Available on the web at: http://www.gao.gov/ responsible for ensuring the safety of the food
supply;
• The Center for Veterinary Medicine should base
(25) The Use of Drugs in Food Animals: drug use guidelines on maximal safe dosage regi-
Benefits and Risks. Report by the mens for specific food animals, consider greater
Committee on Drug Use in Food emphasis on the pharmacokinetics of drug elimi-
Animals and the Panel on Animal
nation from tissues that are consumed in large
Health, Food Safety, and Public
Health quantity, and set drug withdrawal times accord-
ingly;
Organization: National Research Council • Increased funding for basic research that explores
Year published: 1999 and discovers new or novel antibiotics and
mechanisms of their action, including the de-
Selected key findings velopment of more rapid and wide-screen diag-
• “Use of antibiotics increases the risk of emer- nostics to improve the tracking of emerging
gence of microorganisms that are resistant to antibiotic resistance and zoonotic disease;
specific, and perhaps other, antibiotics. Devel- • Establishment of integrated national databases
opment of this kind of resistance is not restricted to support a rational, visible, science-driven de-
to antibiotic use in food animals; it is far more cision-making process and policy development
prevalent because of misuses in human medi- for regulatory approval and use of antibiotics in
cine; food animals, which would ensure the effective-
• A link can be demonstrated between the use of ness of these drugs and the safety of foods of
antibiotics in food animals, the development of animal origin;
resistant microorganisms in those animals, and • The committee recommends that further devel-
the zoonotic spread of pathogens to humans. The opment and use of antibiotics in both human
incidence of the spread of human disease in that medicine and food animal practices have over-
way is historically very low, but data are seriously sight by an interdisciplinary panel of experts
inadequate to ascertain whether the incidence composed of representatives of the veterinary
is changing; and animal health industry, the human medi-
• A major impediment to determining the effect cine community, consumer advocacy, the ani-
of antibiotic use in food animals on human mal production industry, research, epidemiology,
health risk is the complexity of food animal drug and the regulatory agencies;
treatment and subsequent food-processing and • Increased public- and private-sector research on
handling interactions. Post-farm good process- the effect of nutrition and management prac-
ing, storage and improper handling and cook- tices on immune function and disease resistance
ing are major contributors to the chain of events in all species of food animals;
that allows the pathogen to contaminate the • Increased public- and private-sector research on
product, proliferate on or in the food, and at- strategies for the development of new vaccina-
tain the large numbers that cause disease; tion techniques, on a better understanding of
• Substantial information gaps contribute to the the biochemical basis of antibody production,
difficulty of assessing the effect of antibiotic use and on genetic selection and molecular genetic
in food animals on human health.” engineering for disease resistance.”
Key recommendations Implementation suggestions

• “The Center for Veterinary Medicine should Issues concerning antibiotic use in food animals and
continue procedural reform to expedite the drug humans should be coordinated with regard to use
approval review process and broaden its perspec- patterns, resistance trends, surveillance data, and
123
recommendations for use in a partnership of regu- A. Shadduck, Kenneth Berns, Michael P. Doyle, Hollis
latory agencies, pharmaceutical companies, the food N. Erb, John Ferry, Jere E. Goyan, Werner Heuschele,
animal industry, and animal and human health care Helen H. Jensen, Franklin M. Loew, Joy A. Mench,
professionals. Harley Moon, Wilson G. Pond, R. Gregory Stewart.
Board on Agriculture: Dale E. Bauman, John M. Antle,
Conclusions/Executive Summary Sandra S. Batie, May R. Berenbaum, Leonard S. Bull,
“The committee concludes that the use of drugs in William B. Delauder, Anthony S. Earl, Essex E.
the food animal production industry is not with- Finney, Jr., Cornelia Flora, George R. Hallberg, Ri-
out some problems and concerns, but it does not chard R. Harwood, t. Kent Kirk, Harley W. Moon,
appear to constitute an immediate public health William L. Ogren, George E. Seidel, John W. Suttie,
concern; additional data might alter this conclu- James J. Zuiches. Food and Nutrition Board: Cuthberto
sion. The greatest concern is associated with the Garza, John W. Erdman, Lindsay H. Allen, Benjamin
use of antibiotics in food animals in such a way Caballero, Fergus M. Clydesdale, Robert J. cousins,
that there is a potential for antibiotic resistance to Michael P. Doyle, Johanna T. Dwyer, Scott M.
develop in or be transferred to pathogens that can Grundy, Charles H. Hennekens, Janet C. King,
cause disease in humans. This report acknowledges Sanford A. Miller, Ross L. Prentice, A. Catharine Ross,
that there is a link between the use of antibiotics in Robert E. Smith, Virginia A. Stallings, Vernon R.
food animals, the development of bacterial resist- Young.
ance to these drugs, and human disease—although
the incidence of such disease is very low. A sub-
stantial change in the human health risk posed by Pages: 253
antibiotic use would affect not only how animal Intended audience: United States; food-production
drugs are reviewed, approved, and used, but also industry, policy-makers, veterinarians
how food animals are produced. It should be noted
that antibiotics are still effective for their intended Study timeframe: The report considers information
purposes at the recommended dosages. New anti- from 1968 to 1998.
biotic drugs are needed to combat emerging Study process: The Committee reviewed the major
animal diseases that do not respond to traditional classes of drugs used in food animals; reviewed sci-
drugs and so threaten public confidence in animal entific literature; heard testimony on animal-drug-
agriculture and human medicine. Professionals in related issues; reviewed federal regulations that
human health care should be concerned that they provide guidelines and list mandatory practices for
do not have enough specialty antibiotics to treat drug use, monitoring capabilities for drugs and
resistant and emerging infections in humans, as residues in foods, veterinary oversight in prescrip-
should veterinarians. The question is, should newly tion drug use, rates of violations, and instances of
discovered medications be held in reserve for documented health problems.
human or animal use only? Antibiotics should be
Type of organization: Non-profit organization, the
available to treat specific human and animal dis-
working arm of the National Academy of Sciences
ease with proper accountability and oversight of
and the National Academy of Engineering
the drugs used.”
Authors: Committee on Drug Use in Food Animals: James
R. Coffman, George W. Beran, Harvey R. Colten, Key contact
Connie Greig, Jean Halloran, Dermont Hayes, John Ordering information: National Academy Press,
B. Kaneene, Kristin McNutt, David Meeker, Stephen http://www.nap.edu
C. Nickerson, Thomas Seay, R. Gregory Stewart. Panel Content: James R. Coffman, Chair, committee on
on Animal Health, Food Safety, and Public Health: John Drug Use in Food Animals
124
APPENDIX B
Local action around the world
■ APUA Latin American Initiative Activities of the APUA Latin American Initiative
Report prepared by APUA The Latin America Initiative increases the impact
and reach of chapter work by providing a mecha-
The mission of APUA is to promote the prudent nism to link countries and share resources, infor-
use of antibiotics in order to preserve their power mation, and expertise. Activities supported through
for future generations. The establishment of for- the initiative include country-specific projects as
eign-affiliated chapters to conduct research and well as efforts to develop regional communications
education activities tailored to local needs is an and region-wide research and educational activi-
important vehicle for achieving this goal. APUA’s ties. These activities are coordinated to build on
Latin America Initiative was developed to PAHO activities at the country and regional levels.
strengthen and expand existing APUA country ac- This section includes a list of activities in the re-
tivities to curb the development of antibiotic region supported by APUA or conducted in collabo-
sistance and to coordinate these activities with ration with WHO, PAHO, ministries of health,
related activities in the region. Through the Initia- and other institutions and organizations.
tive, APUA’s regional network of chapters has grown
from five to ten, with eight additional countries in
Chapter development activities
the process of developing chapters. This regional
initiative has been funded largely by the United The Latin America Initiative has grown from the
States Agency for International Development initial group of five country chapters to include the
(USAID) and the Pan American Health Organiza- following countries: Argentina, Chile, Colombia,
tion (PAHO) and is being implemented in collabo- Cuba, Dominican Republic, Ecuador, Guatemala,
ration with PAHO’s IMCI (Integrated Mexico, Venezuela and Uruguay. Efforts are cur-
Management of Childhood Illness) Unit. rently underway to establish APUA chapters in the
A key feature of the Initiative is the network of following countries:Bolivia, Brazil, Costa Rica, El
APUA country chapters. With a strong foundation Salvador, Honduras, Nicaragua, Paraguay and Peru.
in microbiology and infectious disease, chapter
members work at the grassroots level to tailor in- Research activities
terventions to local situations and to provide a link
between data and action within their countries. • A study conducted by our Uruguay chapter in
Through the Initiative, APUA is collaborating with 1999 compared the rate at which antibiotics were
PAHO and its Member States to develop interven- prescribed for children with pharyngitis to the
tions to curb antibiotic resistance. PAHO, with actual need for antibiotics, based on the percent-
APUA and other partners, has been involved in age who tested positive for Streptococcus pyogenes.
developing a strategic plan for the surveillance of The study showed that while 75% of the 212
antibiotic resistance as well as laboratory training children who presented with pharnygitis at an
activities to support a regional surveillance network. outpatient clinic were prescribed antibiotics,
APUA has also been working with the IMCI Unit only 15% tested positive for Group A Strepto-
of PAHO to develop and implement projects to coccus pyogenes (GAS). By demonstrating the
curb antibiotic resistance within the context of overuse of antibiotics for children with pharyn-
IMCI. APUA will continue to expand its network gitis, the study aims to persuade pediatricians
of chapters in Latin America and support existing to modify their prescribing habits. The study was
chapters as they work more aggressively towards funded by the Ministry of Health, PAHO, and
documenting, understanding, and containing an- APUA.
tibiotic resistance.
125
• In 2000, APUA funded a study by its Guatema- organizations, such as surveillance, capacity-
lan chapter titled “Study of the Risk Factors for building, and provider trainings.
Antibiotic Resistance of S. pneumoniae among
• APUA provided assistance in the design of a
Guatemalan Children from Different Socio-
comprehensive one-week training course in test-
Economic Strata and Health Care Delivery Sys-
ing organisms for susceptibility to antibiotics and
tems”, to be completed in 2001.
resistance surveillance, which was conducted by
• APUA, in collaboration with PAHO, is conduct- the Ministry of Health in Argentina, in collabo-
ing a regional survey of physician’s knowledge, ration with PAHO and the APUA-Argentina
attitudes, and practices (KAP) regarding antibi- chapter. APUA plans to adapt the course for use
otic resistance and use. The survey, developed in other countries in the region, in collabora-
by APUA and pilot-tested in Argentina, will tion with PAHO.
initially be conducted in 9 countries, and will • In collaboration with PAHO, APUA produced
inform the development of appropriate treat- a Spanish version of the APUA patient educa-
ment guidelines and provider educational tion brochure and health care provider wall
materials. poster for distribution via PAHO and APUA
• APUA provides technical assistance to chapters chapters throughout Latin America.
in the region, including help with meeting and • APUA supported the development or transla-
conference planning, providing speakers, sup- tion of articles in Spanish on otitis media and
porting the south-to-south exchange of exper- the prevention and treatment of pneumococcal
tise, and proposal development for grants from infections, that were published on the APUA
APUA and other funding sources. Web site and in the monthly bulletin of PAHO’s
• Five chapters were awarded grants from the 2000 IMCI programme.
Joint Initiative to conduct research on antibi- • A week-long Latin America regional training
otic use. APUA provided technical support course on laboratory surveillance methods for
during proposal development. detecting antimicrobial resistance, was held in
• APUA chapters contributed to the IMCI News April 2000 in Buenos Aires, Argentina. The
bulletin produced by PAHO. course was organized and designed by the
Argentine Ministry of Health and founding
• The new APUA chapter in Colombia has plans
members of APUA-Argentina, with assistance
to develop a surveillance and reporting network
from PAHO and APUA. One hundred micro-
for antibiotic resistance in tertiary hospitals
biologists from Argentina, as well as 20 partici-
throughout the country using WHONET soft-
pants from other Latin American countries,
ware. The plan includes the dissemination of
attended this hands-on training to improve and
regular reports on resistance to hospitals and
update their skills and knowledge in suscepti-
national health authorities, including a formal
bility testing techniques, specific organisms,
annual report from the network.
interpreting test results, quality control, and the
management of susceptibility data. Participants
Training and educational activities will take these newly-acquired skills and knowl-
edge back to their colleagues. APUA and PAHO
• APUA conducted a Continuing Medical Edu-
plan to sponsor similar trainings in other Latin
cation session on “Improving Antibiotic Use in
American countries, after adapting the course
the Management of Childhood Illnesses” held
to address challenges faced by less developed
in June 2000 at the Global Health Council an-
countries in the area. The refined curriculum
nual meeting in Washington, DC. This session,
will also serve as a model for other countries with
attended by clinicians, public health profession-
limited resources outside of the region.
als and policy makers, featured background in-
formation on the antimicrobial resistance
problem, specifically as it relates to children’s Conference and networking activities
health in Latin America. It also described the • APUA, in collaboration with PAHO and the Pan
APUA-PAHO/ IMCI partnership as a model for American Association for Infectious Diseases,
collaborative work to contain resistance and organized a symposium on “Prudent Use of
other related projects sponsored by the two Antibiotics in the Developing World” during the
126
International Congress on Infectious Diseases potential inappropriate use of antibiotics is a grow-

(ICID) in Buenos Aires in April 2000. The sym- ing concern. The sale of medicines by prescription,
posium covered partnerships to address antibi- including antibiotics, has almost ceased in Moldova.
otic resistance, the application of community Officially, antibiotics are prescription-only drugs
research results to clinical practice, effective strat- in Moldova. In practice, they are widely available
egies for provider education, and the process of in many pharmacies and even on the streets. The
designing clinical guidelines for antibiotic use. doctors’ recommendations are often ignored as pa-
tients are lured by drug store offers. On the other
• APUA has established a Spanish-language
hand, doctors are extremely underpaid in Moldova
listserve for the Latin America region. The
and can gain some money by selling or prescribing
listserve, moderated by APUA’s Latin America
antibiotics. Thus it is often hard to discuss the con-
Project Director, allows Latin American health
cept of a rational choice of an antibiotic with health
professionals to regularly exchange information
care providers and the general public.
on research related to antibiotic resistance and
The situation in Moldova shows several prob-
use, offer or seek technical assistance from other
lems associated with the use of antibiotics includ-
participants, and post announcements of up-
ing widespread inappropriate antibiotic use, young
coming meetings and funding opportunities.
children frequently medicated with antibiotics for
too short a course, and a vast majority of self-medi-
■ Moldova: Nongovernmental cated treatment regimes. Only one-sixth or one-
organizations and antibiotic seventh of the antibiotics are recommended by a
programmes doctor and resistant respiratory pathogens are wide-
Report prepared by Natalia Cebotarenco, Ph.D., Director spread among the children.
of the Association Drugs, President APUA Moldova,
“natalie”@drugs.mldnet.com or
A non-governmental medical organization is formed to
natalie@drugs.moldova.su
provide drug information
Antibiotics have revolutionized the treatment of With new political possibilities in 1995, a medical
common bacterial infections and have a vital role non-government organization, Association
in reducing child mortality. Since antibiotics were DRUGS, was established in Moldova. The Asso-
first introduced, their consumption has increased ciation DRUGS provides unbiased, up-to-date
dramatically in most parts of the world. Resistant information on the safety and efficacy of drugs to
bacterial strains have emerged and spread through- interested health professionals, consumers and
out the world because of the remarkable genetic government institutions such as the Ministry of
plasticity of the microorganisms, heavy selective Health, the National Institute of Pharmacy, the
pressures of antibiotic use, and the mobility of the Moldavian Medical and Pharmacy University
world’s population. “N.Testemitanu”.
The problem of resistance to antimicrobial drugs The first project by the Association DRUGS in
is particularly troublesome in a country like the 1995 was the establishment of the Information
Republic of Moldova that also has economic and Centre with the goal of promoting rational drug
societal problems. After the collapse of the Soviet use and the Essential Drugs concept in Moldova.
system, Moldova instituted an economic reform Since its beginning, the Association DRUGS has
that tried to establish a market economy. The eco- provided 47 seminars and training sessions on vari-
nomic changes led to increasing numbers of ous aspects of rational drug use at the hospitals in
private pharmacies. Moldova has 4.35 million citi- Chisinau (capital of Moldova) and in regions of
zens and 1500 registered pharmacies. More than Moldova, as well as the Postgraduate Faculty of the
85% of the pharmacies are private. This situation Medical and Pharmacy University of the Republic.
brought a flood of medicines on the market in More than 2,700 physicians and pharmacists took
Moldova and created a situation of uncontrolled part in its educational programmes. Since January
dispensing of medicines. 1996, 34 issues of the independent Drug Bulletin
Increasing the availability of antibiotics and en- were published with 1,500 samples distributed free-
hancing their appropriate use are two interrelated of charge for physicians and pharmacists. Through
aims. With the increasing quantity and variety of the activity of Association DRUGS, a network was
pharmaceuticals available today in Moldova, the created for rational drug use in Moldova, which
127
included authorities from the Ministry of Health, ized but were not necessarily interactive. Practically
the National Institute of Pharmacy, Medical and speaking, the treatment guidelines are not available
Pharmaceutical University of Moldova, pharma- to many physicians. Many Moldavian pediatricians’
cists, physicians, journalists and non-governmen- English knowledge is not good enough to allow
tal organizations. them to get information or enable them to follow
From the beginning of the activity in 1995, the international recommendations and guidelines. For
Association DRUGS analysed 1500 records from these reasons the guidelines do not work in Moldova
the children’s hospital “V. Ignatenco” in Chisinau yet.
(the capital of Moldova), focusing on physicians’ Considering that the incorrect prescribing of
antibiotic prescriptions. The most common antibiotics by physicians is one of the factors that
pediatricians’ problems were inappropriate antibi- stimulates the development of antimicrobial resist-
otics prescriptions that included polytherapy and ance, it is necessary to create an appropriate educa-
the overprescribing of antibiotics: tional strategy.
• Acute respiratory infections were treated with
1–2 antimicrobials How can the behaviour of pediatricians be changed?
• Acute pneumonia was treated with 2–3 anti- As poor prescription practices were originally
microbials, occasionally 4 antimicrobials attributed to a lack of appropriate prescribing in-
• Predominance of antibiotic injections formation, the main strategy focused on providing
• Duration of treatment too short (fewer than 3 up-to-date information regarding appropriate pre-
days) or too long (more than 15 days) scriptions of antibiotics and the antimicrobial
• Overuse and too high a dose of antimicrobials resistance problem. Education on the proper use
• Inappropriate choice of antibiotic group of antibiotics has a limited effect if the existing drug
distribution patterns and information sources are
• Predominance of gentamicin and cefalosporins
not rationalized. Health workers who try to change
of the second or third generation
patterns of antibiotic use realize more and more
• Non-consideration of microbiology control that what is rational depends very much on what
before or during treatment course by antibiotic people think is rational, what their living condi-
• Non-consideration of the problem of antibiotic tions are and what drugs and diagnostic tools are
resistance in daily work. available in the health care context.
The survey showed that there was no professional In order to improve the situation with inappro-
awareness of the problem of antibiotic resistance. priate antibiotic prescriptions, a training pro-
Antibiotic resistance problems have not been and gramme has been developed with the support of
are not identified as national priorities of the health the APUA and United States Pharmacopoeia in
care system. collaboration with the Association DRUGS in
Moldova. The health training programme was
created in 1998-1999 to help middle and lower level
Was education of pediatricians carried out continually? health workers, especially pediatricians, learn to use
Were guidelines for treatment developed? antibiotics more wisely and to help prevent antibi-
Given the chronic state of deficient funding that otic resistance.
covers only 5–7% of the hospitals’ needs, the anti- A pilot training programme was conducted at
biotic resistance problem must be approached by the Moldavian Medical and Pharmacy University
changing the educational system for physicians. to explore the practicalities, acceptance and educa-
However, the education programmes in the medi- tional value of the postgraduate department’s
cal school and University of Moldova do not in- pediatricians. During a needs assessment period,
clude the themes “Formulary system in the meetings were held with authorities from the Min-
hospital”, “Analyzing the cost-effectiveness of treat- istry of Health, pediatricians from the different lev-
ment”, “Essential Drugs Lists development”, els of the health system, and pharmacists to help
“Rational drug use” and other items in the update. identify barriers to rational antibiotic use. In addi-
In Moldova, the guidelines for the treatment of tion, teachers from academic institutions became
the most common infectious diseases were devel- involved. These groups see the need to change the
oped and distributed without general discussion or medical curriculum to include the antibiotic resist-
follow-up; a few scientific seminars were formal- ance problem and to monitor prescribing practices
128
in different health care facilities. Concerns expressed hospitals is still largely at a rudimentary level in
included the high number of prescriptions, inad- Moldova. Appropriate training experiences in man-
equate information about antibiotic use, and prob- aged care organizations may be a valuable strategy
lems with the poor quality of donated antibiotics. to address the current disconnect between the
The educational programme had five compo- traditional hospital-based education of pediatricians
nents: and the expanded competencies necessary to prac-
tice in intensively managed, integrated and account-
1. Questionnaire assessment of Knowledge,
able health systems. A main assumption is that a
Attitude and Practice Survey (KAPS) of middle
new learning strategy will either fit into existing
and lower level pediatricians.
patterns or trigger changes in the way that teach-
2. “Improving Antibiotics Use” Training. ers/trainers and learners talk together.
3. Distribution of the manual, “Antibacterial
Therapy”, in Russian to the participants of the References
training issued by the United States Pharmaco- 1. Kunin CM. Ann Intern Med 1993 Apr 1;118(7):
poeia. 557–61.
4. Distribution of the APUA Newsletter among 2. Ansari MZ. JPMA J Pak Med Assoc 1995 Jan;
pediatricians and publishing the result of the 45(1):18–23.
KAPS-survey in the informational bulletin of the 3. Ireland LM; Powell C. Br J Nurs 1997 JUN 26–Jul
Association DRUGS. 9;6(12):686–90.
5. Using mass media to attract the public’s atten- 4. Parsell G; Spalding R; Bligh J Med Educ 1998 May;
32(3):304–11.
tion to the topics of antibiotic rational use and
antibiotic resistance. 5. Okeke IN; Lamikanra A; Edelman R. Emerg Infect
Dis 1999 Jan-Feb;5(1):18–27.
The session of the training “Improving Antibi-
6. Quick JD et al., eds. Managing Drug Supply, 2nd
otics Use”consisted of:
ed. USA Kumarian Press 1997
• How to choose the most cost-effective anti-
biotics for essential drug list and formulary ■ Nepal: Developing a national
• Control the rise of antibiotic resistance antibiotic policy
• Limit antibiotic over-prescribing Report prepared by Mr. Shyam P. Lohani, M. Pharm.,
• Limit over-prescribing due to patient pres- Programme Coordinator, United Hands to Nepal,
sure Chapter Coordinator, APUA Nepal. Contact:
• Guidelines for drug donations uhn@mos.com.np
• Risks of using antibiotics for the treatment
of acute respiratory infections. Background
The effectiveness of the training in increasing The Drug Act was promulgated in Nepal in 1978
the students’ knowledge of rational antibiotic use to 1) control the production, distribution, sale,
and antibiotic resistance problems was measured export and import of drugs and 2) to ensure the
by a pre-test and post-test multiple choice exami- availability of safe, quality and efficacious drugs to
nation. Evaluations showed that the course in- the general public. Its first amendment was added
creased the knowledge and understanding of in 1988. To prevent misuse and abuse of drugs, all
pediatricians, helped them develop more positive of the available drugs are classified into three cat-
attitudes, and demonstrated the importance of egories according to their composition, efficacy and
multiprofessional teamwork and communication use as per the provision of the Drug Act. The three
among the physicians’ different specialities. Partici- categories are:
pating pediatricians believed that postgraduate
1. Group ‘Ka’—Narcotic, psychotropic drugs and
courses should include early and regular opportu-
potent active therapeutic agents.
nities for shared learning.
The key principle underpinning this framework 2. Group ‘Kha’—Antibiotics, hormones and gen-
is that a range of educational transactions may need eral therapeutic agents.
to occur for learning to be effective. 3. Group ‘Ga’—Other common drugs which are
The development of training programmes in safer.
129
Drugs in groups ‘Ka’ and ‘Kha’ are prescriptive • In 1998, PHON conducted a study on Priority
drugs while those in group ‘Ga’ are over the coun- and Misused Drugs in health facilities and pri-
ter drugs. According to the Drug Act, drugs placed vate sector practitioners which showed that
in the ‘Ka’ and ‘Kha’ categories are to be prescribed antibacterials were prescribed in 50.7% of all
by practitioners registered with the Nepal Medical encounters.
Council.
Research on dispensing practices showed recom-
His Majesty’s Government (HMG) of Nepal
mendations of antibiotics for diarrhoeal diseases,
published a National Essential Drug List in 1986,
fevers and viral infections.
which was revised in 1992 and again in 1997. To
Large amounts of antibiotics are used in animals
promote appropriate use of anti-infective drugs, the
not only as curative agents, but also as prophylac-
National Essential Drug List categorized the drugs
tic agents and as growth promoters. The total
according to the different levels of health care.
amount of antibiotics used in food animals and in
• Sub-health posts (the most peripheral health care feed in Nepal is not known. However, restricting
facilities, which are a part of each Village Devel- attention to the human use of antibiotics is not
opment Committee): amoxicillin, cotrimoxazole enough to curb bacterial resistance.
and tetracycline. The participants of a regional drug information
workshop at Nepalgunj and Pokhara on January
• Health posts (775 health care facilities): amoxi-
9–14, 1999, advocated for the need for a separate
cillin, procaine benzyl penicillin, chlorampheni-
policy for antibiotics. It was felt that a policy should
col, cotrimoxazole, and tetracycline.
be developed for prescribing of antibiotics and rais-
• District level (75 public health offices and 50 dis- ing the general public’s awareness of bacterial re-
trict hospitals): amoxicillin, benzathin penicil- sistance to antibiotics.
lin, benzyl penicillin, cloxacillin, procaine benzyl In response to this, the APUA-Nepal chapter,
penicillin, chloramphenicol, ciprofloxacin, on the request of the Department of Drug Admin-
erythromycin, gentamicin, metronidazole, tet- istration and the Ministry of Health, prepared a
racycline, rifampicin, streptomycin, ethambu- draft of a National Antibiotic Policy developed by
tol, sulfaacetamide, doxycycline and a committee of experts from the health, veterinary,
nitrofurantoin. agriculture and other fields. The initial draft of the
• National List: The national list includes all the National Antibiotic Policy was presented in a work-
drugs from the district level plus Cefotaxime. shop on May 18–20, 2000, at Dhulikhel, Nepal.
The participants presented their comments and
In addition to the antibiotics in the national list,
suggestions on the draft. These comments were used
other antibiotics available in the private sector re-
to prepare a final draft which is pending at the
tail shops need to be registered with the Depart-
Ministry of Health for approval.
ment of Drug Administration (DDA), Nepal. A
new molecule, including an antibiotic, is not regis-
tered in Nepal until it is included in the recognized Details of the proposed national antibiotic policy
pharmacopoeia as per the convention adopted by (2000)
the Drug Advisory Committee. The draft policy has nine sections: the preamble,
definition, main policy, objectives, strategic guide-
Antibiotic use pattern in Nepal lines, national antibiotic control committee,
Several research studies examined the prevalence research and development, technical cooperation
of antibiotic prescriptions: and monitoring and supervision. The draft recom-
mends:
• In 1994, in collaboration with the WHO, the • Classifying antibiotics into three categories:
DDA studied the prescribing habits of private reserved, restricted, and semi-restricted.
practitioners; this study showed that antibiotics
were prescribed in 49.85% of all cases. • Dispensing antibiotics only with a prescription
or within a nationally approved protocol.
• In 1997, in collaboration with PHCP/GTZ,
another DDA study (the Rapid Assessment of • Establishing interagency cooperation among
Pharmaceutical Management and Utilization) governmental, non-governmental and private
showed that antibiotics were prescribed in 59% institutions to promote the prudent use of anti-
of all encounters in health facilities. biotics by health care professionals and the gen-
130
eral public, with the assistance of His Majesty’s ■ Viet Nam: Hospital case study and
Government (HMG) of Nepal. national antibiotic policy
• Creating a National Antibiotic Control Com- Report prepared by Dr. Hoang Thuy Long, Director of
mittee comprised of concerned experts from National Institute for Hygiene and Epidemiology,
human and animal health, agriculture, profes- Vietnam. Chapter Head, APUA Vietnam.
Contact: daihocyhn@hn.vnn.vn
sional organizations, and organizations involved
in consumer rights and awareness under the
auspices of HMG. Policy of the Ministry of Health on the rational, safe,
and effective use of drugs
• Establishing a national antibiotic surveillance
system. In 1997–1998, the Vietnamese Ministry of Health
enacted a set of regulations to ensure the rational,
• Developing curricula for training and education safe, effective and economic use of drugs. These
on the prudent use of antibiotics, and incorpo- regulations:
rating them at all levels of prescribers’ and dis-
pensers’ education. • Established a Drug and Therapeutic Commit-
tee (DTC) in each hospital whose function was
• Promoting prudent use of antibiotics by imple- to oversee correct drug provision, management,
menting periodic training of health care work- and use.
ers who are eligible to prescribe drugs.
• Strengthened the policy of rational, safe and eco-
• Creating and regulating a National Antibiotic nomic use of drugs in the clinic and polyclinic
Therapeutic Advisory Committee (NATAC) institutions.
comprised of concerned experts from relevant
sectors, under the auspices of HMG.
The Drug and Therapeutic Committee’s tasks are:
• Facilitating research on prescribing, dispensing,
• To implement the national policy of using drugs
and use of antibiotics as well as antibiotic resist-
in hospitals.
ance.
• To set up basic regulations concerning the sup-
• Encouraging the involvement of national and
ply, management, and use of drugs in hospitals
international agencies in technical training, edu-
and then submit the regulations to the hospi-
cation, and research related to the prudent use
tal’s director for approval.
of antibiotics.
• To set up the lists of drugs used in hospitals and
• Creating subcommittees of the National Anti-
submit the lists to the hospital’s director for
biotic Control Committee to be responsible for
approval.
effective implementation of the antibiotic policy
as well as for monitoring and supervising its im- • To set up the drugs’ distribution procedure, sub-
plementation. mit the procedure to the hospital’s director for
approval and help the director to implement the
• Requiring that antibiotics used for therapeutic
procedure.
purpose in humans and animals not be used as
growth promoters or prophylactic agents in ani- • To help the hospital’s director carry out the fol-
mal feed. lowing activities:
• Developing national antibiotic guidelines, which — Supervise rational prescription of drugs:

will assist individual health and veterinary insti- — Set a rational prescription standard.
tutions to formulate local antibiotic guidelines. — Check the contents of case histories that
refer to the drug use process.
• Developing facilities for antimicrobial resistance
— Supervise adverse drug reactions in the hos-
testing and detection of antibiotic residue in live-
pital.
stock products in health and veterinary institu-
— Organize drug information.
tions, with the help of HMG.
— Organize scientific research and training on
current knowledge of drugs.
— Set up a cooperative relationship between the
pharmacist and the physicians and nurses for
drug use in patients.
131
Prior enactment, these Instructions were tested Anybody can buy antibiotics without a prescrip-
for a year in four city or provincial hospitals in tion. Hundreds of different brands of antibiotic
North Vietnam. In 1999, the Ministry of Health products are on the market and lack of informa-
organized a conference to evaluate the impact of tion favours their misuse, such as unnecessary use,
the Drug and Therapeutic Committees after two incorrect choice, incorrect dose, incorrect admin-
years of operation. istration, or poor drug quality. This misuse is the
reason for increasing bacterial resistance, leading
to prolonged treatments in hospitals and increased
The results of this evaluation showed:
expenses for drugs and services.
• Active participation by the Drug and Therapeu- In March 1996, as one of the four pilot projects,
tic Committee in the drug regulation in the the Ministry of Health established the Drug and
hospitals. Therapeutic Committee (DTC) at the Hospital
• Enhanced supervision of adverse drug reactions. Gynecology-Obstetric Hanoi (HGOH). The
HGOH is a top-ranked hospital in Gynecology and
• The Pharmacy Departments supplied a sufficient Obstetrics in Hanoi City. The HGOH treats
quantity of drugs of good quality. gynecological diseases and pathologic pregnancies,
• In some hospitals: provides sterility treatment, family planning and
obstetric services. The registered capacity of the
— The Pharmacy Department was able to
hospital is 200 beds, but it is always working at
advise and provide drug information.
overcapacity with both out- and in-patients. The
— A good working relationship was established
hospital is a reliable institution for women in Ha-
between physicians, pharmacists and nurses
noi and surroundings.
to consult about drug use in patients.
After being established, the HGOH Drug and
• In many hospitals the Drug and Therapeutic Therapeutic Committee organized regular meetings
Committee had just been established and is not to encourage appropriate prescribing models and
yet a fully functioning entity. drug choice for each patient. As time went on,
models were reviewed and improved as needed. The
Lessons learned from this experience appropriate choice of antibiotic:
• Instruction and management by the Ministry of • Was specific for the pathogen germ.
Health of the activities of the Drug and Thera- • Was quickly and well absorbed at the infection
peutic Committee site.
• Instructional activities of the Drug and Thera- • Was appropriate to the treatment goal:
peutic Committees and of the provincial health gynecological, obstetric, post- obstetric, new-
service born, inpatient, or outpatient.
• Was appropriate to the treatment subject, i.e,
pregnant, newborn.
■ Utilization and management of
antibiotic use in Hospital Gynecology- • Minimized adverse drug reactions.
Obstetric Hanoi (1995–1999) • Was of reasonable cost and acceptable to patients.
Bui Suong, MD, Hospital Gynecology-Obstetric Hanoi
The HGOH’s Drug and Therapeutic Commit-
and Nguyen Thi Vinh PhD, Medical College Hanoi,
tee has observed changes in antibiotic use since the
Viet Nam
Committee was implemented.
This article is from the report of the workshop
“Rational, safety use of antibiotics” held on Febru- 1. The proportion of patients using antibiotics
ary 28–29, 2000 in Hanoi. in the hospital
Bacterial infection remains one of several fac-
About 90% of patients used antibiotics. The re-
tors leading to high mortality rates. Antimicrobial
maining 10% included pregnant patients planning
agents play a decisive role in reducing the mortal-
to nurse their newborns and some doubtful cases
ity and the incidence of bacterial infections. Today
of ex-uterine pregnancies; antibiotics were not used
antibiotics are widely and inappropriately used.
in these cases.
132
TABLE 1. OUT- AND IN-PATIENTS AT HOSPITAL GYNECOLOGY-OBSTETRIC HANOI
1995 1996 1997 1998 1999
1. Total number of patients examined 46,030 52,147 60,868 74,974 75,068

Total number of examinations 68,902 78,061 90,746 105,886 105,021
Total number of abortions 4,931 5,417 6,150 7,099 7,619
2. Total number of inpatients 10,487 12,007 12,342 13,061 14,600

Total number of deliveries 5,778 6,139 6,924 7,204 7,682
* Difficult 2,419 2,893 2,992 3,207 3,057
* Normal 3,359 3,246 3,932 3,997 4,625
Total number of operations 1,943 2,393 2,540 2,979 3,100
* Gynecological 593 784 976 1,193 1,142
* Obstetric 1,353 1,609 1,549 1,777 1,958
3. Average duration of therapy (days) 6.7 6.3 6.0 6.4 5.8
TABLE 2. ANTIBIOTIC USE BY PATIENTS
1995 1996 1997 1998 1999
Number of patients using antibiotics 9,616 10,926 11,207 11,820 11,753
Total number of patients 10,487 12,007 12,342 13,061 14,600
% 91.7% 91% 90.8% 90.5% 80.5%
• Generally, only one antibiotic was used for logic)

prophylaxis after abortion or delivery with epi- — Antibiotic + antifungi
siotomy.
• Antibiotic combination therapy was reduced in
• When necessary, antibiotic combination therapy 1999 because antibiotic prophylaxis was intro-
was used as follows: duced in surgery in 1996 and was implemented
— β-lactam (ampicillin) + aminoglycoside (gen- hospital-wide in 1998.
tamicin) were the main combination used
• Antibiotic use was greatly reduced in 1999
— β-lactam (cephalosporine) + metronidazole
(19.5%) because antibiotic use was removed for
— β-lactam + aminoglycoside + metronidazole
all cases of normal delivery with tidy amniotic
— Quinolone + aminoglycoside (few/gyneco-
fluid, entire placenta, no episiotomy.
TABLE 3. PROPORTION OF PATIENTS USING ANTIBIOTIC COMBINATION THERAPY
1995 1996 1997 1998 1999
Percent of patients using antibiotics 91.7% 91% 90.8% 90.5% 80.5%
Percent of patients using one antibiotic 50.8% 57.4% 71.4% 74.6% 68.6%
Percent of patients using two antibiotics 30.3% 25% 15.3% 12.3% 10.5%
Percent of patients using ≥ 3 antibiotics 10.6% 80.6% 4.1% 3.6% 1.4%
TABLE 4. PROPORTION OF EXPENDITURE FOR ANTIBIOTICS
1995 1996 1997 1998 1999
Expenditure for antibiotics (thousands Vndong) 322,127 646,867 905,159 1,010,433 1,043,799
% of total drugs expenditure 45.8% 45.6% 44.3% 43.8% 43.5%
133
• The expenditure for antibiotics is appropriate been advising the director on the rational, safe and
for a top-ranked hospital for Gynecology and effective use of drugs, including antibiotics. All lead-
Obstetric Surgery in Hanoi City. ers of the hospital understand the necessity of the
rational, safe and effective use of drugs for therapy,
• The proportion of antibiotic expenses was gradu-
as promoted by the Ministry of Health.
ally reduced from 1995 to 1999.
The Drug and Therapeutic Committee guide-
Today about twenty antibiotics are being used, lines for the Pharmacy Department and the
with ten in common use. The Drug and Therapeu- Planning Department are:
tic Committee considers every sort of antibiotic.
To be chosen, the antibiotic must be therapeuti-
Drug providing
cally effective, have few adverse drug reactions, and
be manufactured by a reliable firm. Only one brand • The Pharmacy Department provides sufficient
product of every antibiotic is used, making super- drugs on time and at high quality. Drugs are
vision and management easier. While the kinds of generally obtained from state pharmaceutical
antibiotics may be increased or decreased, the quan- firms.
tity of expensive antibiotics was reduced from 1995 • Only one of several products under the same
to 1999. generic name is used; this product must be of
good quality and meet the therapeutic demand
2. Antimicrobial prophylaxis to facilitate the management and supervision of
antibiotic use in the hospital.
From 1996 the hospital has used cefuroxime 0.75g
x 03 (or 04) ports/case to test for prophylaxis in
surgery (gynecological and obstetric) due to the Prescribing
short duration. Hygienic measures, sterilization and • On a yearly basis, experts are invited to give lec-
disinfection methods reduced the post-operative tures on special topics in clinical pharmacy, such
infection rate considerably (from 19.8% to 11.7% as antibiotics, vitamins, drug interactions,
in the period studied). Because of its success, this adverse drug reactions. The audience is made
is now the standard order for antimicrobial prophy- up of physicians, pharmacists and nurses from
laxis in the hospital. The post-operative infection the whole hospital.
rate is 5% (fever 38.5–39 °C, inflammation at in-
• One pharmacist and two physicians (special first
cision site) with no cases of serious post-operative
level) revise, advise and help the physicians to
infection.
prescribe rational, safe, effective antibiotics.
Today, antimicrobial prophylaxis achieves good
results, reducing pain for patients, shortening an- • A clinic pharmacist helps physicians choose
tibiotic duration, avoiding drug complications, re- appropriate drugs for treatment of patients.
ducing the effect on the mother’s milk (childbirth • At the weekly general meeting of the hospital,
operation). In addition, good economic results were the Pharmacy Department reports the case
achieved, reducing medical service and reducing histories of inappropriate drug use in order to
total expense for treatment in comparison to long- correct future problems.
term therapy with antibiotics. The antimicrobial
• Monthly, if a sudden change in the quantity of
prophylaxis regimen could help to reduce the rise
drug use is recognized, the Pharmacy Depart-
and spread of antibiotics resistant pathogens also.
ment reviews the case histories to find a reason
for the change. It reports to the Drug and Thera-
3. Managing measures for rational, safe use of peutic Committee and makes suggestions for
antibiotics by the Drug and Therapeutic solving the problem to gradually improve the
Committee quality of treatment.
In 1998, the HGOH’s Drug and Therapeutic Com-
mittee became a full-fledged, independent entity Drug use
in the hospital. The Committee has eight mem-
• The Pharmacy Department regularly makes
bers, with the director as the chairman and the head
guidelines and supervises the nurses and mid-
of Pharmacy Department as the permanent secre-
wives in using drugs according to prescription.
tary. Since its establishment, the Committee has
The Pharmacy Department cooperates with the
134
clinical departments to watch the effectiveness of drugs in the whole hospital (including in- and
of drug use and report any decrease in effective- out-patients) from the examination phase
ness to the Drug and Therapeutic Committee. through prescribing and realization of medical
The Pharmacy Department monitors any orders to the final result. There could be pun-
adverse drug reactions in time to recover. In four ishment for infringed cases.
years, fifty cases of adverse drug reaction were
found, in which 38 cases were caused by antibi-
otics. All cases were treated in time with no com- ■ Greece: Hospital case study of an
plication. antibiotic policy
• The physicians prescribe according to the guide- Report prepared by Helen Giamarellou, MD, PhD,
lines and the list of drugs, which are rewritten Professor of Internal Medicine, Athens University School
by the Drug and Therapeutic Committee each of Medicine, Sismanoglio General Hospital, Athens,
Greece; President, APUA Greece; Anastasia Antoniadou,
year, so that the use of antibiotics in the hospi-
MD, Nearchos Galanakis, MD, George Petrikkos, MD,
tal is becoming more rational, safe and effec-
Erasmia Sarmi, Pharmacist. Contact Dr. Helen
tive. The post-operative infection rate is being Giamarellou at: hgiama@ath.forthnet.gr
reduced. Therefore, although the number of
inpatients is increasing, the average duration of
This is a report on the encouraging results of our
treatment is decreasing (from 6.7 days in 1995
implementation of an antibiotic resistance policy
to 5.8 days in 1999).
in Laiko General Hospital during the period 1992–
1998.
Conclusion In Greece, as in other settings, high antibiotic
Enacting the policies of the Ministry of Health with resistance rates run in parallel with huge antibiotic
the determination of the director of the board and consumption in hospitals and in the community.
under the leadership of the Drug and Therapeutic We implemented a antibiotic restriction policy in
Committee, all physicians adhere strictly to the a 500 bed University teaching hospital. In this hos-
prescribing regulations and therapeutic guideline. pital, antibiotic consumption before 1990 ranged
Antimicrobial prophylaxis and the rational, safe use between 62–78% with the highest rates in the Gen-
of antibiotics showed a high degree of effectiveness. eral Surgery and Urology Departments (75–100%).
To improve results, we will promote the effec- The main overuse involved long-term surgical
tiveness of the Drug and Therapeutic Committee prophylaxis, while one-third to one-half of antibi-
activity by: otic consumption involved the unjustified use of
third generation cephalosporins, carbapenems,
• Strengthening science research activities in the newer quinolones and vancomycin. Resistance rates
hospital. among Gram-negative isolates were already high
• Encouraging and providing conditions for (Table 1) and the threat of losing all new active
personnel to improve their professional knowl- compounds because of their unjustified overuse was
edge. a reality.
Since 1991, an antibiotic restriction programme
• Re-educating physicians on prescribing regula-
proposed by Professor Giamarellou and her team
tions, principles of drug use in general and of
was implemented by the Infection Control Com-
antibiotic use in particular.
mittee of the Laiko General Hospital. According
• Regularly providing to physicians, pharmacists to the programme, all new antimicrobials (third and
and nurses sufficient and up-to-date informa- forth generation cephalosporins, aztreonam,
tion about drugs in the drug list and their imipenem and later meropenem, vancomycin and
administration. later teicoplanin and all newer quinolones) were
• Reinforcing surveillance on therapeutical effec- ordered to the hospital pharmacy only after physi-
tiveness of drugs being used in the hospital, find- cians had completed a restricted antibiotic form,
ing out about drugs with bad activity and/or which had to be inspected and signed by the hos-
adverse drug reactions in order to eliminate that pital infectious diseases clinicians (Laiko Hospital
drug from the drug list. had 3 of them) or by physicians with a proven in-
terest in infectious diseases. The programme was
• Strengthening supervision on rational, safe use
also supplemented by enforcement of the rules of
135
TABLE 1. RESISTANCE RATES TO SEVERAL ANTIMICROBIAL AGENTS OF socomial pneumonia (often in the form of clinical
5454 GRAM-NEGATIVE ISOLATES FROM 55 GREEK HOSPITALS
protocols) and limited susceptibility reporting from
DURING A 3-MONTH PERIOD (SPRING 1989)
the hospital’s Central Diagnostic Laboratory. The
Antimicrobial Pseudomonas Acinetobacter Enterobacter Klebsiella results were immediate and restricted antibiotic con-
agent aeruginosa spp spp pneumoniae
sumption was dramatically diminished (Table 2).
Cephalothin — — 95% 63% In order to improve further the quality of pre-
scribing, an Antibiotic Team was formed in 1992,
Cefotaxime — — 77% 51%
composed of an infectious diseases physician, a
Ceftazidime 31% 92% 67% 46% clinical microbiologist and a pharmacist, who un-
Imipenem 14% 1.1% 4.2% 0.5% dertook the mission to apply an audit programme
in close cooperation with the pharmacy, as an ex-
Ciprofloxacin 26% 59.6% 13% 10%
tension to the already active restriction policy. Three
Amikacin 44% 91% 51% 45% times a week, an infectious diseases physician (who
Gentamicin 45% 83% 43% 36%
rotated monthly) audited the antibiotic restriction
forms, before the pharmacy had delivered the re-
Netilmicin 61% 90% 66% 45% quired antibiotics (the pharmacy delivered drugs
to departments three times a week). Whenever an
order form was incomplete or the justification for
hygiene (particularly of hand washing and appro- requiring any restricted antibiotic seemed irrational,
priate use of gloves), educational programmes for the infectious diseases physician visited the clinics
small groups of physicians belonging to different and discussed the case with the resident doctors.
clinics, “consensus agreements” regarding mainly Every justified order form was valid for five days,
surgical prophylaxis, febrile neutropenia and no- after which a new complete and justified order form
TABLE 2. THE INITIAL EFFECT OF A RESTRICTED ANTIBIOTIC POLICIES PROGRAMME ON RESTRICTED ANTIBIOTIC
CONSUMPTION
Number of patients on restricted antibiotics

a
Restricted antibiotic January 1988 September 1989 January 1990 March 1990 June 1990
Vancomycin 118 32 15 16 15
Imipenem 102 28 22 32 13
Ceftazidime 150 60 43 54 26
TOTAL 370 120 80 102 54

a
control = consumption without restriction
TABLE 3. CONSUMPTION OF RESTRICTED ANTIMICROBIALS IN DIFFERENT CLINICS AFTER THE IMPLEMENTATION OF AN

AUDIT PROGRAMME
Percentage of patients on restricted antibiotics
Clinic November 1991 November 1992 November 1993 February 1994 February 1995
(without audit) (with audit) (with audit) (with audit) (with audit)
TOTAL 9.6%* 6.5% 6.2% 6.6% 5.8%
General surgery 12.2% 35 0.9% 1.4% 0.7%
Orthopedics 8.4% 1.9% 3.3% 1.8% 2.5%
Urology 2.7% 0.3% 0.9% 0.8% 1%
Transplant Unit 19% 18% 7% 12% 7.7%
Internal Medicine (neutropenics) 11.6% 12.8% 11.4% 11.4% 11.2%

(14%) (29%) (25%) (41%) (43%)
* before 1991 consumption exceeded 30%
136
needed to be sent to the pharmacy if the treatment TABLE 4. TOTAL CONSUMPTION OF RESTRICTED AND NON RESTRICTED
ANTIBIOTICS
was further prolonged.
In addition, every two months the Antibiotic Year Restricted antibiotics Non restricted antibiotics
Team organized scientific meetings with the staff
1991 12.5% 32%
and the residents of each clinic to discuss irrational
order forms, case studies, and treatment guidelines. 1992 7.5% 36.5%
Such meetings provoked large-scale discussion and 1993 7.3% 38.6%
were considered to be the most effective educational
programme on antibiotic use. At the same time 1994 7.9% 34.7%
surveillance of resistance and in-hospital antibiotic

consumption was performed every 3 months and TABLE 5. INDICATIVE DECREASING RESISTANCE RATES
the results were released to physicians and discussed
during the above-mentioned meetings. Antibiotic Indicative Resistance Rates (%)
After the introduction of the audit programme P. aeruginosa Enterobacteriacea
a further significant reduction in restricted antibi-
1991 1994 1991 1994
otics was observed (Table 3). The reduction was
mainly attributed to the implementation of Ceftazidime 45 8 — —
correct prophylaxis guidelines in the surgery Imipenem 7 7.5 0 0
departments (single dose of a second-generation
cephalosporin perioperatively in clean-contami- Ciprofloxacin 20 35 2 8
nated operations and three doses of vancomycin in Gentamicin 61 28 18 10

orthopedic and vascular surgery with the use of
prosthetic material). It is of interest that despite
the fear that restriction of advanced antibiotics Antibiotic Team decided that the quinolones should
might increase the consumption of non-restricted be totally restricted in the hospital, prescribed only
antibiotics, the overall antibiotics use was reduced in cases where a pathogen was exclusively suscepti-
by more than 50%, ranging between 32% and ble to this class of antimicrobials and after consul-
38.5% (= patients receiving antibiotics/patients tation with an infectious diseases physician and the
hospitalized x 100) (Table 4). approval of the Head of the Infectious Diseases
After three years of applying the audit pro- Department. As a result, consumption of quino-
gramme, there was a significant reduction in the lones decreased abruptly (by 80%) during the first
resistance rates of several classes of antibiotics trimester, but it took two years of continuous
(Table 5). In particular, for P. aeruginosa, a major application of the restriction policy to observe a
nosocomial threat, resistance to ceftazidime was marked decrease in quinolone resistance among the
reduced from 45% before 1990 to 8% in 1995, Gram-negative nosocomial pathogens (Table 6).
while for imipenem it remained low, at the same The above-mentioned policy has been success-
levels as when the antibiotic was introduced into
the Greek market (5–10%). Interestingly, although
aminoglycosides as a group were not officially TABLE 6. RESULTS AND IMPACT OF A TOTAL RESTRICTION PROGRAMME OF
restricted, their prescription in the hospital was self- QUINOLONES ON RESISTANCE RATES
limited due to the introduction of the newer β-
1st trimester 1995 4th trimester 1996
lactams and the fear of nephrotoxicity and were
confined only to septic or profoundly neutropenic Patients hospitalized 5181 5215
patients. As a result of this minimal use, mean
Number of patients taking
resistance rates for amikacin and gentamicin de- quinolones (%) 140 (2.7%) 30 (0.5%)
creased from 55% and 85% respectively before
Defined Daily Dose (DDD) 1167 250
1990 to 12% and 19%. However, it should be
pointed out that resistance to quinolones was not Sensitivity to Ciprofloxacin
influenced by the antibiotic policy programme, but E. coli 92% 95%
showed a steady increase, with levels of 35% and P. aeruginosa 66% 82%
30% for P. aeruginosa, and Enterobacteriaceae, re- P. mirabilis 70% 84%
spectively, observed in the spring of 1995. Conse- K. pneumoniae 74% 94%
quently, the Infection Control Committee and the Acinetobacter baumannii 15% 50%
137
ful in decreasing resistance rates in the closed sys- Background

tem within a university hospital, because: The introduction of an antibiotic policy into hos-
• Although restriction and audit were the main pitals has previously been shown to be an effective
parameters of the policy, as an entity it was a tool in the curbing of antimicrobial resistance. Such
multidisciplinary programme including surveil- policies have not been used extensively in Russia
lance, education, treatment guidelines, limited previously for a variety of reasons, including:
reporting sensitivity testing, consultation, and • Isolation of practicing doctors from modern
implementation of hygiene measures; international trends in antimicrobial chemo-
• The audit was effective because infectious dis- therapy.
eases physicians had the cooperation of the • The results of microbiological investigations
microbiology laboratory and the pharmacy; (including susceptibility testing) have little in-
• The team that tried to apply it consisted mainly fluence on clinical practice.
of infectious diseases physicians who worked • Presence of a ‘gap’ between microbiologists and
with enthusiasm and belief, despite initial diffi- clinicians.
culties with their fellow doctors’ attitude;
• Respected opinion leaders in the field of infec- Description of the antibiotic policy
tious diseases guided the programme, a fact that
made the work of the Antibiotic Team easier. • Clinicians were taught about rational antimicro-
bial chemotherapy on a regular basis via semi-
The lessons we learned from this experience, nars, case discussions, distribution of literature,
especially the fact that controlling and limiting participation in symposia and postgraduate
antibiotic use can reverse increased microbial re- courses.
sistance, can be applied to hospitals and the com-
munity. We are trying now to implement such a • Clinical pharmacologists were appointed to the
policy in hospitals on a national scale. Of course a SRH and provided regular consultation with
prerequisite is the presence of an infectious diseases physicians on the choice of antimicrobials.
physician in every hospital who will be responsible • A Formulary Committee was established with
for the implementation of the policy. the introduction of a formulary and its regular
update.
■ Russia: Hospital Case Studies of • Microbiological services were improved by
Antibiotic Policies means of:
Report prepared by Leonid S. Stratchounski, MD, PhD, — Continuous education of personnel in the
Director, Institute of Antimicrobial Chemotherapy (IAC), microbiological laboratory (including the
Russian Federation, Smolensk; President, APUA Russia; principles of selective reporting of suscepti-
Roman S. Kozlov, MD, MSc, PhD, Deputy Director of bility testing results);
Science, Institute of Antimicrobial Chemotherapy (IAC),
— After-hours coverage;
Russian Federation, Smolensk; Coordinator, APUA Russia;
— Implementation of internationally recog-
Alla S. Andreeva, MD, Clinical Pharmacologist, Smolensk
Regional Hospital, Russian Federation, Smolensk; and nized guidelines (National Committee for
Oleg L. Rozenson, MD, PhD, Assistant Professor, Clinical and Laboratory Standards
Department of Clinical Pharmacology & Antimicrobial (NCCLS)) for susceptibility testing within
Chemotherapy, Smolensk State Medical Academy, the microbiological laboratory;
Russian Federation, Smolensk.Contact Dr. Roman Kozlov: — Establishment of resistance monitoring pro-
roman@cliph.keytown.com grammes and data management (using
WHONET and other software).
Antibiotic Policy: Introduction of an antibiotic policy
into a large regional hospital The main areas addressed in the antibiotic policy
This is a report of the implementation of an anti- • The analysis of antimicrobials use within the
biotic policy in the Smolensk Regional Hospital SRH and by different wards (using the recom-
(SRH): 1,320 beds, 30 wards. mended WHO ATC/DDD methodology).
138
• Education of both microbiologists and clinicians lary system) had financial advantages (a total 2.2-
on clinical pharmacology of antimicrobials and fold decrease in hospital spending on
current issues on antimicrobial resistance. antimicrobials) and led to improvement in the re-
sistance profiles of the most prevalent pathogen in
• Development and implementation of antimicro-
the ICU (P. aeruginosa). An analysis of the influ-
bial drug formularies.
ence of the antibiotic policy on the development
• Policy to restrict the prescription of III-IV of antimicrobial resistance in other hospital wards
generation of cephalosporins, carbapenems, is currently under investigation.
amikacin, vancomycin, and so on.
• Improvements in the microbiological service Lessons learned from the above policy applicable to
provided. other countries
Education of health care providers, implementa-
Level of policy enacted tion of antimicrobial formulary and establishment
of close connections between microbiologists and
This was a regional level policy that could be used
clinicians have proved to be the most crucial
as an example for other hospitals wishing to imple-
issues. Such approaches could be successfully used
ment a similar strategy.
in both industrialized and developing countries.
Interim results of the antibiotic policy

Antibiotic Prophylaxis Policy: Optimization of
In 1999, a total of 33 antimicrobials were used in antibiotic prophylaxis in surgical wards of
the SRH and 4 antibiotics were not given in com- Smolensk Regional Hospital (SRH)
parison with 1997. Background
Over the same time period, hospital expenses
on antimicrobials decreased by 40%. Antibiotic prophylaxis in surgery is an area where
Interim analysis of intensive care unit (ICU) data the consumption of antimicrobials remains very
from 1997 was compared with data from 1997 (be- high. The analysis of indications, regimens and
fore and after implementing the above policy). duration of antibiotic prophylaxis in the hospital
In general, the consumption of antimicrobials indicated that optimization in this area is required,
decreased 1.3-fold in 1999 compared with 1997 due to:
(from 214.43 DDDs to 162.95 per 100 beds/days, • Non-evidence-based administration of antibiotic
respectively). This was mainly due to a 1.2-fold prophylaxis.
decrease in the use of penicillins (from 118.6 to
• Irrational selection of antimicrobials for prophy-
98.23 DDDs per 100 beds/days in 1997 and 1999,
laxis.
respectively), a 1.8 times decrease in the use of all
cephalosporins (from 20.4 to 11.4 DDDs per 100 • Long duration of antibiotic prophylaxis.
beds/days in 1997 and 1999, respectively) and a All the above have led to the establishment of
1.4-fold decrease in the use of aminoglycosides, the main objective of the study: to evaluate the prac-
especially gentamicin (from 48.9 to 34.0 DDDs tice of antibiotic prophylaxis, conduct economic
per 100 beds/days). There was also a decrease in analysis of antibiotic prophylaxis in abdominal sur-
the consumption of imipenem and ciprofloxacin. gery in the SRH, and to evaluate the impact of
There was a decrease in resistance amongst no- educational and administrative activities on anti-
socomial gram-negative bacteria: the resistance of biotic prophylaxis.
P. aeruginosa to gentamicin decreased from 75.0%
to 31.2% in 1997 and 1999, respectively and to
Description of the antibiotic prophylaxis policy
amikacin from 7.0% to 1.8%.
At the same time, no changes were noted in re- • Targeted teaching of surgeons about the mod-
sistance profiles of E. coli, Klebsiella spp., Entero- ern concept of antibiotic prophylaxis. Special
bacter spp. and Acinetobacter spp. attention was given to heads of departments.
In conclusion, the interim analysis showed that • In collaboration with SRH authorities, the de-
the establishment of an antibiotic policy in the SRH velopment and distribution of official recom-
(by means of education of health care providers, mendations on antibiotic prophylaxis within the
antimicrobial resistance surveillance, and a formu- surgical wards of SRH.
139
The main areas addressed in the antibiotic ■ Bulgaria: Hospital Case Studies and
prophylaxis policy National Antibiotic Policy
• The education of surgeons on rational antibi- Emma E. Keuleyan, PhD, Assistant Professor,
otic prophylaxis and the principles of evidence- Department of Microbiology, Head Antimicrobial
based medicine. Resistance Laboratory, Medical University, Sofia,
Bulgaria; Coordinator APUA Bulgaria Chapter.
• The development and implementation of prac- Contact: keuleyan@medfac.acad.bg
tical recommendations on antibiotic prophylaxis
within the surgical wards of the SRH. In Bulgaria, as in other countries, the emergence
• Involvement of the authorities of the SRH in and dissemination of antimicrobial resistance has
the implementation of antibiotic prophylaxis. been recognized as a major obstacle in antimicro-
bial chemotherapy, as well as an event with wide
biologic significance. Several years after R - plasmids
Level of policy enacted have been discovered by Okhiai and Akiba in
This was a regional level policy, which could be Japan, the scientists started investigations on the
used as an example for other hospitals wishing to genetic mechanisms of resistance and its epidemi-
implement a similar strategy. ology.
Some publications from the 1960s are cited
below:
Results of the antibiotic prophylaxis policy impact
• Tyagunenko Y and Z Kyolean. 1967. Transmis-
Analysis was based on patient data, gathered retro- sion of Multiple Antimicrobial Resistance in
spectively in 1993 and 1998. Three hundred and Strains of Fam. Enterobacteriaceae. Epidemiol
twenty-seven patients who underwent open chole- Microbiol Infect Dis (Sofia). 4, 1, 26–31
cystectomy (OCE), appendectomy (AE) and
• Tyagunenko Y and Z Kiolean. 1968. Studies on
hernia repair (HR) were included in the analysis.
some characteristics in the transmission and
Antibiotic prophylaxis frequency and quality
manifestations of an episome with 5 R–mark-
(selection of antimicrobials, dosage regimens, route
ers. Proceedings of the Postgraduate Medical
of administration, post-operative duration) were
Institute ISUL. 15, 1, 35–41 (English).
assessed. In 1993, none of the patients received
preoperative antibiotic prophylaxis, however, many With time, new aspects, new methods, and new
patients received antimicrobial treatment after their approaches got more people interested in the anti-
operation for 5 to 8 days. In 1998, the following biotic problem. The Department of Microbiology
preoperative antibiotic prophylaxis frequency was at Medical University,Sofia and the National
registered: OCE–78%, AE–0%, HR–46%. In Centre of Infectious and Parasitic Diseases have
1993, antibacterial administration without evidence played the leading role in this evolution of knowl-
of postoperative infection was registered for OCE edge, research, and activities.
in 82% cases compared to 31% cases in 1998. As shown by experience, antibiotic resistance
continues to increase and spread globally. Bulgaria
Lessons learned from the antibiotic prophylaxis policy has had some success in decreasing the antibiotic
applicable to other countries resistance problem, illustrated by the following
examples.
• Educational and administrative activities have a
positive impact on antibiotic prophylaxis prac-
tice in surgery. A. Institutional level
• The monitoring of antibiotic prophylaxis prac- Some hospitals, primarily at universities, have ini-
tice and feedback to surgeons needs to be tiated programmes for resistance surveillance and
implemented in hospitals for the optimization control of infections, and established therapeutic
of antibiotic prophylaxis. committees to optimize antibiotic use.
In our opinion, this policy can also be used in

developing countries. 1. Alexander’s Hospital—Medical University, Sofia
(1, 2)
While third generation cephalosporins, tetracyclines
and aminopenicillins were widely used in 1993–
140
TABLE 1. ALEXANDER’S HOSPITAL 2. Military Medical Academy

Antimicrobial resistance rate Antimicrobial resistance monitoring was performed
Microorganism Resistance in % for a 20 year period. (3; and E. Savov–DSci thesis
“Contemporary approaches to study problematic
1997 3/1993–3/1994
microorganisms for hospital pathology”, 1999)
Penicillin – R S. pneumoniae 33 32 Significant resistance to gentamicin was devel-
MRSA 23 31 oped around the middle of the 1970s. Amikacin
was introduced in 1979. Like earlier experience in
HLGenR Enterococcus 21–46 42
the world, the decision was made to restrict
Ampicillin – R E. coli 75 65 gentamicin and use amikacin as a first line
ESBLs Enterobacteriaceae 5–16 2–5
aminoglycoside.
P. aeruginosa – R to Ciprofloxacin 55 22
TABLE 2. MILITARY MEDICAL ACADEMY
R to Ceftazidime 28 17 Resistance towards aminoglycosides in %
R to Amikacin 45 9 Microorganism First Period Second Period
A. baumannii – R to Ciprofloxacin 50 20
Gentamicin Amikacin Gentamicin Amikacin
R to Ceftazidime 51
1975 94 75 94 1994 95 96 1994 95 96
Emerging in 1997: VRE <5%, R to Imipenem in P. aeruginosa – 30%; in
E. coli 5 15 4 2 15 5 3 2 0 0
A. baumanni – 5%
K.pneumoniae 13 60 3 8 60 63 25 8 12 5
Antibiotic consumption (grams x 1000)
E. cloacae 27 60 5 8 27 26 21 8 6 9
(DDD/100/day)
S. marcescens 13 55 9 11 55 30 22 11 4 3
1996 1997 3/1993–3/1994
P. aeruginosa 27 57 12 17 57 73 60 (data from thesis)
Aminopenicillins 10 17.5 3.2
Aminopenicillins/inhib Bla 11 9.5 0.3

As a result, by the end of the second period, a 2
Cephalosporins 1st gen 21.5 68.0 2.0 to 3-fold decrease in resistance to gentamicin was
Cephalosporins 2nd gen 27.5 26.5 2.7–3.4 achieved in enterobacteria, without significant
dynamics in resistance to amikacin. There was also
Cephalosporins 3rd gen 19.5 7.5 1.4–3.5
some decrease in gentamicin resistance among
Aminoglycosides 7.0 8.5 0.7–2.5 Gram-positive bacteria (S. aureus, S. epidermidis,
E. faecalis). Data from the Hospital Pharmacy about
Tetracyclines 2.1 4.0 3.3
antibiotic consumption showed that antibiotics
Quinolones 10.45 4.5 3.3 prescriptions had decreased in 1997 by 30% from
Trimethoprim/ 1996 and by 56% from 1995. The author’s opin-
Sulfamethoxazole 6.8 10.3 0.8 ion is that personal contact between microbiologists
and clinicians was more effective than written
1994, the comparative analysis of 1997–1996 shows guidelines and programmes.
some improvement (decrease in third generation
cephalosporins, tetracyclines, which need further 3. Queen Ioanna Hospital–Medical University, Sofia
restriction, and aminopenicillins for Gram-
In 1993, a Therapeutic Committee was proposed
negative infections).
and a Hospital Antibiotic Policy was established
Comment: The reported success in antibiotic usage after wide discussions. This document suggests an-
could be explained by: 1) introducing the tibiotic prescribing to be at three levels: antibiotics
WHONET programme in 1993; 2) establishing a for common use (prescribed by every physician);
Therapeutic Committee; 3) introducing the prac- restricted antibiotics (to be discussed with the chief
tice of a visiting microbiologist; 4) restricting some of the unit, e.g., 3rd generation cephalosporins);
broad-spectrum antibiotics; 5) cycling of antibiot- reserved antibiotics (for particularly resistant mi-
ics for empiric therapy; 6) and the personality of croorganisms, severe infections, or emergency; they
the head of laboratory. need permission from the department and repre-
141
sentative of the Therapeutic Committee, e.g., Her results show that the most common errors
imipenem, vancomycin). Because of the higher re- in prescribing practice were:
sistance rate to gentamicin, it was restricted and
• Antibiotics given without objective data about
amikacin suggested to be the first line amino-gly-
bacterial infection
coside.
• Antibiotic prescribing not taking into account
the results from the Microbiology Laboratory
TABLE 3. QUEEN IOANNA HOSPITAL–MEDICAL UNIVERSITY, SOFIA
• Lack of strategy about the empirical choice of
Resistance to aminoglycosides in % antibiotic (misuse of broad-spectrum antibiot-
Microorganism Gentamicin Amikacin ics)
1993 1995 1999 1993 1995 1999 • Frequent use of tetracyclin, tetracycline–olean-
domycin and chloramphenicol
E. coli 9 6 8 3 3 6
• Frequent use of ampicillin p.o. and subdosing
Klebsiella spp 41 34 26 7 5 17
of azlocillin
Enterobacter spp 34 30 22 11 13 19
• Late initiation and long lasting antimicrobial
Serratia spp 62 53 24 9 35 22 prophylaxis in surgery
Proteus spp 25 18 16 5 8 19 • Use of expensive and reserved antibiotics when
P. aeruginosa 24 60 59 5 37 50 other possibilities are available
Acnetobacter spp 51 77 66 36 70 69 • Occasional long therapies for pneumonia and
pyelonephritis.
A decrease in resistance rates to gentamicin was A survey about national antibiotic consumption
achieved in Enterobacteriaceae, the most signifi- showed that the most frequently prescribed antibi-
cant decrease occurring in Serratia. However, this otics were:
hospital had an increase of resistance to amikacin. 1. Tetracyclines
This may be due to the strains with ESBLs (genes
2. Broad-spectrum penicillins (ampicillin and
located on the same transposon).
amoxicillin)
Comment: It may be time to restrict amikacin.
The data cited above are from “Queen Ioanna 3. Sulfamethoxazole–Trimethoprim
Hospital Antibiotic Policy”, 1993 and from
4. Aminoglycosides (gentamicin)
“Annual Analysis of Antibiotic Resistance Rate and
Antibiotic Use in QIUH”, 1994, 1995, 1996, 5. Chloramphenicol
1997, 1998, 1999", N. Hadjieva; N. Hadjieva and 6. Narrow spectrum penicillins, macrolides,
D. Ivanova. They have been presented at national cephalosporins, lincozamides, and quinolones.
and international congresses.
This list, while similar to those from other Cen-
tral and Eastern European countries (4, 5) does not
B. National level of the efforts to fight reflect contemporary principles of antibiotic usage.
antimicrobial resistance The author explains this non-prudent antibiotic
In her PhD thesis “Pharmacotherapeutic and policy by:
pharmacoeconomic aspects of treatment with an-
• Lack of systematic data about the dynamics of
timicrobial drugs in Bulgaria”, 1997, M. Popova
resistant strains
evaluated the approaches for antibacterial treatment
of respiratory tract and urinary tract infections and • Lack of a regular drug supply and insufficient
antibiotic prophylaxis in surgery. She conducted budget
the studies at two university hospitals, one general • Lack of basic, independent drug information
hospital in Sofia, one general district hospital, one
• Lack of an official strategy at most hospitals
specialized hospital, and several polyclinics. She also
analysed the national antibiotic consumption dur- • Lack of “sensitivity” in the society towards the
ing the period from 1979 to 1994 by implement- problems of antibiotic use
ing DDD/1000/ day methodology. • Lack of a pharmacoeconomic approach.
142
To overcome these problems she suggested: As it can be seen from the table, in 1999
pencillins and broad-spectrum penicillins were the
• Optimizing the contacts between clinicians and
most commonly used antibiotics. From 1994 to
microbiologists
1999, use of aminoglycosides decreased nearly
• Establishing a hospital Therapeutic Committee three-fold and use of tetracyclines decreased nearly
• Publishing guides for antimicrobial treatment two-fold.
and prophylaxis Many factors have contributed to a better
understanding of the consequences of antimicro-
• Establishing a Society for rational antibiotic use bial resistance and the necessity of prudent antibi-
with wide participation of antibiotic prescrib- otic use. Among them, special attention has to be
ers, consumers, and providers. given to:
This measure, according to M. Popova, would • The impact of scientists in research and educa-
be able to curb self-medication, irrational prescrib- tion
ing, free sales, and the unethical promotion of an-
• Political changes
tibiotics.
• International collaboration and support.
Comment: It is also necessary to establish a National
Antibiotic Policy for both the hospital and ambu-
Impact of scientists in research and education
latory settings with strong legal and financial sup-
port of the Ministry of Healthcare, Government, Different aspects of epidemiology and mechanisms
and Parliament. of resistance in Bulgaria, and methods for their
Recent data about approaches in antimicrobial detection have been studied (3, 10–42). A total of
treatment indicate significant improvement (6–9). seventeen fellowships on the problems of antibi-
While some past examples of antibiotic prophy- otic policies, methods for detection of mechanisms
laxis in surgery sound anecdotal, today most insti- and epidemiology of antimicrobial resistance, and
tutions use antibiotic prophylaxis consistent with susceptibility testing were performed in leading
international standards. Similarly, recent data about world centres during the last 15 years. Eight re-
national antibiotic consumption show some im- search projects received grants from Bulgarian
provement (Bulgarian Drug Agency, M. Popova; (Ministry of Education and Sciences, Medical Uni-
data have been sent to EURO DRUG): versity–Sofia) and international (APUA) organiza-
tions. These issues have been the focus of 8 theses.
Pharmacodynamics, pharmacokinetics, and
Antibiotics DDD/1000/Day pharmacoeconomics studies were performed and
1994 1995 1999 several clinical trials were carried out.
Educational activities have been addressed to
Tetracyclines J01A 7.38 7.09 4.24
practitioners, providers, and consumers of antibi-
Amphenicols J01B 0.29 0.20 0.18 otics. More working hours for studying antimicro-
Penicillins J01C 7.23 7.76 7.64 bial chemotherapy and antimicrobial resistance
have been included in the education of students in
Broad-spectrum Penicillins J01CA 5.15 6.22 5.96
medicine, dentistry and pharmacy. Written mate-
Comb.Penicillins/Bla inhibitor J01CR 0.54 0.14 0.27 rials on principles of rational antibiotic therapy have
Cephalosporins J01D1 1.21 1.95 1.37
become available for junior doctors. Post-graduate
education courses on strategies of antimicrobial
Carbapenems J01DH 0.004 chemotherapy for different audiences (microbio-
Sulfonamides & Trimetoprim J01E 1.35 1.03 1.08 logists, physicians, nurses) have been organized on
a regular basis by the Medical University of Sofia
Macrolides & Lincosamides J01F 0.85 0.61 0.42
and NCIPD. Popular articles were published in
Aminoglycosides J01G 2.42 1.70 0.87 mass media and television discussions took place
Quinolones J01M 0.09 0.27 0.034 for the education of antibiotic consumers.
Glycopeptides J01XA 0.001

Political changes
Imidazoles J01XD 0.41
Since 1989, when democratic changes started in
Urinary antiseptics G04A 0.67
Bulgaria, new criteria and new standards of drug
143
use were developed. State laws about drugs and ance Programme; European Study Group on Anti-
pharmacies in human medicine were published and biotic Policy; European Study Group for Antimi-
updated. Significant changes were made in drug crobial Resistance Surveillance; European Study
regulation. As new antibiotics are licensed, each is Group of Nosocomial Infections; European Soci-
given a complete description of dosage regimen and ety for Clinical Microbiology and Infectious
indications for all forms. The Ministry of Health- Diseases (ESCMID); European Antimicrobial Re-
care, National Drug Institute and Medical Univer- sistance Surveillance System (EARSS); etc. All these
sity’s Pharmacy Faculty elaborated “Indicators to forms of international collaboration are playing a
Follow up the National Drug Policy in Bulgaria” substantial role in developing different activities to
(1994–1996)—P. Uzunov, T Benisheva, G Petrova, overcome the antimicrobial resistance problem.
Y Uzumov. A health care reform started on July 1, Numerous additional organizations are taking
2000, whose aim is to change the previously cen- part in the improvement of antibiotic use in Bul-
tralized state health care system to an insurance- garia; they can not all be cited and acknowledged
based practice. in this brief review. It is also difficult to assess the
particular impact of all factors, events, activities,
and works that are dealing with developments in
International cooperation and support
this area. The author’s opinion is that fellowships
The progress during the last few years would not in the prestigious world centres play a very impor-
have been possible without the support of differ- tant role for the development of future leaders in
ent international organizations. The World Health science, clinical work, and education. Among the
Organization (WHO) supported many different activities that have not been mentioned, some that
projects and activities. Professor Thomas O’Brien deserve to be noted are:
came personally to Bulgaria to speak on antimicro-
bial resistance and to introduce his WHONET • In 1994 a National Society of Chemotherapy
programme for resistance surveillance. This pro- was created, which became a member of the In-
gramme now performs most resistance monitoring ternational Society of Chemotherapy (ISC), the
in Bulgaria. APUA supported the establishment of European Society of Chemotherapy (FESCI)
the APUA Bulgaria Chapter in 1998. The APUA and the Mediterranean Society of Chemo-
has funded the current research project: “Survey of therapy. The First National Conference on
Antimicrobial Resistance in Bulgaria—first step in Chemotherapy took place in Sofia in 1995.
understanding the necessity of rational antibiotic • In 1998, the First National Conference on
policy” (E. Keuleyan and E. Savov) and recently Pharmacoeconomics was organized in Sofia.
supported another project: “Attempt to improve
• Materials about antibiotic resistance are being
antibiotic use in Bulgarian hospitals” (E. Keuleyan
discussed at the meetings of the National Socie-
and T. Sokolov). The European Community has
ties of Clinical Microbiology and Medical
several programmes to support education (Tempus),
Microbiology,.
research, and other activities (PHARE). Due to a
PHARE project, many international journals be- • Efforts have begun for standardization and qual-
came available to Bulgarian scientists. PHARE sup- ity assessment in Clinical Microbiology (43). A
ported the edition, “Bulgarian Therapeutic School”, specialized laboratory for these purposes was es-
in 1995. tablished at the National Center of Infectious
The Open Society Foundation has supported and Parasitic Diseases. In April 2000, a Confer-
activities for Bulgarian scientists, including train- ence on Standardization and Quality Control
ing courses, fellowships, participation at congresses, was organized by Becton Dickinson—Bulgaria
and organizing of symposia. During 1998 it sup- and NCIPD in Borovetz.
ported a conference in Sofia on anaerobic infec-
• An Expert Committee on Antibiotic Policy
tions with participation of the American Society
working with the Ministry of Healthcare was
for Microbiology. Bulgarian scientists participate
created in August 2000, to work on developing
in different international programmes, projects and
and establishing a national programme for a
organizations: WHO (Essential Drugs, EURO
rational antibiotic strategy.
DRUG, Emergency Diseases); APUA; National
Committee for Clinical and Laboratory Standards In conclusion, these are some examples of what
(NCCLS); WHO/CDC External Quality Assur- has been done in recent years in Bulgaria to curb
144
antimicrobial resistance. This experience is on a microbiologists with foreign participation; 1998 V.

small scale. Many more people need to be engaged 1. Clinical Microbiology, Sofia. 1998;1:380–382.
to accomplish the goal. Many more people need to 11. Grigorova V, Sredkova M, Popova V. Susceptibility
be educated and convinced of the problem. The of S. pneumoniae strains towards different antibiot-
perfection of antimicrobial chemotherapy will not ics. Ibidem. p.392–396.
come with the efforts of a small group of people or 12. Keuleyan E. Aminoglycoside-Aminocyclitols.
with fleeting interest. World experience shows that Mechanisms of action and antimicrobial resistance.
this is a difficult and long process. Curbing anti- Medico-biologic information 1990;3:3–11 (English/
Russian).
microbial resistance will take more knowledge,
work, education and funds. 13. Keuleyan E and R Avramova. Gentamicin-resistant
Enterobacteriaceae and the problem of their
polyresistance. Probl Infect Parasit Dis NCIPD,
References Sofia 1994;21:19–20.
1. Markova B. Analysis of resistance of bacterial patho- 14. Keuleyan E, Avramova R, Barzashka S, Boyanova L,
gens in order to optimize antibacterial therapy. In- Gergova R, Mitov I. Analysis of antibiotic suscepti-
formative bulletins of Department of Microbiology, bility in orthopedics and trauma hospital. Probl
Medical University, Sofia and Clinical Microbiol- Infect Parasit Dis 1998;26(1):24–27.
ogy Laboratory, Alexander’s University Hospital.
15. Keuleyan E, Gergova R, Haralambieva I, Markovska
1993–1998;1–8.
R, Sredkova M, Savov E, Dragijeva E, Genova V,
2. Markova B, Bobtcheva S, Topalova S, Kolevsky A. Gergova G, Toshkova K. Problematic MRSA/
Approaches for the optimization of diagnosis and MRSE-comparative susceptibility to antimicrobial
antimicrobial therapy of infections at the agents. Proceedings of the Ninth Congress of the
Alexandrovska State University Hospital. Proceed- Bulgarian microbiologists with foreign participation.
ings of the Ninth Congress of the Bulgarian 1998 V. 1. Clinical Microbiology, Sofia. 1998;1:363–
microbiologists with foreign participation. 1998 V. 367.
1. Clinical Microbiology, Sofia. 1998;1:324–329.
16. Keuleyan E, Markovska R, Savov E, Toshkova K,
3. Savov E. Analysis of the structure of bacterial infec- Dragijeva E, Genova V, Borissova V, Sredkova M.
tions and antimicrobial resistance in order to Susceptibility of clinically significant S. aureus
optimize antimicrobial chemotherapy. Department towards Macrolides, Lincosamides and Strepto-
of Military Epidemiology, Hygiene and Microbiol- gramins. Ibidem. 358–362.
ogy, Military Medical Academy, Sofia. 1996, 1997,
17. Keuleyan E, Savov E, Sabtcheva S, Balabanova M,
1998.
Gergova R, Haralambieva I, Guirgitzova B. Prob-
4. Kiivet RA, Biba V, Enache D, Fottau V, Guilbinovic lematic Enterococcus: HLAR and Van-resistant:
J, Oltvanyi N, Orazem A, Popova M, Stika L. Comparative study of strains from different hospi-
Changes in the use of antibacterial drugs in the coun- tals. Ibidem. 401–405.
tries of Central and Eastern Europe. Eur J Clin
18. Nashev D and K Toshkova. Information on dissemi-
Pharmacol 1995;48:299–304.
nation of methicillin-resistant Staphylococci during
5. Popova M, Popova P, Guencheva G. Consumption 1996. Informative Journal of National Center of
of anti-infective drugs in Bulgaria for the period from Infectious and Parasitic Diseases 1998;2:4–7.
1979 to 1994. Pharm World 1997;19(2):93–100.
19. Ribarova N and Y Mitova. Etiological characteris-
6. Hadjiisky O. Antibacterial therapy in burns-phar- tics of the nosocomial infection in different types of
macokinetics, particularities and indications. J Emerg high risk hospital departments. Infectology 2000;
Med 1999;7(2):5–12. 37(1):27–32.
7. Pentcheva P. Strategy of antimicrobial chemotherapy 20. Sabtcheva S, Borissova V, Kantardjiev T. Occurrence
in emergency medicine. J Emerg Med 1993;1(2):6– and fetection of β-lactamases in clinical isolates of
13. the family Enterobacteriaceae. Proceedings of the
Ninth Congress of the Bulgarian microbiologists
8. Terziisky G. Programme for Antibiotic Policy of
with foreign participation. 1998 V. 1. Clinical Micro-
Medical Institute of Transport. Sofia, 1993.
biology, Sofia. 1998;1:333–342.
9. Vachkov P. Contemporary treatment of deep
21. Savov E. Plasmids as epidemiological markers of
mycoses. Infectious Diseases. Medical Review
microorganisms in hospital infections. V Med Delo
2000;31(2):3–22.
1993;2:41–44.
10. Detcheva A, Chankova D, Kotcheva B, Savov E,
22. Savov E. Clonal conception in epidemiology and
Dragijeva E, Genova V, Zamfirova E, Protich N,
clinical microbiology. Military Medicine and Phar-
Tomova I. Monitoring of the Antibiotic Suscepti-
macy 1997;1:41–43.
bility in Group A Streptococci 1994–1997. Proceed-
ings of the Ninth Congress of the Bulgarian
145
23. Savov E, Toshkova K, van Belkum A, van Leenwen Antimicrobial susceptibility patterns of Enterococci
W. Use of AP-RAPD polymerase chain reaction for causing infections in Europe. Antimicrob Agents
typing of Staphylococcus aureus strains. Infectology Chemother 1999;43(10):2542–2546.
1997;1:15–18.
37. Keuleyan E In: Jones RN, Hare RS, Sabatelli FJ and
24. Sotirova P, Tyagunenko Y. Plasmid Profile Analysis the Ziracin Susceptibility Testing Group. In Vitro
of Clinical Isolates of A. baumannii. Proceedings of Gram-positive antimicrobial activity of Evernimicin
the Ninth Congress of the Bulgarian microbiologists (SCH 27899, Ziracin®), a new oligosaccharide com-
with foreign participation. 1998 V. 1. Clinical Micro- pared with other antimicrobials: a multicenter in-
biology, Sofia. 1998;1:427–433. ternational trial. J Antimicrob Chemother, in press.
25. Sredkova M. 1998. Resistance to penicillins, 38. Setchanova L, Tomasz A. Molecular characterization
aminoglycosides and vancomycin of clinical strains of penicilln-resistant Streptococcus pneumoniae
of enterococci. Ibidem. 397–400. isolated from Bulgaria. J Clin Microbiol 1999;
37(3):638–648.
26. Sredkova MP and SI Patchkova. Informative Bulle-
tins: Resistance towards antimicrobial agents in clini- 39. Setchanova L In: Jacobs MR, Dagan R, Appelbaum
cal isolates. Department of Microbiology, Higher PC, Burch DJ. Prevalence of antimicrobial-resistant
Medical Institute–Pleven (1996, 1997; 1, 2). pathogens in middle ear fluid: multinational study
of 917 children with acute otitis media. Antimicrob
27. Toshkova K. Methicillin-resistant Staphylococcus.
Agents Chemother 1998;42(3):389–395.
Sofia; 1995.
40. Toshkova K, Savov E, Soedarmanto I, Lammler CU,
28. Vatcheva R, Savov E. Detection of clinical isolates
Chankova D, van Belkum A, Verbrugh HA, van
of Family Enterobacteriaceae producing broad spec-
Leenwen W. Typing of Staphylococcus aureus isolated
trum β-lactamases. Proceedings of the Ninth Con-
from nasal carriers. Zbl Bact 1997;286:547–555.
gress of the Bulgarian microbiologists with foreign
participation. 1998 V. 1. Clinical Microbiology, 41. Toshkova K In: Marples RR, Rosdohl VT and Mem-
Sofia. 1998;1:330–332. bers of the IUMS Subcommittee. International qual-
ity control of phage typing of Staphylococcus aureus.
29. Avramova R, Keuleyan E, Ekimova E. Resistance to
J Med Microbiol 1997;46:511–516.
third generation cephalospoins in clinical strains of
Enterobacteriaceae. J Chemother 1993;Suppl 3:262– 42. Von R Prager, Savov E, Tschape H. Nosokomiale
264. Verbreitung von Resistenzplasmiden durch die Praxis
der Kombinationstheraie mit Aminoglycosid- und
30. Boyanova L, Spassova Z, Kraslev Z, Petrov S,
β-Lactam–Antibiotika. Bundesgesunbl 1994;1:24–30
Stancheva I, Docheva J, Mitov I, Koumanova R.
(Germany).
Characteristics and trends in macrolide resistance
among Helicobacter pylori strains isolated in Bulgaria 43. Kantardjiev T, Batchvarova A, Velinov T, Kouzmanov
over four years. Diagn Microbiol Infect Dis 1999; A. Development of external quality assessment for
34(4):309–313. microbiology in Bulgaria. Infectology 2000;37(1)27–
32.
31. Boyanova L, Stancheva I, Spassova Z, Katzarov N,
Mitov I, Koumanova R. Primary and combined re-
sistance to four antimicrobial agents in Helicobacter
pylori in Sofia, Bulgaria. J Med Microbiol 2000; ■ Sweden: National Antibiotic Use and
49(5):415–418. Surveillance Projects
32. Keuleyan E. Biochemical determinants of amino- Major change in the use of antibiotics following a
glycoside resistance in Gram-negative microorgan- national programme: Swedish Strategic Program for the
isms, isolated from urocultures. J Hyg Epidemiol Rational Use of Antimicrobial Agents and Surveillance
Microbiol Immunol 1989;33(3):289–97(Czechoslo- of Resistance (STRAMA). Sigvard Molstad, Otto Cars.
vakia). Scand J Infect Dis 31:191–5, 1999. Report prepared by
33. Keuleyan E. Aminoglycoside resistance among Gram Otto Cars, Swedish Institute of Infectious Disease
negative bacilli in Sofia, Bulgaria. APUA Newsletter Control, Solna, Sweden; Chairman, STRAMA, Leader,
1992;10(4):1–2, 7. APUA Sweden, otto.cars@smi.ki.se
34. Keuleyan E. Presence of acetyltransferases and adeny-
lyltransferases in gentamicin-resistant trans- STRAMA
conjugants. Pathol Biol 1992;40(5):556–60 (France).
The increase in bacterial resistance in Europe, the
35. Keuleyan EE, Haralambieva YH, Gergova RT,
Markovska RD, Mitov IG. Antibiotic resistance in increasing sales of antibiotics in Sweden and the
two University Hospitals in Sofia, Bulgaria. APUA spread of penicillin-resistant S. pneumoniae (PRSP)
Newsletter 1997;15(3):1, 4–5. in southern Sweden have alarmed both the medi-
36. Keuleyan EE In: Schouten MA, Voss A, Hookamp- cal profession and national health authorities.
Korstanje JAA and the European VRE Study Group. Therefore a national project named STRAMA,
146
Swedish Strategic Program for the Rational Use of concentrated on the treatment of respiratory tract
Antimicrobial Agents and Surveillance of Resist- infections and antibiotic usage in pre-school
ance, was initiated in 1994. children.
National STRAMA-group Antibiotic sales statistics

A national STRAMA group (www.strama.org) was Apoteket AB (Corporation of Swedish pharmacies)
appointed which was composed of specialists in keeps records of sales of medicinal products from
infectious diseases, microbiology, general practice, the wholesalers to the pharmacies. From these
ear, nose and throat (ENT), and pediatrics, from databases, raw data on sales of antibiotics are ex-
the Swedish Reference Group for Antibiotics. In tracted. The Anatomical Therapeutic Chemical
addition, the national STRAMA-group included classification system (ATC) is used for classifica-
members from the Swedish Institute for Infectious tion of drugs. The unit of measurement is defined
Disease Control, the Swedish Medical Products daily doses (DDD) for human medicine and for
Agency, the National Board on Health and Wel- veterinary medicine mostly in Kg of active sub-
fare, the National Corporation of Pharmacies, the stance. Dispensing of antinbiotics is monitored by
Swedish Veterinary Agency, the Society of County all pharmacies. This implies that data are broken
Medical Officers for Communicable Diseases, and down according to hospital or community use. Pre-
the Swedish Network for Pharmacoepidemiology scriptions statistics are available for outpatients as
(NEPI). The primary goal of the National DDD as well as number of prescribed items/ 1000
STRAMA-group was to stimulate the formation inhabitants/ day. From 1980 to 1995 this has been
of STRAMA-groups in each county. Together with based on a sample of 1 out of 25 prescriptions,
these regional groups, the national STRAMA-group after 1996 all prescriptions served have been regis-
mission was to increase knowledge and understand- tered. The statistics are produced at national, county
ing of the relationship between antibiotic consump- and since 1998 also at community level. It can be
tion and bacterial resistance by both the medical broken down to individual drugs, sex and age
profession and the public at large. The main objec- groups.
tives were to minimize the development and spread The Swedish Reference Group for Antibiotics
of resistance, both in outpatients and in hospitals, (SRGA) and the Swedish Institute for Infectious
by a reduction of inappropriate antibiotic use, Disease Control have developed a national recom-
especially of broad-spectrum antibiotics, and to mendation for standardized antimicrobial suscep-
further develop and support resistance surveillance tibility testing (www.srga.org). All 30 Swedish
programmes. microbiological laboratories use the SRGA stand-
ardized disc diffusion method. The species related
MIC and zone-diameter breakpoints from SRGA
Regional STRAMA-groups have been uniformly adopted as well as SRGA rec-
In each county at least one STRAMA-group has ommendations for external and internal quality
been formed. The County Medical Officers for assessment programmes. SRGA and the Swedish
Communicable Diseases are chairing these regional Institute for Infectious Disease Control perform
groups, which include specialists from different yearly surveys of approximately 3000 strains (100
medical fields, e.g., infectious diseases, ENT, per laboratory) of each of S. pyogenes, H. influenzae,
pediatrics, microbiology, general practice and phar- S. pneumoniae and every second year of E. coli,
macy. Some of the groups also include primary care Klebsiella spp., Enterobacter spp, against a specified
nurses. The groups’ main objective is to evaluate number of commonly used antibiotics. Special sur-
the use of antibiotics in the area and the pattern of veys have been directed towards antibiotic resist-
resistance. After identifying problems in the area, ance in Gram-negative hospital isolates, UTI
the group uses its knowledge to influence health pathogens from primary care isolates and patho-
care workers to improve diagnostic procedures and gens isolated from patients at Intensive Care Units.
the prescribing pattern of antibiotics. In some coun- Findings of methicillin-resistant pneumococci
ties with tertiary care hospitals, special groups are (MIC>0.5 mg/l) and vancomycin-resistant entero-
formed to influence the use of antibiotics in hospi- cocci (VRE) has been made notifiable.
tals. Since the immediate threat was the increasing In 2001, an Antibiotic Resistance Steering
incidence of PRSP, in most counties the initial work Group was formed at the Swedish Institute for
147
Infectious Disease Control. The aim of this group dations was started in Malmöhus County, in March
is to coordinate an extended national surveillance 1995. The project is still running and has been fol-
of resistance built on existing networks of clinical lowed by similar initiatives in most other Swedish
laboratories. counties.
Since March 1995, all PRP with MIC for PcG
Activities and results ≥0.5 mg/L have been directly reported from the
three microbiology laboratories in the county to
Between 1993 and 1997 the total antibiotic use the Regional Center of Communicable Disease
was reduced by 22%; the reduction was especially Control (RCCDC) in Malmö. Comprehensive ret-
evident for macrolides and broad-spectrum antibi- rospective data are available from January 1995.
otics. The reduction of antibiotic consumption has Whenever an individual with an infection due
been more prominent in Sweden than in the other to PRP is identified (“index case”), the RCCDC
Nordic countries. Recommendations have been contacts the local health care centre of that patient.
produced for the use of macrolides, vancomycin, The local physician is then responsible for secur-
fluoroquinolones and on the treatment of urinary ing nasopharyngeal specimens from family mem-
tract infections, chronic bronchitis and skin and bers and other close contacts (e.g., day care group)
wound infections. A folder with information on of the index case, in order to identify carriers in the
respiratory tract infections, antibiotics and resist- surrounding area (“contact cases”). All carriers
ance has been distributed to all Swedish medical (index cases as well as contact cases) are followed
health care centres. Three symposia have been with weekly nasopharyngeal cultures, until two con-
arranged for the regional groups. Media interest for secutive negative specimens have been obtained
the project has further increased the knowledge and (“PRP negative”). All control cultures, and other
understanding of the problem in the general popu- health care contacts due to the project, are free of
lation. During the last year Sweden has been en- charge for the individual patient. If an identified
gaged in several European Union (EU) projects carrier is a child participating in any form of child
concerning antibiotic resistance. The national day care, nasopharyngeal specimens are also ob-
STRAMA-group will continue to regularly follow tained from the staff and other children in that day
the use of antibiotics and the incidence of resist- care group. If more carriers are found, the screen-
ance, coordinate necessary surveillance programmes ing procedures can be extended to the whole day
and other activities in the counties and, if needed, care centre. Repeated cultures are then obtained
make recommendations on identified problem areas. every 1–2 weeks from the children and staff, until
no more carriers are identified. Pre-school children
The South Swedish Pneumococcal who are identified as carriers stay away from group
Intervention Project day care until they are PRP negative. The parents
of these children are able to stay at home with full
Role of communicable disease control measures in
affecting the spread of resistant pneumococci: the reimbursement from the social security system, if
Swedish model. Karl Ekdahl, Otto Cars. Clin Microbiol the day care cannot be arranged in any other way.
Infect 1999; 5: 4S48-4S54. During the period from January 1, 1995 to June
30, 1998, 1545 PRP carriers (1492 individuals)
During the last 20 years, the spread of penicillin were identified in Malmöhus County. Of the 1545
resistant and multiresistant Streptococcus pneumo- episodes, 642 (41%) were in index cases and 903
niae has become an increasing international prob- (59%) in contact cases. The pattern of carriage has
lem. In the early years of the 1990s, the incidence shown a pronounced seasonal pattern, with most
figures in Malmöhus County in southern Sweden cases occurring during the winter months. Alto-
increased to 8–15%, while the corresponding fig- gether 170 of approximately 600 day care centres
ures for the rest of Sweden have remained at lower in the county have been screened for PRP during
levels. Recommendations from a national expert the period. The number of PRP carriers in each
committee were issued in 1995, outlining possible day care centre has varied within great intervals
intervention measures against the spread of peni- (median 2, interval 1–23), and in half of the day
cillin-resistant pneumococci (PRP) with minimal care centres no further PRP carrier was identified.
inhibitory concentration (MIC) for penicillin G Screening cultures were, on average, obtained twice
(PcG) ≥0.5 mg/L among small children. The first in each day care centre, before the day care centre
large-scale attempt to implement these recommen- could be declared “PRP-free”.
148
The “Swedish intervention model” has applied served as a control. The first registration took place
traditional communicable disease actions (contact during 4 weeks in January–February and the
tracing and isolation) to a new phenomenon (anti- second during 4 weeks in November–December.
biotic resistance). The measures are under continu- The physicians registered diagnosis, diagnostic
ing evaluation and the final conclusions have not methods, C-reactive protein, bacterial culture,
yet been drawn. X-ray, ultrasound, antibiotic prescribing (penicil-
lin V, ampicillins, macrolides, tetracyclines,
Audit project cephalosporins, “other antibiotics” and “no antibi-
otic”).
Medical audit changes physicians’ prescribing of
In Orup, 33 physicians participated in the first
antibiotics for respiratory tract infections. Eva Melander
et al. Scand J Prim Health Care 1999; 17:180–84. registration, 25 in the second. Twenty GPs who
participated in both registrations were included in
In Sweden a prescription is needed to receive an the study and registered 1124 consultations for
antibiotic, and 60% of all antibiotics are prescribed RTIs during the first period and 926 during the
for respiratory tract infections (RTIs). Several guide- second. In the control group the 25 GPs registered
lines have been issued on a national level, giving 1313 consultations for RTIs during the first pe-
rather strict criteria for antibiotic prescribing for riod and 1309 during the second.
RTIs. However, the actual sales of antibiotics do The proportion of patients not prescribed any
not show compliance with given recommendations antibiotic increased in both groups—in the inter-
in guidelines. Different methods have been tried vention group from 45 to 55% and in the control
to change the prescribing of antibiotics for RTIs, group from 36 to 40%.
but the habits of physicians seem difficult to change. The APO model is a method for internal revi-
A group studied the diagnostic procedure and pre- sion of medical practice. The method is based on
scribing of antibiotics in clinical practice by apply- knowledge of recorded aspects of work and, through
ing the special Audit Project Odense model (APO) discussion, the participants agree on what is better
for quality development. The APO model has been and what is worse general practice and change their
applied in Denmark and Sweden for some years, care accordingly. The registrations are anonymous
and the method is based on a registration of con- and the individual physician’s result is known only
sultations in a diagnostic area (e.g., hypertension, to himself. The APO model has been used on sev-
diabetes), where each participating physician dur- eral occasions in Sweden but has not previously
ing a limited period of time should be able to reg- been evaluated.
ister a considerable amount of consultations.
Participating physicians choose the registration
parameters before the registration. Statistics are col- ■ United Kingdom: Tackling antibiotic
lected from the registered parameters. Each par- resistance in the UK and Europe
ticipating physician receives his own personal result, A Personal Perspective by Ian M. Gould, Consultant
making a comparison between his own prescribing Microbiologist, Department of Medical Microbiology,
and the general group possible. The aggregated data Aberdeen Royal Infirmary, Aberdeen Royal Hospital,
of all consultations reflects clinical practice, which Aberdeen, Scotland. Contact: i.m.gould@abdn.ac.uk
in turn can be compared with guidelines, national
recommendations or other studies in the same field. In 1988, the British Society for Antimicrobial
The same registration shall be performed after ap- Chemotherapy (BSAC) formed a working party
proximately one year. Most importantly, between (WP), having been stimulated into action by the
the two registrations a discussion should take place Infectious Diseases Society of America (IDSA) Task
and an educational programme based on the result Force Reports. Up until then, there had been no
of the first registration be formulated. national initiatives concerning antibiotic prescrib-
The APO method was asked for in Orup, a ing, which historically was probably at a lower level
medical district in Malmöhus County, to see if a than in the United States.
change in the antibiotic prescribing habits of par- In addition, because of the National Health Serv-
ticipating physicians could be obtained. Consulta- ice, with free care for all, there was less of an issue
tions for RTIs during the same periods among 25 in the costs of antibiotics which, at least in hospi-
doctors from a neighboring area who had not taken tals, amounted to less than 20% of hospital drug
part in any intervention or follow-up discussion use.
149
With a nationwide survey the BSAC WP estab- lance, nosocomial infection, and antibiotic policies
lished which control measures were then opera- such as ESGAP (www.escmid.org). Community
tional in UK hospitals, amounts of consumption action groups such as SWAB (Holland) and
in general practice, and educational practices for STRAMA (Sweden) were formed to educate both
medical students. Serious deficiencies were noted the public and prescribers; the European Medicines
in antibiotic policies and other control measures. Evaluation Agency (EMEA) and the Office Inter-
Recommendations were made for minimum national des Epizooties (OIE) formed working
control measures to be implemented in hospitals. groups to address resistance and surveillance issues;
Educational activities were established as sub-opti- and the Copenhagen meeting brought all the
mal and levels of consumption in general practice European Union (EU) countries together to address
were noted to be rising at 2–3% per year (past num- the issues in 1998.
bers). However, as measured by DDDs, consump- The most notable result of this meeting was the
tion levels seemed moderate by comparison to many ban on the use of antibiotic growth promoters in
other European countries (20 DDD/ 1000 patient 1999, which is currently implemented but is being
days). debated in the courts by two pharmaceutical manu-
These working party reports were published in facturers. Nevertheless, it seems to have had a
1993–4. In subsequent years little seems to have major impact on the animal consumption of anti-
happened except for local initiatives complicated biotics in all European Union countries, if official
by reforms of the National Health Service and in- figures are to be believed. No doubt there is a large
troduction of the purchase-provider split which may black market which we know little about.
have been counter-productive by reducing the use In light of the House of Lords Report (1998),
of laboratory services by general practitioners who the UK government was stimulated into action with
then had to pay for these services. The same cost- its own expert Standing Medical Advisory Com-
conscious reforms in hospitals led to a marked mittee Report and its separate response to the House
reduction in bed numbers with consequent over- of Lords Report (1999). The first result of this was
crowding, bed shortages, and boarding possibly a public education campaign advising patients not
leading to an upsurge in nosocomial spread of to pressure their doctors to give them antibiotics for
multidrug-resistant bacterial clones. There was also colds and flu and recommending 3 days treatment
pressure to increase the emphasis on broad-spec- for simple UTIs. There is some evidence now, from
trum empiric therapy and reduce the use of timely this and similar local campaigns, of reduced expecta-
laboratory investigations to discharge patients early. tions by patients, but no sudden downturn in com-
At this time an increase in hospital cases of munity prescribing of antibiotics-there has been a
C. difficile colitis was attributed to over-zealous in- slow (3%) annual downturn since the mid 1990s.
terpretation of the British Thoracic Society guide- Meanwhile, the Public Health Laboratory Serv-
lines for hospital treatment of community-acquired ice in England and Wales (PHLS), WMA (Welsh
pneumonia which recommended third generation Microbiological Association), SMA (Scottish
cephalosporin therapy for severe pneumonia but Microbiology Association) and a local Northern
which were commonly re-interpreted as recom- Ireland initiative have been using computerized
mending this treatment for any case of pneumonia laboratory facilities to organize national surveillance
requiring hospital admission. systems both for nosocomial infection and antibi-
At the time of the House of Lords enquiry into otic resistance, although all are still in their pilot
the problem (1997), which may have been initi- phases. The Scottish Government produced two
ated by the personal experiences of one or two of documents underlining the importance of infec-
their Lordships after they or their relatives acquired tion control and nosocomial infection surveillance
a methicillin resistant Staphylococcus aureus (MRSA) and the PHLS published results of a large survey
infection in a hospital, there had already been some on nosocomial infection. Combined with a report
activity at a European level with the Commission from the National Audit Office (NAO) and
starting to give grants for Pan-European surveil- others, criticizing the levels of nosocomial infec-
lance of resistance. Learned societies like the Euro- tion and poor standards of hospital cleanliness, the
pean Society for Biomodulation and Chemotherapy UK government (1999) (and latterly the Scottish
(ESBIC) and The European Society for Clinical Government) have formed multi-disciplinary
Microbiology and Infectious Diseases (ESCMID) expert advisory groups on antibiotic resistance
formed study groups to study resistance surveil- surveillance and nosocomial infection.
150
It is also the intention to monitor antibiotic con- The BSAC has also reformed its Education Work-
sumption and quality of prescribing and there is a ing Party and the National Prescribing Centre in
commitment to computerized prescribing in hos- Liverpool has developed a computer self education
pitals by 2005 and computer links between labora- and assessment programme for changing doctors’
tories and general practitioners by 2001. All general practices, which looks specifically at antibiotic
practitioners should have had computerized pre- prescribing.
scribing facilities and links to the Internet by the With the merger of many pharmaceutical com-
end of 2000. At the moment, all prescriptions in panies, consequent movement out of the UK, and
general practice are monitored but there is little data the development of European Registration of new
available on the indications for prescribing. antibiotics, there is a great concern in the UK at
Approximately 80% of antibiotic consumption the loss of a research base from which to develop
takes place in the community. At the moment there new antibiotics, so new initiatives in this field are
is no formal measurement of prescribing in hospi- likely. While there are always counter rumors, there
tals but the little data in the public domain sug- does seem to be a genuine, continued desire both
gests a continued annual increase in cost and DDD, at a UK and a European level to continue with these
although, as a percentage of hospital drug budgets, initiatives, not withstanding the politics!
it probably remains stable at 20%. It is too early yet to evaluate the success of any
The little available comparative data suggests the of this activity. With devolution and the establish-
UK hospital antibiotic consumption compares ment of the Scottish Parliament and the Welsh and
quite well with most European countries (40DDD Northern Ireland General Assemblies there is even
per 100 Patient Days). This area is also a priority more danger of duplication of activities than there
for the EU. would have been otherwise, so one of the main
It is hoped that the latest round of reforms of concerns will be to ensure coordination. To this end
the National Health Service, with its drive to im- there are a relatively small number of core opin-
prove quality and ensure better education of and ion-leaders who seem to serve on most of the UK
performance by doctors, will improve antibiotic central and devolved advisory committees and
prescribing. This includes the introduction of Clini- working parties and it is hoped that they will en-
cal Governance which intends to make doctors sure as little duplication as possible.
responsible for the quality of their antibiotic pre- At a European level the commission in Luxem-
scribing and empower their employers to ensure bourg has an interest in many aspects of the issues
that this quality is achieved. At the moment, and has recently issued a draft resolution calling
accreditation of doctors (and hospitals) is in its infor a publicity campaign with an annual Antibi-
fancy but developing rapidly, and it is hoped that otic Free Day. They are also interested in as much
CPD will have a large part devoted to antibiotic harmonization of antibiotic use and control meas-
resistance although legislatively. The matter of how ures between member states as is possible and there
much can be done legislatively to force the issues is some possibility of legislative control on meas-
of Antibiotic Resistance and Nosocomial Infection urement of antibiotic consumption, both in
with hospitals is another matter. animals and humans. On the issue of antibiotic re-
The newly formed Clinical Standards Board sistance surveillance, Pan-European initiatives are
(Scotland) and Commission for Health Improve- proving expensive and there is a move to improv-
ment (England, Wales & Northern Ireland) should ing the quality of routinely generated data from
have the teeth to deal with this and consideration diagnostic laboratories so that it can be used for
is being given to benchmarking hospitals of simi- European surveillance purposes.
lar types for infection and antibiotic resistance rates. Unfortunately there are several systems of sus-
There are encouraging signs from the government ceptibility testing in common use in Europe in
that they intend hospitals to carry the issue of anti- addition to National Committee for Clinical and
biotic resistance forward as a Strategic Goal. Laboratory Standards (NCCLS). These include
The drive towards evidence-based guidelines and Swedish, French (CA-SFM), German (DIN) and
policies is slowly progressing with separate govern- UK (British Society for Antimicrobial Chemo-
ment, PHLS, BSAC, Royal College of Physicians, therapy, BSAC) methods, all with different inter-
and other institutions’ initiatives, and the PHLS pretative criteria. There have been calls for a
have published evidence-based guidance for pri- European system, perhaps adopting NCCLS in all
mary care doctors on the Internet (www.phls.co.uk) countries, but we are nowhere near reaching agree-
151
ment. Many people consider the diversity of sus- In hospitals, audits repeatedly show unnecessary
ceptibility testing methods a strength, especially antibiotic use in the absence of positive microbiol-
when discovering new resistance mechanisms, and ogy and in patients with no sepsis parameters.
they suggest that establishing comparability Often unnecessary, expensive, broad spectrum,
between different systems will be a satisfactory com- toxic agents are administered by the IV route for
promise. They have, though, been saying this for too long, in often inappropriate doses. There is both
30 years and we don’t seem to be any further for- inappropriate and under-utilization of laboratories.
ward. Scotland, which does not have a PHLS, has There is a lack of understanding of how the labo-
decided to adopt NCCLS and also the NISS sys- ratories can help in therapeutic decision-making,
tem for nosocomial infection surveillance and Wales such as deciding the need for empiric therapy, the
and Northern Ireland may well do the same. Eng- choice of antibiotic, or how to streamline or stop
land (through the PHLS) looks as though it will the therapy. Finally, there is poor compliance with
adopt the BSAC methodology for susceptibility antibiotic policies.
testing and the NINS (Nosocomial Infection Poor compliance with policies for hospital clean-
National Surveillance) system for nosocomial ing, hand washing, standard precautions, barrier
infection surveillance. This latter system uses a dif- nursing, and isolation of colonized or infected
ferent set of risk factors than NISS (Nosocomial patients also occurs due to ignorance, bad practice,
Infection Surveillance System) overcrowding, or lack of facilities.
The solutions are:
■ Scotland: Antimicrobial Resistance 1. Via education, persuade all doctors, health ad-
Strategy and Action Plan 2001 ministration and managers to accept ownership
Ian M.Gould, Consultant Microbiologist, Department of of the problem.
Medical Microbiology, Royal Infirmary, Aberdeen Royal 2. Use incentives, penalties, or extensive, aggres-
Hospital, Aberdeen, Scotland. sive education to get doctors to change their ways
Contact: i.m.gould@abdn.ac.uk
of practice (known to be very difficult). Imple-
mentation and audit should become priorities
The main causes of antibiotic resistance bacteria in
for health boards, hospital trusts, etc.
diseases of humans in the UK at present are:
3. Increase resources to allow better patient isola-
1. Excess antibiotic use in primary care
tion, improved laboratory facilities, (including
2. Excess use in hospitals exacerbated by epidem- access to them and communication by them),
ics of antibiotic resistant bacteria in our hospi- improved hospital cleanliness, increased staff-
tals. patient ratios and reduced overcrowding/board-
ing of patients.
The underlying reasons are prescriber ignorance
and lack of ownership of the problem. Animals and horticulture, surveillance and re-
Audits repeatedly show poor quality, often com- search are all important (but side) issues. We know
pletely unnecessary antibiotic prescribing, poor there is a major problem, albeit much greater in
cleaning standards in hospitals, and poor compli- most other countries than in the UK, and we
ance with infection control procedures. The action understand enough about the causes to address
plan concentrates on recommendations to address them now.
these areas with detail on implementation.
152
APPENDIX C
About the authors
Alliance for the Prudent Use of Antibiotics August of 1998 was President of the International
(APUA) Society of Pharmaco-Epidemiology. Dr. Avorn is
75 Kneeland Street the author of over 150 papers in the medical litera-
Boston, MA 02111-1901 ture on medication use and its outcomes.
Phone: 617-636-0966
Fax: 617-636-3999 John F. Barrett, Ph.D.
E-mail: apua@opal.tufts.edu
Executive Director, Microbiology Department
Bristol-Myers Squibb Company
Jerry L. Avorn, M.D. Pharmaceutical Research Institute
Director, Program for the Analysis of Clinical 5 Research Parkway
Strategies Wallingford, CT 06492-7660
Brigham and Women’s Hospital Phone: 203-677-6499
Suite 341 Fax: 203-677-6771
221 Longwood Avenue E-mail: john.barrett@bms.com
Boston, MA 02115-5822
Phone: 617-278-0930 Currently Executive Director of Anti-Infectives
E-mail: javorn@partners.org Research at Bristol-Myers Squibb, Wallingford, CT.
With 16 years experience in the pharmaceutical
Associate Professor of Medicine at Harvard Medi- industry, he has experience in a wide breadth of
cal School and Chief of the Division of Pharmaco- antibacterial and antifungal discovery and devel-
Epidemiology and Pharmacoeconomics at Brigham opment efforts at Pfizer and Johnson & Johnson’s
and Women’s Hospital. An internist, geriatrician, RW Johnson Pharmaceutical Research Institute. Dr.
and pharmaco-epidemiologist, his research centres Barrett received his B.S. in Biochemistry from Tem-
on medication use, with particular reference to eld- ple University in Philadelphia, PA, and his doctor-
erly patients and chronic disease. Topics of particu- ate in Microbiology and Microbial Physiology from
lar interest include: scientific, policy, and social Temple University School of Medicine, with the
determinants of physician prescribing practices; late Gerry Shockman, Ph.D. He completed a
efficacy and effectiveness of specific medications; postdoctoral fellowship in genetic engineering with
compliance by patients with prescribed regimens; Roy Curtiss III, Ph.D. (UAB and Washington
methods to improve the appropriateness of drug University), and joined Pfizer in 1985, RWJPRI in
prescribing and drug taking; quantification of risks 1989, and BMS in 1997. His research efforts have
and benefits of drugs; and pharmaceutical cost- included β-lactams, penams, penems, β-lactamase
effectiveness analysis. Dr. Avorn is also director of inhibitors, quinolones, novel gyrase inhibitors, HIV
the Program for the Analysis of Clinical Strategies, gp120/CD4 antagonists, cephems, signal transduc-
a research unit with faculty and staff representing tion inhibitors, virulence factors, and mammalian
the disciplines of epidemiology, internal medicine, topoisomerase II inhibitors. Dr. Barrett is a mem-
health services research, psychiatry, and biostatis- ber of numerous editorial boards and author of over
tics. He attended Columbia College and Harvard 160 publications, as well as the 1999–2000
Medical School, and completed a residency in Division A Chair of the American Society of Micro-
internal medicine at the Beth Israel Hospital in Bos- biology. He became a Fellow in the American
ton. Dr. Avorn serves on several national and Academy of Microbiology in 2000. He leads a
international panels as an expert on the determi- group of research scientists seeking the identifica-
nants and outcomes of medication use, and until tion and development of novel antimicrobials and
153
antifungals through a combination of classical dis- Phone: 617-636-6765

covery strategies and techniques and a proprietary Fax: 617-636-0458
genomics effort. Dr. Barrett has been involved with E-mail: stuart.levy@tufts.edu
the development of several antibacterials currently
on the market including ofloxacin, levofloxacin, and President and founder of the Alliance for the Pru-
gatifloxacin, and is currently working on the de- dent Use of Antibiotics, and immediate past presi-
velopment of a novel MRSA-cephem (BMS- dent of the American Society for Microbiology. A
247243) and the des-quinolone (BMS-284756/ microbiologist and physician, Dr. Levy discovered
T-3811) at Bristol-Myers Squibb. the mechanism for tetracycline resistance (efflux)
and was among the first to document the transfer
of drug resistance among animals and humans. Dr.
Peter G. Davey, M.D.
Levy is the author of one of the most important
Professor of Clinical Pharmacology books on the subject, The Antibiotic Paradox: How
University of Dundee Miracle Drugs are Destroying the Miracle, which has
Nethergate, Dundee DD1 4HN been widely cited in both the lay and scientific
Scotland, UK media. He has also written more than 200 scien-
Phone: +44 (0)1382 660111 tific and medical papers and special journal edi-
E-mail: peter@memo.dundee.ac.uk tions on the topic. A world-renowned leader in the
field of antibiotic use and resistance, he has chaired
Has expertise in clinical pharmacology, infectious and served on numerous national and international
diseases, and health economics. He has served as a advisory boards and committees, including: the
Professor of Pharmacoeconomics, Clinical Pharma- NIH Fogarty Center’s study on The Use of Antibi-
cology and Infectious Diseases at the University of otics Worldwide (as Chairman); the advisory panel
Dundee, Scotland. Among his many teaching ac- for the USA Office of Technology Assessment re-
tivities, he has developed new curricula focusing port on the Impacts of Antibiotic Resistant Bacte-
on antimicrobials for a number of courses for medi- ria; the EPA Subcommittees on Health and
cal and dental students. He has extensive research Antibiotic Resistance; and the WHO Scientific
experience, including clinical trials and evaluations Advisory Group on Antimicrobial Resistance. Dr.
of antimicrobials, assessments of antimicrobial ac- Levy has also served as a consultant for the World
tion in vitro and in experimental animals; clinical Health Organization, the USA FDA, the National
pharmacokinetic studies of antimicrobials, and Institutes of Health, and other national and inter-
studies of gentamicin treatment. Since 1996, Dr. national organizations. He is currently Professor of
Davey has served as Head of Pharmacoeconomics Medicine and of Molecular Biology/Microbiology,
for the Medicines Monitoring Unit (MEMO), the Director of the Center for Adaptation Genet-
where he focuses on economic evaluation and out- ics and Drug Resistance at Tufts University School
comes research of drug treatment, and on antibi- of Medicine, and a Staff Physician at the New Eng-
otic policies and their influence on the development land Medical Center.
of drug resistance in hospitals and the community.
He has helped develop treatment guidelines and
national policies on antibiotic use in Scotland,
Scott A. McEwen, D.V.M.
served as an advisor to the House of Lords Com- Professor, Department of Population Medicine
mission on Antimicrobial Resistance, and has University of Guelph
spoken extensively on antimicrobial use at interna- Guelph, Ontario N1G 2W1
tional symposia, conferences, and meetings. Canada
Phone: 519-824-4120, ext. 4751
E-mail: smcewen@uoguelph.ca
Stuart B. Levy, M.D.
President, Alliance for the Prudent Use of Anti- Professor in the Department of Population Medi-
biotics cine, Ontario Veterinary College, University of
Room 704, South Cove Guelph. He is a veterinarian whose research focuses
Tufts University School of Medicine on the epidemiology of food-borne infections in
136 Harrison Avenue food animal populations, particularly Salmonella,
Boston, MA 02111-1817 E. coli and antibiotic resistant organisms. He has
154
conducted extensive research on human health lance program. He also set up the WHO Collabo-
impacts of antimicrobial use in animals, including rating Center for Surveillance of Resistance to
studies of antibiotic and chemical residues in milk Antimicrobial Agents at Brigham and Women’s
and meat, and the association between resistance Hospital in Boston in 1985, which has established
and antibiotic use on farms, and has published more an international network of microbiology labora-
than 80 papers in peer review journals. Dr. McEwen tories dealing with antimicrobial resistance surveil-
has served as a consultant for WHO on the human lance. Dr. O’Brien has served as an advisor on
health impact of antimicrobials in food animals, numerous national and international committees
and as panel member for the U.S. FDA on antimi- dealing with antimicrobial resistance, including the
crobial resistance risk assessment. He also chaired NIH Task Force on Antibiotic Resistance, which
the Health Canada Advisory Committee on Ani- he chaired from 1984 to 1986; the WHO Scien-
mal Uses of Antimicrobials and their Impact on tific Working Group on AMR (1981); the FDA’s
Resistance and Human Health. Dr. McEwen Veterinary Medicine Advisory Committee (since
teaches food safety to veterinary students and gradu- 1994); the Office of Technology Assessment
ate students at the University of Guelph. Advisory Panel on Impacts of Antibiotic-Resistant
Bacteria; the Inter-Agency (FDA, CDC, USDA)
Working Group on Antimicrobial Resistance; and
Thomas F. O’Brien, M.D.
the CDC Working Group on Drug Resistant Strep-
Medical Director, Microbiology Lab tococcus pneumoniae. He has also served as a con-
Brigham and Women’s Hospital sultant on antimicrobial resistance to WHO (in
75 Francis Street Geneva and Manila), PAHO, the British House of
Boston, MA 02115-6110 Lords, and the National Health Research Institute
Phone: 617-732-6803 of Taiwan, among others. Medical Director of the
E-mail: tobrien@rics.bwh.harvard.edu Microbiology Laboratory at Brigham and Wom-
en’s Hospital for the past 20 years, Dr. O’Brien is a
Vice President of APUA, is a leading authority on pioneering researcher in the area of antimicrobial
antibiotic resistance and AMR surveillance. An in- resistance, having conducted microbiological stud-
fectious disease specialist and microbiologist, Dr. ies on resistance since the mid-1960s.
O’Brien helped develop the WHONET surveil-
155

Apua, 2011

Uploaded by

Copyright:

Available Formats

Apua, 2011

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Apua, 2011

Uploaded by

Copyright:

Available Formats

WHO/CDS/CSR/DRS/2001.

ANTIBIOTIC RESISTANCE: SYNTHESIS OF RECOMMENDATIONS BY EXPERT POLICY GROUPS

World Health Organization

© World Health Organization 2001

ICARE Intensive Care Antimicrobial NNISS National Nosocomial Infections

National and municipal organizations Health care workers

titioners (and potentially the patients) who Health care workers

— Provide incentives to companies to invest in — Screening methods.

National and municipal organizations — Support developing countries in creating

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

Year Study nature, location,

Year Study nature, location,

Year Study nature, location,

Year Study nature, location,

General review Control & prevention

1. (1987) Antibiotic use and anti-

2. (1990) Healthy People 2000:

3. (1992) Emerging Infections:

4. (1994) Addressing emerging

5. (1995) WHO Scientific Working

6. (1995) Impacts of Antibiotic-

7. (1995) Infectious Disease–

8. (1995) Report of the ASM Task

9. (1997) The Medical Impact of

10. (1997) America’s vital interest

11. (1997) New and Re-emerging

12. (1997) Resistant organisms :

13. (1997) SHEA Position Paper on

14. (1997) Antibiotic Resistance:

15. (1998) The Current Status of

General review Control & prevention

16. (1998) Papers from the Inter-

17. (1998) Preventing Emerging

18. (1998) Human Health Safety

19. (1998) The Path of Least

20. (1998) British Medical Journal

21. (1998) Resistance to antibiotics

22. (1998) Antimicrobial Resistance:

23. (1998) Protecting the Crown

24. (1999) The Agricultural Use of

25. (1998)The Use of Drugs in Food

Improve and expand surveillance

Abstract The groups made generally similar recommen-

planning interventions so as to preserve the Clinical microbiology laboratory information

Level Observation Use

Increase awareness: optimize patient

them disinclined to accept guidelines or antibi- by addressing either audience separately.

System-wide interventions A number of strategies for improving the knowl-

Similarly, the US Agency for International Conclusions

Strengthen sanitation,infection control,

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

Category and designation Basis for assignment

A. Comprehensive 1. No free sale allowed.

B. Partial 1. No free sale allowed.

C. Minimal 1. No free sale allowed.

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

Application in practice and enforcement of compliance with regulation

A. Complete Tightly controlled availability; regulations rigorously enforced.

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