BLURP TO INTODUCE ON ISMR WEB SITE---EDIT FREELY
The George Mason University Office of International Medical Policy and the International
Society of Microbial Resistance collaborated with the American Medical Association and the
World Medical Association (WMA) in a policy development process update the international
organization’s policy on microbial resistance for its 8 million member physicians. An
invitational Microbial Resistance Policy Forum was conducted on the GMU Fairfax Campus on
23 October 2006. A briefing and background paper was prepared and circulated to the invited
experts prior to the forum. This paper providing an international overview and the microbial
resistance and of its related issues is provided as a PDF.
Microbial Resistance Policy Forum
1
ANTIMICROBIAL RESISTANCE POLICY EVALUATION AND FORMULATION:
A BRIEFING AND BACKGROUND PAPER PREPARED FOR THE WORLD
MEDICAL ASSOCIATION (WMA)
I.
Purpose
The American Medical Association (AMA) in collaboration with the International
Society of Microbial Resistance (ISMR), and the Office of International Medical Policy
(OIMP), School of Pubic Policy, George Mason University propose a revised evidencebased WMA antimicrobial policy in light of the alarming increases in antimicrobial
resistance over the past decade.
The ultimate purpose of this revised information, based upon the accumulated scientific
and epidemiological evidence and supplemented by the judgments of stakeholders was
captured in the present briefing paper and can assist in the development of a WMA
Declaration on Antimicrobial Drug Resistance for consideration at the spring 2007 WMA
Council Meeting, and subsequently by the WMA Assembly in the fall of 2007.
II.
Introduction
The World Medical Association (WMA) sounded the alarm about a pending global crisis
in resistance to antimicrobial drugs in a 1996 policy statement, which was adopted at the
WMA 48th General Assembly, Somerset West, in the Republic of South Africa
(Appendix A). Unfortunately the predicted crisis is now a 21st century global public
health threat, economic burden and biological challenge.
This briefing paper is the initial step in policy review and formulation. The paper’s
objectives are to present the:

Review of the clinical knowledge and related literature published since 1996
(when the last scientific review was performed for the 1996 WMA statement).
The literature review, while conducted using English-language sources, sought to
include an international spectrum of authors, sources, and data.

Escalating scope and impact of antimicrobial resistance since publication of the
1996 WMA statement.

Framework for the core issues and policy revision.
This paper was circulated for deliberation by a panel of expert stakeholders at a forum
held on 23 October 2006 at George Mason University in Fairfax, Virginia, USA. The
paper was intended to provide a common frame of reference, stimulate examination of
Microbial Resistance Policy Forum
2
the subject matter, and generate recommendations for integration into a revised and
strengthened policy formulation. The paper will also serve as an interim report to the
WMA Fall 2006 Council meeting.
III. Antimicrobial Resistance: The Scope of the Problem
The late Martin Wood of the United Kingdom and Robert Moellering of the United States
documented the complex and dynamic relationship between microbes and humans. In a
jointly authored article they noted that microbial ingenuity and resilience are evidenced
by their remarkable ability to develop resistance to chemotherapeutic agents.1 No
boundaries appear to limit the ability of some microorganisms to develop resistance, and,
indeed, human history is marked by a continuing battle between humans and the
multitude of microbes.2 Nobel Laureate Joshua Lederberg, who launched the study of
molecular genetics and the study of the dynamic evolution of the microbe, suggests that
in this scenario, humanity will be the likely loser unless it continues to adapt with the
microbes.3
Infectious diseases continue to be a leading cause of death, illness, and socioeconomic
instability around the world. The World Health Organization (WHO) estimates that in
2002 slightly more than 11 million deaths were attributable to infectious and parasitic
diseases.4 More than 90% of these deaths were attributable to a handful of infections,
suggesting that targeted guidelines for treatment of well-described disease entities can
have a powerful effect on morbidity and mortality The chart below summarizes the
impact of these killer diseases from a global perspective.
Table (1) Leading Infectious Diseases as
Cause of Death (2002)5
No. of
Percent
Deaths of Deaths
(millions)
Lower respiratory infections
3.9
19
HIV/AIDS
2.8
3
Diarrheal diseases
1.8
17
Tuberculosis
1.6
n/a
Malaria
1.2
8
Measles
0.6
4
Neonatal causes
37
Other
10
The development of effective anti-infective agents is one of the most important
breakthroughs of the 20th century. At one time, antimicrobial drugs coupled with
infection control stratagems appeared to be winning the battle with microbes.6 However,
almost as soon as these drugs were deployed, microbes responded by forming
Microbial Resistance Policy Forum
3
mechanisms to resist their effects.7 Recent evidence suggests that the rising prevalence
of antibiotic resistance worldwide poses a serious global threat to the treatment of
infectious diseases.8
Drug resistance has emerged across the spectrum of microbes—viruses, fungi, parasites,
and bacteria.9 Major pathogens that have become resistant to antimicrobials include:








Bacteria causing diverse infections such as Staphylococci, Enterococci (E. coli)
Agents causing respiratory infections such as tuberculosis (including
“extensively-drug resistant TB” or XDR-TB) and influenza
Food-borne pathogens such as Salmonella and Campylobacter
Sexually transmitted organisms such as Neisseria gonorrhoeae
Candida and other fungal infections
Parasites such as Plasmodium falciparum, the cause of malaria
Pseudomonas and Acinetobacter
Potential metronidazole resistant epidemic strain of Clostridium difficile
(BI/NAP1)
As a result, infectious diseases have become more complicated and costly to treat, and
antimicrobial resistance has imposed substantial costs on society. For example, in 1995,
the Congressional Office of Technology Assessment estimated that antibiotic resistance
minimally costs the United States $1.3 billion annually.10 (Discussed in greater detail
below.)
The accelerating cascade of drug resistance includes: the ineffectiveness of chloroquine
as a primary anti-malarial agent, multidrug-resistant tuberculosis (MDR-TB), a diversity
of antibiotic-resistant diarrheal diseases and acute respiratory infections, HIV/AIDS, and
methicillin-resistant Staphylococcus aureus (MRSA) (now spreading from hospitals into
the community). Many complex mechanisms of resistance to antifungal drugs have been
observed.11 Fluconazole was introduced in the early 1990s as therapy for candidiasis and
was rapidly followed by the emergence of fluconazole-resistant oral candidiasis, which is
seen in one-third of patients with advanced AIDS.12
Macrolide resistance among Streptococcus pneumoniae isolates from various countries is
summarized in the following table:13
Table (2) Global Sampling of Macrolide Resistance*
Country
Brazil
Europe
Hong Kong
Japan
Mexico
Microbial Resistance Policy Forum
% Resistant
3.0
19.7
81.0
71.3
28.9
4
Russia
3.2
Saudi Arabia
15.6
Singapore
46.9
South Africa
18.7
USA
26.0
*Resistance is defined as erythromycin MIC 1 mg/L.
The U.S. media has recently given extensive coverage to a possible avian flu pandemic.
Moellering posits, however, that a U.S. epidemic of community-acquired methicillinresistant strains of S. aureus (CA-MRSA) is a more challenging public health problem.14
The accumulated evidence of the past decade indicates that a global pandemic of
antimicrobial resistance is the more likely scenario.
Antimicrobial Drug Resistance: Global Glimpses
No part of the world is exempt from antimicrobial drug resistance. The U.S. National
Intelligence Council provides these stark assessments:15

First-line drug treatment for malaria is no longer effective in 80 of the 92
countries where the disease is a major health problem.

Penicillin has substantially lost its effectiveness against pneumonia, meningitis,
and gonorrhea in many countries. Note: There is still debate about whether
penicillin resistance is clinically significant in bacteremic pneumococcal
pneumonia. Many experts still recommend penicillin as first line therapy for
proven pneumococcal infection, even if it is resistant to penicillin.

Eighty percent of Staphylococcus aureus isolates in the United States are
penicillin- resistant and 32 percent are methicillin-resistant.
The following examples illustrate the global manifestations of antimicrobial drug
resistance:

Russia’s epidemic of MDR-TB is one of the worst in the in world; an estimated
26 million individuals are infected, or one in six people.16

The Canadian Nosocomial Infection Surveillance Program found the incidence of
MRSA jumped from 1 percent in 1995 to 8 percent at the end of 2000.17 The
prevalence of Streptococcus pneumoniae with reduced susceptibility to penicillin
(both intermediate-level and high-level resistance) was found to be 12 percent.
Vancomycin-resistant enterococci (VRE), Shigella and Salmonella species
resistant to multiple antibiotics, enteric gram-negative bacilli (Klebsiella and
Enterobacter species) resistant to extended-spectrum β-lactams, and penicillinresistant Streptococcus pneumoniae (PRSP) all provide further evidence of the
extent of the resistance problem in Canada.
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
In Pakistan, Salmonella paratyphi A is emerging as a major pathogen, and
resistance to conventional antityphoid drugs has increased from 14 percent to 44
percent between 1996 and 2003. Susceptibility to the fluoroquinolones is
decreasing.18

A Brazilian investigation examined the antimicrobial resistance of bacteria
isolated from cockroaches, which are a major hospital and community vector.19
Enterobacteria were found in almost three-quarters the cockroaches sampled.
Ninety-six percent were resistant to gentamicin, 84 percent to ampicillin, 75.3
percent to caphalothin, 66.7 percent to ampicillin-sulbactam, 50 percent to
aztreonam, and 30 percent to chloramphenicol.

In a study of antibiotic drug sensitivity to Pseudomonas aeruginosa isolates
conducted in Nigeria, appreciable resistance was found to ceftazidime, the drug of
choice for P. aeruginosa meningitis.20 Similarly, resistance to gentamicin is
increasing, resulting in the shift of first line treatment to more complex and
expensive protocols.

Candida albicans is the most common yeast isolated at the University of
Medicine Hospital in Kaunas, Lithuania.21 Significant resistance was found to
both fluconazole and itraconazole.

Of 128 patients receiving antiretroviral therapy in an HIV/AIDS outpatient clinic
in Cameroon, 16.4 percent developed drug resistance after a median of 10
months. Of these, 12.5 percent had resistance to nucleoside reverse transcriptase
inhibitors (NRTIs), 10.2 percent to non-NRTIs, and 2.3 percent to protease
inhibitors.22 The investigators were unable to evaluate the association of
resistance with adherence, support, and prescribing practices. They did note that
the clinical and biological follow-up and drug supply were irregular and that
many patients interrupted their treatment.

Surveys conducted in Botswana in 1995 and 2002 determined that resistance to at
least one anti-tuberculosis drug rose from 3.7 percent to 10.4 percent over that
period.23

The SENTRY Antimicrobial Surveillance Program found S. aureus to be the most
frequently isolated pathogen causing blood stream infection in the United States,
Canada, and Latin America, and coagulase-negative Staphylococcus (CoNS) to be
the third most frequent cause. The National Nosocomial Infection Surveillance
(NNIS) found that the prevalence of methicillin resistance among S. aureus
increased from 2.1 percent in 1975 to 35 percent in 1991. CoNS resistance
increased from 20 percent to 60 percent.24 The following table from the SENTRY
data shows the rates of methicillin resistance among S. aureus isolates for regions
around the world:
Table (3) Rates of Methicillin Resistance among Staphylococcus aureus Isolates
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Nation\Region
Argentina
Australia
Austria
Belgium
Brazil
Canada
Chile
Columbia
England
France
Germany
Greece
Hong Kong
#Isolates
% Resistant
424
606
117
82
814
1419
428
139
131
718
347
128
172
42.7
23.6
9.4
25.6
33.7
5.7
45.3
8.6
27.5
21.4
4.9
34.4
73.8
Nation\Region
#Isolates
Italy
Japan
Mexico
The Netherlands
Poland
Portugal
South Africa
Spain
Switzerland
Taiwan
Turkey
United States
297
299
88
147
159
318
77
352
114
90
104
7169
%
Resistant
50.5
71.6
11.4
2.0
25.8
54.4
42.9
19.3
1.8
61.1
37.5
34.2
Source: SENTRY Program 2001
Physicians in developing countries may have to use older antimicrobial drugs that have
become increasingly ineffective, resulting in increasingly high rates of treatment failure.25
These physicians lack drug susceptibility testing and/or the option to change therapies.
Given the increasing rates of resistance in developing countries, this makes their burden
even greater. While microbial resistance is a serious concern in developed countries, it is
potentially devastating in developing countries.
The effects of antimicrobial drug resistance
Howard and colleagues caution that quantifying the burden of antimicrobial drug
resistance remains challenging.26 Several studies document treatment failures, excess
morbidity and mortality, and increased cost as some of the fundamental effects, but
financial and psychological costs are also associated with widespread fear of infection
and behavior change in populations living in high prevalence areas.27
In a limited study, the U.S. Office of Technology Assessment calculated that the direct
hospital costs from five classes of nosocomial infections were associated with only six
different strains of antibiotic-resistant bacteria.28
Table ( 4): Organisms Included in Hospital Cost Study of Antibiotic Resistance
methicillin resistant S. aureus [MRSA]
vancomycin-resistant enterococci [VRE]
imipenem-resistant Pseudomonas aeruginos
methicillin-resistant coagulase-negative staphylococci
ampicillin-resistant Escherichia coli
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resistant Enterobacter
It was concluded that the minimum U.S. nationwide aggregate hospital cost of these
infectious diseases was $1.3 billion in 1992 dollars (US). Including infections associated
with other bacteria and other costs in addition to direct hospital costs would increase the
total to several billion dollars. This number is expected to increase as the numbers of
antibiotic-resistant bacteria also increase. An Institute of Medicine report estimated that
the total cost to society of antimicrobial resistance in the United States was at least $4 to
$5 billion annually.29
Antimicrobial drug resistance not only exacerbates the economic burden of infectious
diseases, it also aggravates and accelerates economic decline, loss of productivity, and
social disintegration. Affording increasingly costly drugs is a challenge for developed
economies and is devastating for developing economies. In some countries, it is
politically destabilizing and can be a threat to global security.
In the 21st century, biological warfare (e.g., drug-resistant “super bugs”) is a realistic
threat. Furthermore, fear of biologic agents in the aftermath of 9/11 has led to empiric
preventive measures, as in the broad use of ciprofloxacin for possible anthrax exposure in
the United States. Such sporadic, widespread use over a broad population has serious
resistance implications in the affected communities.
Physicians, with an increasing awareness of drug resistance, escalate use of newer and
more costly drugs. One study found that in the late 1990s, rising levels of resistance
increased antibiotic expenditures for otitis media by 20 percent.30 It is calculated that the
use of quinine versus chloroquine as first-line therapy in 150 million patients with
malaria would increase spending by as much as $100 million (US).31 ). In many
countries the first line regimens available to a majority of HIV/AIDS patients may be
easily compromised such as non-nucleoside reverse transcriptase inhibitors (NNRTI).
The spread of NNRTI resistant viruses would result in the need for other more costly
drugs.
Societal and Behavioral Factors Contributing to Spread of Antimicrobial Resistance
Travel and Migration
International travel is a major transmission vehicle for infectious diseases and increased
exposure to resistant microbe strains. Statistics on U.S. international travel illustrate its
robust growth32; between 1990 and 2000, such travel increased 16 percent. In 2000 a
total of 366 million inbound and outbound trips were made between the United States and
other countries. In a recent survey of 17,353 travelers from 31 countries, who visited
developing countries from June 1996 to August 2004, systemic febrile illnesses (malaria,
dengue fever, mononucleosis, etc), and acute and chronic diarrhea were among the top
five reasons why returning travelers sought medical attention.33 In 2000, 27 million U.S.
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8
residents traveled to overseas destinations, while 26 million overseas residents came to
the United States.
Global migration carries a similar threat. In 2005, 191 million persons lived outside their
country of birth compared to 75 million in 1960.34 Sixty percent of the world’s migrants
currently reside in more developed regions.
Table (5) Leading Regions Where Migrants Live
Region
Europe
Asia
North America
Millions
64
53
45
Three-quarters of all international migrants are concentrated in 28 countries. During
2000-2005, the more developed regions of the world gained an estimated 2.6 million
migrants annually from the less developed regions. North America experienced the
greatest net migration: 1.4 million migrants annually. Latin America and Caribbean
countries had the highest net emigration rate.
Global Nature of the Food Supply
Globalization of the food supply increases the probability of the spread of resistance. In
2004 the volume of trade exports increased by 9 percent, the greatest rise since 2000.35
Agricultural trade is estimated to have grown by 3.5 percent in 2004. The inappropriate
use of antimicrobials in agriculture does contribute further to resistance problems, and
agricultural trade could facilitate the dissemination of resistant organisms.
Increased Density of Vulnerable Populations
Aggregation of vulnerable populations into dense institutional settings amplifies the
hazards of resistance. In the United States, this has been demonstrated in hospitals,
prisons, the military, sports teams, and child care sites.36 David Livermore of the
Antibiotic Resistance Monitoring and Reference Laboratory in London expresses concern
that social policies that concentrate human beings in dense living situations are likely
exacerbating resistance and are socially and politically difficult to change.37
Poor Hygiene and Infection Control
Inadequate infection control practices contribute substantially to the spread of resistance,
and the absence of essential hygiene resources in group settings remains a serious
concern.38 This includes environmental contamination, deficient cleaning protocols, and
poor aseptic technique. Deficient personal hygiene, especially infrequent and ineffective
hand washing, is noted in studies of groups who have a higher risk of contracting MRSA.
Patient Expectations and Compliance
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Patient attitudes and expectations play an important role in the use of antimicrobial drugs.
Demand for and use of antibiotic drugs is second only to that of analgesics.39 Twenty
percent of prescribed antibiotics is used in hospitals while 80 percent is used in the
community. In the United States, per prescription antibiotic spending increased 22
percent from 1980 to 1996. This corresponds with a steep increase in resistance levels
over the same period.40 Misuse and inappropriate use are far-reaching. A 2003 Los
Angeles Health Survey found that only one in three consumers understood that antibiotics
were effective only against bacteria and almost half reported not taking the full
prescribed course of antibiotics. Thirty percent obtained antibiotics without a prescription
from family or friends.41
Health literacy is a serious problem and a significant element of the resistance dilemma.
The problem begins with basic literacy. Using the United States as a point of reference
(and noting it is a highly developed economy), 90 million adults score in the lowest of
five categories of literacy skills.42 Illiteracy creates health disparities43 and impairs
functioning in health care environments.44 It leads to poor communication and
compliance and results in substandard care.
Patients and families expect and frequently demand an antimicrobial drug from their
physician45 in the belief that an antibiotic will provide a quicker recovery. There is
limited awareness that inappropriate prior use of antibiotics increases patients’ risk of
developing a resistant infection. To preserve a comfortable relationship with his/her
patient, a physician may not wish to challenge these patient expectations, and instead
prescribes an antimicrobial without identifying the pathogen or its susceptibility to the
drug.46 The focus is on a hypothetical benefit to the individual, without consideration of
the risks to the broader society, or for blunting the potential effectiveness of the drug for
the individual should future use be necessary. Another reason that physicians give
antibiotics to patients who may not require them is fear of a litigious society particularly
in the United States.
Proliferation of Counterfeit Antimicrobials
Particularly insidious for the treatment of infectious diseases in general and with a
potential impact on resistance in particular is the global explosion of counterfeit drugs. If
the counterfeit drug is absent antimicrobial content, then there likely will not be any
significant impact on antimicrobial resistance, although the detriment to patient health is
obvious. However, if the counterfeit drug has sub-potent levels of antimicrobial content,
then the impact to resistance may be tremendous. The U.S. Center for Medicines in the
Public Interest projects counterfeit drug sales will reach $75 billion (US) globally in
2010,47 an increase of more than 90 percent from 2005 levels. As much of half of the
antimalaria medications in Africa are probably counterfeit. A WHO survey of 20
countries conducted from January 1999 to October 2000 found that 60 percent of
counterfeit drugs cases occurred in poor countries. The remaining 40 percent originated
in industrialized countries.
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Stewardship of Antimicrobial Drugs
Overuse and inappropriate drug use is a problem for industrialized nations. There
appears to be a correlation between the increased number of prescriptions written and an
increase in reduced susceptibility to antimicrobial drugs. France, Australia, the United
States, Canada, Italy and the United Kingdom have the highest rates of oral antimicrobial
prescriptions, which corresponds to an elevation in resistance.48 In 2000 Wenzel reported
that 160 million antibiotic prescriptions are written annually in the United States for
human use, constituting 11.35 million kg of antibiotics.49
The Canadian Medical Association’s Committee on Antibiotic Resistance suggests that
antimicrobial stewardship may be the key to controlling antimicrobial resistance.50
Antimicrobial stewardship programs attempt to achieve an ecological balance between
susceptible and resistant microbes in humans. Care must be exercised in establishing the
need for and the choice of antimicrobial drugs. As with patients, physician attitudes are
important. Does the physician perceive resistance as a problem? Does the physician
understand his/her personal role in advancing antimicrobial resistance? These attitudes
will influence a physician’s treatment decisions.
Appropriate antimicrobial drug choices begin with knowledge of the pathogens involved
in a particular infection.51 Physicians should know which pathogens are susceptible to
which drug and if the drug is capable of penetrating the target infection site. Knowledge
of pharmacodynamics and pharmacokinetics is also essential.
The physician’s role and responsibility for the management of antimicrobial drug
resources is substantial. The goal of any clinical intervention with an antimicrobial agent
is concisely expressed by Tenover: the prudent use of the appropriate drug at the
appropriate dose and for the appropriate duration.52 Paskovaty et al. describe the goal
as eradication of the infection while minimizing side effects.53
There are critical barriers to achieving the ideal standard of infectious disease
management in clinical practice, including lack of timely laboratory diagnostic
information to confirm the identity of the pathogen and lack of community or regional
antimicrobial drug sensitivity information. In less developed nations, access to the most
effective agents is limited. Community, regional, and global surveillance networks are
also needed.
Stewardship requires knowledge and practice of known critical infection control
technologies.54 In a recent article, Goldman emphasizes that infections such as MRSA
are transmitted primarily by the contaminated hands of health care providers who have
touched a colonized patient or something in the patient's environment.55 It is estimated
that 30 to 40 percent of endemic institutional antibiotic resistance is caused by
ineffective or absent hand washing .56
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Status and overview of antimicrobial drug development
The Infectious Diseases Society of America’s 2004 report notes that resistance to existing
drugs is accelerating, while the development of new drugs for infectious diseases is in
rapid decline.57 In the United States, until the Food and Drug Administration’s (FDA)
approval of oxazolidone, no new class of antibacterial drug had been approved for 25
years.58 Most of pharmaceutical industry’s activities have targeted chemical modification
of existing classes of drugs. Few are “narrow spectrum”; e.g., directed at specific
organisms. Most are “broad spectrum”; e.g., directed at a wide range of organisms and
thus more likely to facilitate the spread of resistance.
Based on a survey of public reports of the 15 largest pharmaceutical companies, a total of
418 agents are in development. Of these, 315 are new molecular entities (NME). Only
10 percent are anti-infectives..59 Five are new antibacterial agents, and none appears to
possess novel mechanisms of action. Even though industry research and development
budgets are increasing, antibacterial drug development has been curtailed.
Table (6): Anti-infective NMEs Publicly Disclosed in R&D of World’s
15 Largest Pharmaceutical Companies
Agent Type # of NMEs
Anti-HIV
12
Other antiviral
5
Antibacterial
5
Antiparasitics
5
Antifungals
3
Topical
1
(need to request permission to use table)
A similar picture emerges in a survey conducted by the same investigators on
biotechnology development. Public reports and disclosures of seven of the largest
biotechnology companies reveal a total of 88 drugs in development. Only one is a new
antibacterial agent. The authors project that for at least a decade into the future, the
availability of new antibacterial agents will decline.
The economics of new drug development do not favor antimicrobial drugs. An average
of eight to 10 years is required to bring drugs from the early phases of clinical testing to
the market.60 The FDA projects that bringing a new drug to market can cost from $800
million(US) to $1.7 (US) billion.61 The risks of new drug development are extremely
high. With demographic shifts toward aging populations in developed nations, the
market strongly favors the development of drugs for chronic diseases and lifestyle issues.
An effective antimicrobial drug cures the disease, and its use is time limited while drugs
for chronic conditions are used continuously. Furthermore, there is little incentive to
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12
develop new antibiotic drugs, because a new antibacterial agent is generally placed on
“last resort” lists in medical facilities in order to preserve its potency. While certainly
appropriate, this practice reduces revenue for the manufacturer, creating a disincentive to
invest in the development of new antibacterials. To a pharmaceutical company, a
musculoskeletal drug is worth about $1 (US) billion, while an antimicrobial drug is worth
only$100 (US) million.62 Industry withdrawal from antimicrobial drug development has
serious public health consequences.
These economic realities create a bleak situation for developing countries. The cost of
the new antimicrobials makes them virtually inaccessible without special dispensation.
The world’s leading companies have donated drugs for the treatment of river blindness,
AIDS, malaria, and tuberculosis. The absence of laboratory support for both pathogen
identification and susceptibility testing necessitates empiric treatment with available
broad-spectrum agents, further facilitating the development of resistance.
Advances in the basic sciences that have stimulated drug innovation in other areas hold
potential for antimicrobial drug development. Most antibacterial agents are natural
products and have only a limited period of practical clinical utility.63 Innovative
applications of science and technology have promise for the development of novel
antimicrobials as follows:

Antibiotics from Xenobiotics: Compounds based on non-natural compounds that
are chemically foreign to the biosphere.

Advances in Synthetic Chemistry: Many believe that antibiotic discoveries will be
driven by advances in chemistry, genetics, structural biology, bioinformatics, and
engineering.64

Genomics and Bioinformatics: The bacterial genome project provides the
opportunity to view the entire genetic blueprints of organisms. More than 30
bacterial genomes have been sequenced.65
o Bacterial Functional Genomics: Targeting of genes in the genome that
appear to have no apparent function but may prove to be associated
growth and viability.
o Integrative Infectious Disease Biology: Leveraging the explication of the
human genome and genomic sequences of the most important bacterial
and fungal pathogens to aid rational drug design against infectious
agents.66
The approach to infectious diseases may be dramatically changed given emerging
evidence that infectious agents potentially cause and contribute to many cancers and
chronic diseases previously attributed solely to environmental and lifestyle factors.67
Realization that an organism can produce slowly progressive chronic disease may result
in a new perspective, and a corresponding increase in investment in treatments for
infectious diseases.
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13
Vaccines targeting microbial pathogens provide some hope in combating resistance.
Plasmid DNA technology is under intensive study for vaccine development but remains
limited by its low immunogenicity.68 Techniques for boosting the level and skewing the
nature of the immune response have been developed and are under study. DNA vaccines
continued to be studied as a potential preventive measure against infectious organisms to
prevent the occurrence and progression of disease. Using surveillance data from 1996 to
2004, the rate of antibiotic-resistant invasive pneumococcal infections decreased in
young children and the elderly following introduction of the conjugate vaccine.69
Vaccinology research continues in hepatitis C, HIV-1, and bacterial infections that cause
tuberculosis and meningitis. Commercial vaccines already exist for Japanese encephalitis
and yellow fever. A good example is influenza. Decreasing viral infections (via
vaccination) also will decrease secondary bacteria infections and thereby decrease
antibiotic use.
Appropriate treatment of infectious diseases demands timely and accurate
microbiological laboratory testing, both to ensure accurate targeting of the pathogen and
for susceptibility of the antimicrobial drug. Pharmaceutical and diagnostic companies are
investing heavily in molecular testing. Rapid diagnostics are expected to lead to a greater
synergy between diagnostics and therapy.70 They will provide for early detection of
asymptomatic disease, allow monitoring of treatment, and facilitate more appropriate use
of drugs. Rapid visual test results at low cost hold great promise in the fight against
resistance. Resistance testing technology for HIV/AIDS and TB would have special
significance in the developing world as both surveillance tools and for clinical purposes.
However, problems remain, such as the clinical interpretation of quantitative polymerase
chase reaction (PCR).
III. Policy Formulation: Addressing Antimicrobial Drug Resistance
Policy is an adopted plan, a determined course of action. Policy formulation is a group or
social enterprise striving to achieve a consensus from a broad spectrum of informed
points of view and diverse interests. It is an interdependent and methodical process. In
many respects, the process is counterintuitive to the instincts of the clinical culture that
values independence and individual expert judgment.
Policy formulation implies reaching decisions after conscientious review of available
alternatives and options, but ideally is evidence-based and incorporates considered expert
judgments in the face of uncertainty. It should also select strategic objectives and identify
the methods or tactics for achieving them.
Selecting Attainable Strategic Goals
Antimicrobial resistance is a multifaceted challenge. It is a dynamic biologic story that
continues to unfold, revealing both new possibilities and new levels of complexity.
Awareness of the intricate nature of resistance increases as scientific knowledge expands.
Microbial Resistance Policy Forum
14
Livermore suggests that it is probably naïve to envision reaching a grand “control” over
resistance.71 He suggests that “management” rather than “elimination” is the more
realistic and attainable goal. Furthermore, it is suggested that a secondary strategic
objective be slowing the development of resistance coupled with increased development
of new agents and intervention alternatives.
Strategies of disease prevention and of interruption of transmission are a significant part
of an antimicrobial drug resistance plan. Costs to prevent illnesses are a magnitude less
than the costs of treatment regimens, but require additional efforts in health education and
literacy in order to achieve positive societal and professional behavioral changes. As
noted above, infections such as MRSA are transmitted primarily by the contaminated
hands of health care providers who have touched a colonized patient or something in the
patient's environment and can be reduced by proper hand washing techniques.72
Identifying reservoirs of developing resistance within the general population may focus
efforts to reduce their threat to the general population. Examples include reservoirs of
community-acquired MRSA in prisons, the military, child care centers, and sports
teams.73 This would also include domestic pets and agricultural sources.
Tactics Employed to Achieve Strategic Goals
The following is a summary of the major tactics being employed to address antimicrobial
drug resistance:
Education is the fundamental method to reach the strategic goal of management. The
target audiences are manifold: health care professionals, patients and families, legislators
and regulators, the drug and device industry, educators, and the general population.
Educational methods may include one-on-one consultations, traditional classrooms,
multimedia digital modular menus of lesson resources distributed electronically, and
Internet-based resources.74 Education is an integral element of any antimicrobial
resistance management strategy, but it must be supplemented with other tactics. However,
a recent literature review by the Agency for Healthcare Research and Quality (AHRQ)
found that education has limited effect on consumers and physicians.75 Physicians must
be held accountable if they prescribe unnecessary antibiotics, e.g. for simple bronchitis.
One policy option used in Taiwan is the withholding of payment to physicians who
prescribe antibiotics for viral illnesses. Additionally, the focus should extend to the
outpatient setting. In the U.S. the predominant focus has been on the inpatient setting.

Consumer, patient and family education campaigns using a full range of
communications media and with formation of public-private collaborations are
being deployed. The U.S. Centers for Disease Control and Prevention “Prevent
Antimicrobial Resistance” program is illustrative. An important element of the
program is the “Get Smart: Know When Antibiotics Work” campaign.76
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
Epidemiologic surveillance of resistance, antimicrobial usage, and disease burden
is a critical tool.77 These methods are applied at the local level where outbreaks
and clusters appear,78 and are implemented at national levels where patterns of
resistance can be revealed. Applied at the international level, they give vital
information on the spread of resistance between countries and continents.

Governmental regulation of access to antimicrobials; e.g., requiring a physician’s
prescription, is a proven tool. Countries with the fewest controls on the use of
antibiotics have the greatest frequency of resistant microbes.79

Scientifically-developed, peer-reviewed, and continuously updated guidelines and
algorithms designed for management of particular infections.80 These are
intended to streamline decision making processes and lead to the appropriate use
of antimicrobial drugs.

Application of new information technologies such as computer-assisted decision
support and critical pathways. These include the logic of guidelines but add the
power, memory, and speed of the computation devices and systems. Such
systems can provide pertinent information, cueing, feedback, and side effect
alerts.81

Formularies that control which drugs are available within an organization are
used both to influence antimicrobial drug utilization and to contain costs.82 This
method is also employed to modulate which antimicrobials are used. The
selection of available drugs should ideally respond to changes in local pathogens
and susceptibility patterns.

Antibiotic cycling, e.g., scheduled revolving rotation of comparable spectra drug
classes within a predetermined time schedule, is being evaluated.83 The theory on
which cycling is predicated is that a bacterial population causing an infection may
include strains resistant to more than one drug class. By frequently rotating drugs
it is hypothesized that resistance to any single agent and overall emergence of
resistance will be reduced or at least impeded. Controlled studies are needed to
confirm the benefits of cycling.

Limiting the antimicrobials used for veterinary, growth promotion, agricultural,
aquacultural, and industrial purposes. As discussed above, all these uses
contribute to the emergence of resistance.84

Reducing the transmission of infectious pathogens by the use of health care
provider and environmental infection control procedures and guidelines. These
measures stress both systemic improvements and increased personal
accountability.85
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
Legislative advocacy that promotes governmental policy, programs and
regulations intended to address and ameliorate the emergence of resistance. Such
legislation should consider strengthening the public health and sanitation
infrastructures consistant with the United Nations 1996 Istanbul Declaration on
Human Settlements (UN-Habitat). These may be at local, national, international
or global levels. An example in the United States is the national policy action
agenda adopted by the Infectious Diseases Society of America (ISDA).86 This
agenda focuses on policy actions to stimulate development and use of new antiinfective drugs.
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Appendix A:
World Medical Association Statement on Resistance to Antimicrobial Drugs
Adopted by the 48th General Assembly Somerset West, Republic of South Africa,
October 1996
Preamble
The global increase in resistance to antimicrobial drugs, including the emergence of
bacterial strains resistant to all available antibacterial agents, has created a public health
problem of potentially crisis proportions.
The development of resistant microorganisms is a problem whenever antimicrobial
agents are used. The increase in high risk populations who frequently require
antimicrobial therapy, including immunocompromised patients, those undergoing
invasive medical interventions, and patients with chronic debilitating diseases has
amplified the problem.
In addition, substantial misuse and overuse of antimicrobial agents has exacerbated the
problem by adding selection pressures to microbial populations that favor mutation to
antibiotic resistance. This includes inappropriate prescribing of antibacterial
prophylactics and/or treatment of bacterial infections by physicians, poor compliance
with antimicrobial regimens by patients, and the availability of antimicrobial agents
without a prescription in many developing countries.
Recommendations:
1. The World Medical Association and its member national medical associations
should encourage the World Health Organization (WHO) and individual
governments to cooperate with and enhance the effectiveness of the WHO's
global network of antimicrobial resistance surveillance.
2. National medical associations should encourage their governments to fund more
basic and applied research directed toward the development of innovative
antimicrobial agents and vaccines, and on the appropriate and safe use of such
therapeutic tools.
3. The pharmaceutical industry should be encouraged to pursue research and
development programs leading to the availability of innovative antimicrobial
agents and vaccines.
4. National medical associations should urge their governments to require
antimicrobial agents to be available only through prescription by licensed
qualified health care and veterinary professionals.
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5. National medical associations should encourage medical schools and continuing
medical education programs to educate physicians about appropriate use of
antimicrobial agents.
6. Physicians especially trained in infectious diseases and clinical microbiology,
should assume leadership roles in their local hospitals and communities regarding
appropriate antimicrobial agent usage and antimicrobial resistance prevention and
control programs.
7. Physicians should raise awareness amongst their patients of their antimicrobial
therapy, the risks and benefits, the importance of compliance with the prescribed
regimen, and the problem of antimicrobial resistance.
8. Governments, medical associations, and physicians should educate the public in
the appropriate use of antimicrobial agents and increase the awareness of the
problem of antimicrobial resistance.
9. National medical associations in collaboration with veterinary authorities should
encourage their governments to restrict the use of antimicrobial agents as feed
additives for animals strictly to those which are not used for humans.
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