The Resistance Phenomenon in Microbes and Infectious Disease Vectors: Implications for Human Health and Strategies for Containment: Workshop Summary (2003)

The emergence of resistance to therapeutics is not a new phenomenon among microbes—whether viral, bacterial, or protozoan. Following the introduction and subsequent widespread use of penicillin, the first major “miracle” antibiotic, in the early 1940s, microbiologists soon discovered that a number of bacterial strains had become resistant to this antibiotic. Over the years, successive introductions of new classes of antimicrobial¹ drugs have been followed, often quickly, by the emergence of resistant microbes. Nor is the emergence of microbial resistance to therapeutics surprising, as these pathogens follow the same general rules—including survival of the fittest—that guide evolution among all organisms. However, they are capable of evolving much more rapidly than higher, multicellular organisms, due to their simpler genomes, capacity for inter-species exchange of genetic elements encoding for resistance, and much shorter generation times.

What is perhaps most notable today is the increasing degree to which microbial resistance has become an important health threat—and the continuing failure of the nation, indeed the world, to mount an adequate response. Drug resistance is accumulating and accelerating, thereby reduc

ing in number and power the drugs available for combating infectious diseases. Resistance to available therapies is a major confounding factor in effective treatment of human pathogens that account for the majority of the global infectious disease burden—malaria, tuberculosis, and AIDS. Today, some pathogenic strains of bacteria that were previously readily amenable to antibiotic therapy have become resistant to all available antibiotics, while strains of many other serious pathogens are now resistant to all but one easily administered drug, placing them on the brink of being untreatable. Coupled with the unrelenting emergence of antimicrobial resistance among common pathogens, there is a growing sense that drug discovery efforts are yielding fewer and fewer truly new leads toward novel classes of antimicrobial agents. This raises the specter of a real shift in the balance of the battle being fought by health professionals against a wide array of infectious agents.

Concerns about microbial resistance are further compounded by the possibility, made vivid during autumn 2001, that terrorists or a rogue nation might use biological weapons to trigger large-scale disease outbreaks. The ability to respond effectively to such events could be significantly compromised by the purposeful introduction of genetically engineered drug-resistant pathogens. Furthermore, the use of prophylactic antimicrobials or biologics in large populations of humans and/or animals in response to such a threat also may hasten the development of drug resistance and thus compound the risks of both immediate and longer-term problems in treating infectious diseases.

The Forum on Emerging Infections convened a two-day workshop discussion—the subject of this summary—to take a fresh look at a variety of issues related to microbial resistance. The goal was not to lament continuing shortcomings, but to reconsider our understanding of the relationship between microbes, disease vectors, and the human host, and to identify possible new strategies for meeting the challenge of resistance. Central to the discussion was an exploration of the many similarities inherent in the emergence of resistance to antimicrobial drugs, and the development of resistance to pesticides among insect vectors of serious pathogens such as the malaria parasite.

Drug-resistant bacterial, viral, and protozoan pathogens pose a serious and growing menace to all people, regardless of age, gender, or socioeconomic background—a picture that holds true for developed and developing nations alike. Indeed, microbial resistance threatens to reverse many of the therapeutic miracles of the past half century. A rapidly expanding list of antimicrobial-resistant organisms is affecting us in a variety of ways.

The vast majority of infections that people acquire in hospitals, for example, are caused by bacterial agents, such as Staphylococcus aureus, that are resistant to penicillin. In many hospitals in the United States, nearly half of these penicillin-resistant staphylococci are also resistant to second-generation, penicillinase-resistant drugs, such as methicillin. Compounding matters, the antibiotic vancomycin, currently one of the few available treatments for methicillin-resistant staphyloccocal infections, is now showing increasing signs of losing ground as vancomycin resistance becomes ever more common among the most frequent infectious agents in hospitals (i.e., staphylococci, streptococci, pneumococci, enterococcus, and Clostridium difficile). Indeed, since this workshop, two different strains of S. aureus with full-fledged vancomycin resistance mediated by the vanA gene were isolated in the United States. Moreover, bacteria are now beginning to appear that are resistant to linezolid, introduced in 2000 for the treatment of vancomycin-resistant infections.

Drug-resistant microbes also are becoming more common in the community. At least five major bacterial pathogens,² including Streptococcus pneumoniae, which remains a major worldwide cause of pneumonia, meningitis, sepsis, and otitis media, and Mycobacterium tuberculosis, which causes tuberculosis, have developed resistance to a number of drugs. This problem is further compounded by the ability of microbes to share important resistance genes within and across bacterial species via a variety of genetic transfer mechanisms.

Infections caused by resistant microbes that fail to respond to treatment result in prolonged illness and greater risk of death. When infections become resistant to first-line antimicrobials, treatment must be switched to second-line or even third-line drugs, which are sometimes more toxic than the drugs they replace. Treatment failures also lead to longer periods of infection, and this factor increases the numbers of infected people moving from hospitals into the community. Moreover, even healthy patients colonized with drug-resistant, hospital-acquired bacterial flora may be discharged from hospitals. Both phenomena enhance the likelihood that resistant pathogens will spread into the community.

In addition to its direct threat to human health, microbial resistance exacts an economic cost that can trigger adverse health consequences. Treating individuals with alternative drugs is nearly always much more expensive than conventional treatment. In some settings, the drugs needed to treat multi-drug-resistant forms of tuberculosis, for example, are more than 100-fold more expensive than the standard drug regimen used to treat nonresistant forms of the bacteria. In many resource-poor countries, the

high cost of such replacement drugs is prohibitive, with the result that some diseases are no longer treated in areas where resistance to first-line drugs has become widespread.

The added costs of treating drug-resistant infections also place a burden on society. For example, the American Society for Microbiology estimated in 1995 that health care costs associated with treatment of resistant infections in the United States amounted to more than $4 billion annually— a figure then equivalent to approximately 0.5 percent of total U.S. health care costs. It is clear, however, that this figure significantly underestimates the actual cost of resistance, since it includes only direct health care costs and excludes an array of other costs, such as lost lives and lost workdays. Moreover, these costs are expected to increase considerably given increasing rates of microbial resistance. The bottom line: coping with microbial resistance diverts a significant amount of dollars from other areas of the health care enterprise.

Although the emergence of microbial resistance cannot be stopped— since nature provides pathogenic organisms with too many mechanisms for survival—the challenge is to transform this growing threat into a manageable problem. Over the past 10 years, a number of organizations, domestic and international, public and private, have provided recommendations and options for addressing microbial resistance. Some common recommendations have included improving surveillance for emerging resistance problems, prolonging the useful life of current antimicrobial drugs (through parsimonious use, attention to completion of prescribed courses of therapy, or use as part of combination therapies that may be less likely to permit development of resistance), developing new drugs, and using other important measures (such as improved vaccines, diagnostics, and infection-control methods) to prevent or limit the spread of microbial resistance.

Despite the urgency of the problem, however, converting these ideas into widespread practice has not been simple or straightforward, and accomplishments to date have been insufficient, according to a January 2001 report by a U.S. government multiagency task force. Yet, recent years have brought encouraging signs of progress made and progress possible. At perhaps the most fundamental level, there is greater recognition—within government, the health care and research communities, the pharmaceutical industry, and society at large—that antimicrobial resistance is a major problem, and that this problem can be solved only with wide-ranging and coordinated actions. Such recognition is increasingly international. For example, the World Health Organization (WHO) recently declared antimicrobial resistance to be one of the top issues in global health.

To manage microbial resistance over the long term, a sea change is needed in how we view the ecology and evolution of infection. The emergence of resistance must be recognized as an integral part—not an aberrant part—of the ecology of microbial life. Developing a fuller understanding of how microbes evolve when faced with drugs that threaten their survival may lead to innovative ways to bring them under control. While we once concentrated primarily on developing chemicals to use in an all-out war aimed at eradicating pathogens—a strategy almost guaranteed to promote microbial resistance—it may be possible now to devise treatment approaches that make an organism’s genetic bent work in our favor.

“Smarter” approaches to drug discovery might seek compounds to which changes in the structures of the microbial targets (proteins or nucleic acids) that are required for resistance to the drug also lead to a loss of function, or the development of combinations of drugs with mutually incompatible resistance mechanisms. Although arrived at serendipitously, the combination of AZT and lamivudine shows such activity when used for treatment of AIDS, while another nucleoside analog, adefovir, appears to be incapable of stimulating the emergence of resistance in its target virus, hepatitis B virus, most likely because mutations in the viral polymerase that would confer resistance render the enzyme inactive. Such examples suggest what might be possible with continuing advances in understanding the structure-activity relationships of new compounds. However, this is predicated on acquiring a more detailed understanding of the structure and function of the microbial targets of various therapeutic agents, and increasingly more sophisticated structure-aided (i.e., “rational”) approaches to drug design.

Workshop speakers presented updates on the genetics and ecology of several important pathogens. Among the microbes and infectious diseases discussed:

The bacterial strains staphylococci, enterococci, and pneumococci are ancient evolutionary companions of humans. In modern times, they have taken on major roles in microbial resistance. The various types of staphylococci, taken together, are among the most frequent causes of nosocomial, or hospital-acquired, infection, while enterococci are ranked second. S. pneumoniae is one of the most frequent causes of community-acquired infection.

Recently, scientists have acquired detailed information concerning how these various bacteria develop drug resistance. In staphylococci, one key change is that the mechanism of resistance is no longer considered to be the

product of a single resistance gene. Rather, there is an entire stress-response pathway involving a central resistance gene and a number of auxiliary genes, all of which are essential for the bacteria to optimize resistance. Halting the function of any of these genes will reduce the microbe’s propensity to develop drug resistance. Thus, there may be more targets than previously suspected for developing drugs to fight this microbe.

Malaria remains one of the leading killers in the developing world. The traditional first-line drug for treating the disease was chloroquine. Its widespread use, however, has led to increasing microbial resistance. For years, scientists struggled to understand how malaria parasites develop resistance. They have now identified a single gene as the culprit and pinpointed a particular type of mutation at a specific location in the gene as being critical in the development of resistance. Researchers are now using this knowledge to explore new drugs that precisely target the resistance mechanism.

Schistosomiasis, a debilitating disease caused by a parasitic worm that is transmitted to humans from snails, remains a public health problem in many regions, including Africa, the Middle East, Asia, and South America. For many of the species that infect humans, there is only one effective drug available: praziquantel. However, this drug has been in use for more than 20 years, and concern is increasing that resistance has emerged, or will soon emerge, in the parasite. This means planning must now focus on extending the drug’s useful life and on developing new drugs before resistance emerges fully.

Workshop participants outlined a number of specific issues and priorities that will aid in better understanding microbial resistance and mitigating its impact on human health:

• Recognize that microbial infection, evolution, and resistance is an integral part of the ecology of life, and develop a fuller understanding of how microbes evolve when faced with drugs that threaten their survival.

• Develop therapeutic agents that are “engineered” to make evolution work in favor of humans, rather than in favor of microbes.

• Pursue drug-development strategies that will lead to therapeutics that are less likely to provoke additional waves of resistance. One strategy would be to develop narrow-spectrum drugs that will not challenge the entire microbial world each time they are used in therapy.

• Develop therapeutic interventions that target the “ecological reservoirs” of bacterial pathogens, particularly drug-resistant strains.

• Use drugs prudently in all patient care settings and in national and international disease-control programs, especially when a drug has not yet triggered widespread microbial resistance. Model programs for surveillance of antimicrobial resistance on a global scale also will be important to monitor and anticipate the emergence of resistance and begin developing alternative drugs and treatment programs.

Beyond the development of resistance in pathogenic microbes, the ever-increasing resistance of disease vectors (the insects and arachnida that pass pathogens to humans) to chemical and biological pesticides looms as another complicating factor in efforts to control the emergence of infectious diseases. Resistance to insecticides has appeared in every major species of vector—including mosquitoes, ticks, fleas, lice, and sand flies—and various vectors have developed resistance to every class of pesticide. Where resistance has not contributed to disease emergence, it is expected to threaten disease control. A prime example was the emergence of DDT resistance in the mosquito species that serves as a vector for the transmission of malaria among humans. Widespread emergence of DDT resistance contributed heavily to derailing WHO’s global efforts to eradicate the disease, setting back malaria control by decades. Malaria control programs that already face complex challenges presented by multi-drug-resistant strains of the parasite are additionally undermined by mosquito populations that show increasing resistance to the pyrethroid-treated bed nets commonly used to reduce malaria transmission.

Workshop participants agreed that scientists studying microbial resistance can learn much from the work of those studying these aspects of vector control, including how to prevent vectors from developing resistance to pesticides. Likewise, policy makers developing programs to control the spread of microbial resistance can benefit by examining the successes and failures of current pest-control programs. The underlying principles, pitfalls in control strategies, and possible approaches to solutions to resistance are not necessarily all that different.

One promising strategy discussed is to develop an integrated approach to control efforts. In the field of vector control, such coordinated efforts are called integrated pest management, or IPM. Although a number of factors, including cost, have prevented IPM from being adopted on a widespread basis, its potential remains clear. Tackling a pest problem in numerous ways at once—including the use of pesticides in a timely manner at select locations—will likely yield more thorough and longer-lasting control than would result from any single method applied individually.

Speakers also cited the value of developing and applying mathematical models to help understand complex aspects of resistance, including efforts to control the emergence of resistance, in both pests and pathogens. One advantage of modeling is that it enables researchers to conduct experiments that would be impossible, too expensive, or unethical to conduct otherwise. Models can serve a variety of purposes, including examining trends in data, exploring questions of population dynamics, developing and testing different management options, and generating new hypotheses for study.

Although scientists studying microbial resistance are increasingly us

ing mathematical models, there currently is little interdisciplinary work involving scientists studying insecticide resistance. One primary reason for this gap is that bacterial population genetics differ substantially from the population genetics of most pest organisms. Still, there is much to be gained by cross-fertilization between the disciplines. It is important that modelers in both arenas become familiar with the results and efforts of the other. Such cooperation will help form a more complete understanding of the resistance phenomenon.

Workshop participants described a range of actions that can help improve vector-control efforts and minimize the spread of microbial resistance:

• Expand surveillance programs to monitor the susceptibility of vector populations to pesticide resistance. Once data have been gathered, it is crucial that the results be interpreted practically, in terms of control efficiency, so that effective strategies for remediation can be undertaken.

• Promote the use of integrated pest management programs, which in most cases are more effective than “single shot” programs in controlling pest populations and minimizing their resistance to chemical control agents.

• Foster multidisciplinary research efforts involving scientists studying microbial resistance and those studying various aspects of vector control, including how to prevent vectors from developing resistance to pesticides.

• Expand and apply knowledge of the basic molecular mechanisms underlying resistance to insecticides in order to develop novel control strategies that can truly manage resistance.

• Develop and apply mathematical models to help understand complex aspects of resistance, including efforts to control the emergence of resistance, in both pests and pathogens. Researchers studying microbial resistance and those studying insecticide resistance can benefit by working together.

• Examine the successes and failures of current pest-control programs when developing public policies aimed at controlling the spread of microbial resistance.

To best meet the problem of microbial resistance, it is necessary to understand not only the scientific basis of how organisms become resistant but also the social and administrative practices that contribute to the emergence of resistance. A variety of factors have been identified, and important

advances continue to be made in understanding their roles and how they might be mitigated.

Among the leading forces at work in the United States and other developed countries is the over-prescription of antimicrobials, particularly antibiotics, by physicians. Such overuse is fueled, in part, by patient expectations and demands. Growing patient awareness of antimicrobial agents (sometimes generated by direct-to-consumer marketing and not necessarily accompanied by understanding) sets up an expectation among patients that they should receive such drugs, even in the absence of appropriate indications. A variety of factors—including diagnostic uncertainty, lack of opportunity for patient follow-up, pressure to minimize length of office visits that precludes proper patient education, and lack of knowledge regarding optimal therapies—may influence a physician’s response to patient demands. Meanwhile, in many developing countries, antimicrobial agents are readily available and can be purchased as a commodity without the advice or prescription of a physician or other trained health care provider. In such settings, drugs are often of questionable quality, with less than full potency, thereby possibly promoting the emergence of resistant pathogenic organisms—whether simply colonizers or in fact those involved in producing disease—in people taking them.

Hospitals also are fertile breeding grounds for microbial resistance. The combination of highly susceptible immunosuppressed patients (e.g., AIDS patients, cancer patients, or transplant recipients) who lack the basic immune mechanisms so essential to elimination of pathogens, intensive and prolonged antimicrobial use, close proximity among patients, and multiple invasive procedures have resulted in hospital-acquired infections that are highly resistant to available therapeutics. Large hospitals and teaching hospitals generally experience more problems with drug-resistant microbes, probably because they treat greater numbers of the sickest patients and those at highest risk of becoming infected. The failure of health care workers to practice simple control measures that have been known for decades (e.g., hand washing) frequently contributes to the spread of infection in hospitals.

Some common types of human behavior increasingly play a role in promoting resistance. Such behaviors as failure to complete recommended treatment or self-medication are among the most frequent factors associated with the development of resistance. Noncompliance occurs when individuals forget to take medication, prematurely discontinue the medication as they begin to feel better, or realize that they are unable to afford a full course of therapy. Self-medication with antimicrobials almost always involves unnecessary, inadequate, and ill-timed dosing—creating an ideal environment for microbes to adapt rather than be eliminated. As mentioned

above, in many countries, antimicrobials are also readily available to consumers without a medical prescription. Moreover, in some countries, problems of noncompliance and self-medication are magnified because significant amounts of the available antimicrobials (particularly antibiotics) are poorly manufactured, counterfeit, or have exceeded their effective lifetimes and are thus less than fully effective.

Another important contributing factor is the overuse of antimicrobial agents in animals raised commercially for food, such as poultry, pigs, and cows. According to one estimate, approximately 40 percent of the 50 million pounds of antibiotics produced in the United States in 1998 was given to animals, either for therapeutic use or to promote growth. Overuse of these agents can lead to the development of drug-resistant microbes (largely bacteria, such as salmonella and campylobacter) that subsequently are transmitted to humans, usually through food products. Concern also is growing about the role played by the accumulation of low levels of antimicrobials derived from consuming animal products in the emergence of resistant pathogens among humans.

Workshop participants cited a number of specific initiatives that could help to control the emergence of resistance:

• Expand efforts to prevent hospital-acquired infections. Important activities include surveillance, outbreak investigation and control, sterilization and disinfection of equipment, and proper confinement of patients infected with resistant microbes.

• Enforce infection control measures among health care workers in acute and long-term care facilities, and other environments such as child care facilities.

• Improve physicians’ prescribing practices through such means as education, formulary restrictions, multidisciplinary drug utilization evaluation, and computerized decision support systems. In all cases, the commitment and participation of the prescribing clinician and the health care institution are essential. Hospitals and clinics may derive direct financial benefits from such improved prescription practices.

• Ensure that patients comply with recommended drug therapies. This is one of the most important lessons that evolutionary biology can contribute to health management—that when it comes to the evolution of resistant diseases, half measures can increase problems of resistance.

• Expand research efforts to determine the effectiveness of short-course antimicrobial therapy for acute and self-limiting infections.

• Tailor education and intervention programs to specific communities and countries, especially in the developing world, since cultural factors will greatly determine their success.

• Conduct research to better understand the social and behavioral determinants that influence the emergence of resistant pathogens.

• Prevent misuse and overuse of antimicrobial agents in agriculture. This should include identifying critical control points along the continuum of food production. For example, management changes carried out at the farm level will not prevent the transfer of pathogenic organisms if there is significant contamination post-harvest or in the processing of food.

• Expand public education efforts to explain why treatment with antibiotics is not always the best medicine. In addition, numerous household products now contain antimicrobial agents that can encourage the selection of resistant organisms; education efforts are needed to explain that the same level of protection can be obtained with standard soap and household disinfectants.

The issue of how to counter microbial resistance continues to grow more complex. The traditional means to overcoming resistance problems has been to extend the useful life of current classes of antimicrobial drugs, often by developing slightly different chemical derivatives, or to develop wholly new classes of drugs that are not yet subject to resistance. However, the first route often provides marginal gains at best. And while completely novel classes of antimicrobials were discovered and subsequently introduced rapidly into clinical practice during the 1940s and 1950s, only a single new chemical class of antibiotics has emerged during the past several decades. Looking forward, many at the workshop viewed the antimicrobial pipeline as dismally empty.

Workshop participants described a variety of efforts to gain better understanding of the genetics and biochemistry of pathogens and the molecular mechanisms by which they develop resistance to antimicrobials. The genomics revolution, in particular, may be opening promising new avenues for exploration, but the pharmaceutical pipeline has yet to be populated with new classes of compounds under development. The promise seems present, but it has yet to be realized.

One class of antibiotics that has received considerable attention is the ß-lactams. These drugs, which include penicillin, methicillin, oxacillin, and the newer cephalosporins comprise particularly important classes of antibacterials. Scientists have now demonstrated that nature has devised at least four strategies by which bacteria can develop resistance to ß-lactam antibiotics. Of these, the most prevalent is the occurrence of certain enzymes, called ß-lactamases, that break apart critical components of the

drugs. Moreover, four distinct and independent mechanisms have evolved for the catalytic functions of these enzymes. Individually, the enzymes have undergone additional diversification. These observations provide strong evidence that random mutation and selection lead along different evolutionary tangents depending on the environment a pathogen finds itself in, the genetic composition of the organism, and the resources available to it.

Other research groups are taking a radically different approach to drug design. Nearly all bacteria enter humans at a mucous membrane site, such as the upper and lower respiratory tract or the intestines. These membranes thus act as reservoirs for many pathogenic bacteria. To date, however, there are essentially no drugs that can control pathogens on mucous membranes. Because of the fear of developing resistance, antibiotics are not indicated for control of the “carrier state” of pathogenic bacteria in most instances. This means physicians must wait for infection to occur before treating the patient. Yet, it is clear that by reducing or eliminating such human reservoirs of infection, the incidence of disease in the community will in turn be markedly reduced. Some scientists are now exploring the potential use of enzymes derived from viruses that infect bacteria (Yes, even bacteria are subject to infections themselves!) that may have the capacity to treat or prevent certain bacterial infections by safely and specifically destroying the pathogenic microbes on mucous membranes, in spinal fluid, or possibly in other closed compartments. For example, lytic enzymes derived from bacteriophage that are specific for S. pneumoniae and S. aureus could be administered nasally to control these organisms in people who spend time within institutions where such infections are rampant, such as day care centers, hospitals, and nursing homes.

However, getting promising candidate drugs to market is a long and expensive venture. As part of the current regulatory approval process, drug developers must evaluate whether their candidate achieves a clinical cure; that is, whether a person receiving the agent becomes free of symptoms. But this marker of success may not correlate with the extent to which the drug killed and eliminated the pathogen. If the pathogen persists, despite improvements in the signs and symptoms of infection, then conditions are ripe for the emergence of resistance.

This conundrum may be addressed by critically examining the pharmacokinetics and pharmacodynamics of new drugs using a technical approach known as PK/PD. PK/PD is built on taking regular cultures from a person receiving a therapeutic agent, and determining at which point pathogenic microbes are no longer present. In this way, the technology offers a direct measure of the agent’s ability not only to cure the patient but also to eliminate the pathogen. PK/PD will not replace current evaluations of drug efficacy. But conducting a complementary PK/PD analysis, which can be done with a relatively small number of patients studied intensively but at a

modest cost, can provide data that may indicate how likely a drug candidate is to stimulate the emergence of microbial resistance.

Workshop participants highlighted a range of actions that will help in developing new tools and technologies for countering resistance. These included:

• Expand research to prolong the useful life of current antimicrobial drugs and to develop new drugs, especially those with minimal potential for triggering antimicrobial resistance.

• Identify and eliminate any economic or regulatory “disincentives” that act to discourage pharmaceutical companies from undertaking research in this area. In some cases, creating positive economic incentives to encourage such research may be warranted.

• Ensure that the regulatory process provides a clear and feasible path for gaining approval of new therapeutic agents. This effort should include identifying and adopting ways to keep the cost of clinical trials required by regulation as low as safety allows.

• Develop ways to assess the potential emergence of microbial resistance as a part of traditional clinical trials. One promising approach may be to examine the pharmacokinetics and pharmacodynamics of new drugs as a complementary aspect of drug trials.

• Expand the development of a variety of non-drug-related measures (such as improved vaccines, diagnostics, and infection-control methods) to prevent or limit the spread of microbial resistance.

• Conduct research to better understand the interactions among pathogens, medical devices, and human hosts, and to develop rapid, reliable diagnostic techniques to identify the presence of infection, the specific infecting organism, and its antimicrobial susceptibilities.

• Explore alternative approaches to the application of therapeutics, such as alternating drug regimens. Both in medicine and agriculture, cyclic use of chemical control agents can often retard the evolution of resistance.

Given the complexity of microbes—and their evolutionary drive to survive—it follows that managing the varied problems associated with microbial resistance will require a richly interwoven response. Workshop participants stressed that this response will require participation by individuals, organizations, and governments at the local, state, national, and international levels.

The primary blueprint for federal actions in the United States is the Public Health Action Plan to Combat Antimicrobial Resistance, issued in

2001 by a multiagency task force led by the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the National Institutes of Health. The task force developed a plan with input from state and local health agencies, universities, professional societies, pharmaceutical companies, health care delivery organizations, agricultural producers, consumer groups, and other members of the public. This plan will be implemented incrementally, in collaboration with these and other partners, as resources become available. The task force is now developing a second part of the plan, which will identify actions that more specifically address international issues.

The domestic action plan has four focus areas: surveillance, prevention and control, research, and product development. Among proposed efforts to improve surveillance, the plan calls for developing and implementing a coordinated national plan for monitoring antimicrobial resistance; ensuring the availability of reliable drug susceptibility data; tracking patterns of antimicrobial drug use; and monitoring antimicrobial resistance in agricultural settings. Efforts to improve prevention and control include extending the useful life of antimicrobial drugs through policies that discourage overuse and misuse; improving diagnostic testing practices; and preventing infection transmission through improved infection-control methods and use of vaccines. Expanded research also will be critical, as basic and clinical research provide the fundamental knowledge necessary to develop appropriate responses to antimicrobial resistance emerging in hospitals, communities, farms, and the food supply.

The plan calls for increasing understanding of microbial physiology, ecology, genetics, and mechanisms of resistance; augmenting the existing research infrastructure to support a critical mass of researchers in antimicrobial resistance and related fields; and translating research into clinically useful products, such as novel approaches to detecting, preventing, and treating antimicrobial-resistant infections. Strategies include fostering product development to ensure that researchers and drug manufacturers are focused on current and projected gaps in the arsenal of antimicrobial drugs, vaccines, and diagnostics and of potential markets for these products; stimulating the development and appropriate use of products for which customary market incentives are inadequate; and optimizing the development and use of veterinary and related agricultural products that reduce the transfer of resistance to pathogens that can infect humans.

Various federal agencies already are implementing parts of the action plan. The FDA, as part of its mandated regulatory responsibility, has played and continues to play an important role in ensuring that drugs and other chemical agents used in humans and in animals being raised for human consumption do not pose unacceptable health risks, including risks that may arise as a result of antimicrobial resistance. For example, the agency

has developed a Framework Document that proposes a modified approval process for antimicrobials used in animals. The process is intended to ensure the human safety of such antimicrobials by prioritizing them according to their importance in medicine and establishing required mitigation actions with increasing resistance.

The FDA also uses a variety of other approaches to address the issue of antimicrobial resistance. For example, its Center for Drug Evaluation and Research searches for ways to enhance the available approaches to the development of new antibiotics. Among other efforts, the FDA is fostering early communication with pharmaceutical companies, using the product-labeling system to help educate physicians and other health care workers about antimicrobial resistance, and exploring methods for using data collected in clinical trials to make reliable inferences about a drug’s potential to trigger antimicrobial resistance.

The CDC is active in promoting and implementing surveillance efforts, prevention and control activities, and applied research, including prevention research. One prevention and control effort, for example, focuses on health care settings, where infection with resistant organisms—many of them resistant to multiple drugs—has become a major patient safety concern. The agency has initiated the Campaign to Prevent Antimicrobial Resistance in Health Care Settings, a nationwide effort that targets front-line clinicians, patient care partners, health care organizations, purchasers, and patients. Its general goals include informing clinicians, patients, and other stakeholders about the escalating problem of antimicrobial resistance in health care settings; motivating interest in and acceptance of interventional programs to prevent resistance; and providing clinicians with tools to support needed practice changes.

The campaign centers around four basic strategies that clinicians can use to prevent antimicrobial resistance. These strategies include preventing infections so as to directly reduce the need for antimicrobial exposure and the emergence and selection of resistant strains; diagnosing and treating infections properly, which will benefit patients and decrease the opportunity for development and selection of resistant microbes; using antimicrobials wisely, since optimal use will ensure proper patient care while avoiding overuse of broad-spectrum antimicrobials and unnecessary treatment; and preventing transmission of resistant organisms from one person to another by emphasizing the importance of infection control. The CDC is now developing similar programs that target other groups of high-risk patients, including hospitalized children, geriatric, obstetrical, critical-care, and surgical patients as well as nursing home residents and those on dialysis.

International organizations also are stepping up efforts to contain antimicrobial resistance. Of particular note, the WHO in 2001 issued the WHO Global Strategy for Containment of Antimicrobial Resistance. Its portfolio

of actions are intended for use by national governments and health systems, patients and communities, prescribers and dispensers, hospitals, pharmaceutical companies and marketers, growers of food-producing animals, and international organizations and partnerships concerned with containing antimicrobial resistance. The plan details a comprehensive framework of interventions designed to reduce the disease burden and the spread of infection, improve access to and improve use of appropriate antimicrobial agents, strengthen health systems and their surveillance capabilities, introduce and enforce regulations and legislation, and encourage the development of new drugs and vaccines.

Much of the responsibility for implementing WHO’s strategy will fall on individual countries, and some of them—especially in the developing world—will need assistance. One such effort is being conducted by the Rational Pharmaceutical Management Plus Program, directed by a nongovernmental organization supported by the U.S. Agency for International Development. In conjunction with several partners, the program is developing a systematic approach to designing national-level efforts to contain antimicrobial resistance. This approach will provide a framework by which various stakeholders, working with technical consultants when necessary, can assess policies, drug use, and levels of resistance in their countries, and then tailor a range of strategies for advocacy, policy development, and systems change. Although this approach is generic, its implementation likely will be country-specific and unfold in distinct ways, according to circumstances in each country. Whatever its specific character, it is anticipated that the systematic approach will result in an increased level of awareness about this issue, heightened activity among local health organizations, and the introduction of stronger policies to monitor and contain the spread of antimicrobial resistance.

In light of the increasing magnitude of the problem, many workshop participants noted the need for implementing a vigorous, comprehensive attack on antimicrobial resistance. Too many studies have highlighted the problem—with their conclusions and recommendations remaining largely unfulfilled. Participants also suggested a number of specific issues and priorities that will help in containing the development and consequences of antimicrobial resistance:

• Complete implementation of the Public Health Action Plan to Combat Antimicrobial Resistance. This will require providing adequate funding across a range of public agencies and private organizations.

• Continue implementation of the WHO Global Strategy for Con tainment of Antimicrobial Resistance. Special priority should be given to the development of national legislation that eliminates the distribution of antibiotics without prescription from a trained health care provider; educa

tion directed at distributors and consumers as well as prescribers of antibiotics; infection control to prevent the dissemination of resistant strains; quality assurance of antibiotics and other medicines; and the establishment of functional and sustainable laboratories for antibiotic resistance surveillance.

• Implement and expand surveillance efforts, at all levels, to ensure early detection of antimicrobial resistance problems. In the United States, disease reporting is mandated by state laws, but most states do not require reporting of drug susceptibility information, and the completeness of reporting varies. Some current surveillance systems need enhancement using updated laboratory and informatics technologies.

• Expand professional education and training, such as through expanded use of the CDC’s “12 Steps to Prevent Antimicrobial Resistance” programs aimed primarily at front-line clinicians dealing with high-risk patients. Professional societies also can take a more active role in promoting education for their members.

• Conduct economic studies of antimicrobial resistance to complement scientific and epidemiological studies. Such studies can both inform the policy making process and suggest ways to provide incentives to individuals and institutions, such as hospitals, to adopt practices that will help limit the spread of antimicrobial resistance.

Stanley M. Lemon, M.D.

Dean of Medicine

The University of Texas

Medical Branch at Galveston