Workshop Report

INTRODUCTION

The Topic

In the first meetings, Forum members concurred that antimicrobial resistance should be awarded high priority as a matter for concern—not, however. because the issue is a new one: penicillin-resistant strains of Staphylococcus aureus were isolated as early as 1945. By 1959, there was already enough evidence of resistance to stimulate a review article in the Journal of the American Medical Association.2 The sense of urgency among Forum members was provoked by the acceleration and accumulation of a number of variables, expressed as documented increases in:

  • the number of pathogens displaying resistance and, within these, a mounting number of multidrug-resistant strains;

  • the number of compromised hosts;

  • mortality attributable to antimicrobial resistance;

  • the speed with which resistant microbes can spread globally; and

  • the costs of health care deriving from resistant microbes.

These increases were, in turn, accompanied by decreases or limitations in:

  • the power of the antimicrobial armamentarium to deal with many resistant pathogens,

  • the amount of research and development dedicated to antimicrobials during a period when resistance was not generally seen as a major threat, and

  • funding for public health infrastructure.



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Workshop Report INTRODUCTION The Topic In the first meetings, Forum members concurred that antimicrobial resistance should be awarded high priority as a matter for concern—not, however. because the issue is a new one: penicillin-resistant strains of Staphylococcus aureus were isolated as early as 1945. By 1959, there was already enough evidence of resistance to stimulate a review article in the Journal of the American Medical Association.2 The sense of urgency among Forum members was provoked by the acceleration and accumulation of a number of variables, expressed as documented increases in: the number of pathogens displaying resistance and, within these, a mounting number of multidrug-resistant strains; the number of compromised hosts; mortality attributable to antimicrobial resistance; the speed with which resistant microbes can spread globally; and the costs of health care deriving from resistant microbes. These increases were, in turn, accompanied by decreases or limitations in: the power of the antimicrobial armamentarium to deal with many resistant pathogens, the amount of research and development dedicated to antimicrobials during a period when resistance was not generally seen as a major threat, and funding for public health infrastructure.

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The Workshop The workshop agenda consisted of three major components: (1) resistance as a phenomenon and the major factors contributing to its increasing prevalence; (2) surveillance activities and needs; and (3) options for response. Its primary objectives were to extract those aspects of resistance that seemed most pressing, to inspect the potential of new scientific advances to spur needed diagnostic and therapeutic advances, and to examine areas of intervention most likely to return the biggest payback to investments of funding, research, advocacy, and education. A compendium of currently active systems that include surveillance of antimicrobial resistance is provided in Appendix A. Appendix B presents the outline of the global and national resistance surveillance system proposed in 1995 by the American Society for Microbiology (ASM) Task Force. Appendix C is a glossary. Appendix D contains the workshop agenda and participants list. THE COSTS OF ANTIMICROBIAL RESISTANCE* Background Before proceeding to discuss the major categories of concern relative to antimicrobial resistance—that is, issues of surveillance, the potential offerings of new scientific developments, and the range of possible responses to the problem—workshop participants considered the costs of resistance. These costs can include such factors as the direct cost of time in a hospital, extra physicians' visits when antibiotics are ineffective, extra hospital days and hospitalizations due to community-acquired resistant infections, the costs of newer antibiotics to replace antibiotics to which bacteria have become resistant, and lost workdays and deaths. The one study to date that has taken all of these factors into account used mathematical models to estimate the costs of resistance, including the effect of a resistant infectious agent that appears in one year on the cost to society in later years.3 Depending on whether or not death was a consequence, this study determined that in then-current dollars, the total societal costs of antibiotic resistance ranged from $150 million (without deaths) to $3 billion (with deaths) annually in the United States. In 1990, the National Foundation for Infectious Disease estimated that the costs only of nosocomial (hospital-acquired) infections caused by antibiotic-resistant bacteria could be as high as $4 billion annually. The Centers for Disease Control and Prevention (CDC) estimated these costs at $4.5 billion when costs from both antibiotic-resistant and susceptible infections were included. In 1992, *   Presented by Robert Rubin.

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the 19,000 deaths directly caused by nosocomial infections made them the eleventh leading cause of death in the U.S. population.4 In 1995, an analysis by the Office of Technology Assessment (OTA) of the United States Congress concluded that antibiotic-resistant bacteria generated costs of a minimum of $1.3 billion (1992 dollars) yearly in the United States. OTA emphasized that the estimate was a minimum, since it considered only in-hospital costs and the resistance of only six species of bacteria to just one antibiotic, and excluded the costs of multidrug resistance and all other costs.5 Recent Case Material Because, as the OTA report also indicated, the passage of time, inflation, and an increase in the number of antibiotic-resistant infections would make any estimate of the costs of resistance significantly higher, there is interest in more current calculations. Workshop participants heard a recent analysis of the costs of one multiple drug-resistant pathogen in one major metropolitan area, which indicates that the costs of resistance to the U.S. economy now may be well above the 1989 estimates. In New York City in 1995, methicillin-resistant Staphylococcus aureus (MRSA) infections cost almost a half-billion dollars and claimed 1,409 lives. Institutional infections represented 57 percent of those costs, as shown in Table 1; nosocomial infections accounted for 46 percent, of these institutional infections, 42 percent of total direct medical costs in dollars, and 62 percent of total mortality. Long-term care facility infections accounted for 11, 12, and 15 percent, respectively. Table 1 Costs and Attribution of Staphylococcus aureus Infections, New York City, 1995   Total Direct Medical Costs Type of Infection Percent of Total Incidence No. of Infections Million Dollars Institutional infections       Hospital-acquired (nosocomial) 46.0 6,300 180.8 (42%) Long-term-care facility 11.0 1,500 51.7 (12%) Community-acquired infections 43.0 5,750 203.0 (46%) SOURCE: Robert Rubin, The Lewin Group, July 30, 1997. Among hospital discharges in 1995, 13,550 had S. aureus infections. The cost to treat hospitalized patients with these infections was $435.5 million; the average cost per case was $32,110, almost double the average hospital charge for all New York City Primary Metropolitan Statistical Area (PMSA) discharges. Of the nosocomial infections, pneumonia, surgical site infections, and catheter-

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associated bacteremia were the most expensive. Mortality averaged 10 percent compared to an in-hospital AIDS mortality rate of 14.1 percent. The average value of life lost was estimated at $105,000. The limit of clinical ability to deal with S. aureus infections is best expressed in the percentages of these infections that were methicillin-resistant. Methicillin-resistant infections represented 20 percent of the incidence of all S. aureus infections, accounted for 21 percent of the costs of these infections, and were responsible for 41 percent of the mortality attributed to S. aureus infection. When the denominator is limited to nosocomial infections, these proportions rise to 29 percent of incidence, 32 percent of medical costs, and 48 percent of mortality. Not surprisingly, methicillin-resistant infections have higher per-case costs and attributable mortality than methicillin-susceptible S. aureus infections: $31,400 versus $27,700 per case, and 17 percent versus 8 percent, respectively. More effective institutional infection control programs could decrease costs and mortality by reducing the incidence of S. aureus infections, especially if methicillin-resistant S. aureus were to be targeted. There would be other, very large benefits as well. Dealing with methicillin-resistance typically entails greater use of vancomycin, which in turn increases the prevalence of vancomycin-resistant enterococci (VRE) and, perhaps not too far in the future, vancomycin-resistant S. aureus (VRSA). Strains of S. aureus with diminished susceptibility to vancomycin have already been reported in Japan. These costs and the dynamics of antibiotic resistance suggest that the time has come for another comprehensive analysis, ideally including attention to the costs of resistance worldwide. TRACKING THE PROBLEM: CURRENT APPROACHES TO SURVEILLANCE* The purpose of surveillance is to ask and answer questions that will provide information for action. Its effectiveness is in large measure a function of who is posing the question and for what purpose. The surveillance of antimicrobial resistance has as its goal the gathering of information for several purposes at every level where health care is provided. Each level has different needs, and all are critical: to help individual health care providers make rational clinical decisions; to inform health facility managers about which antibiotics to include in their formularies for cost containment and, more importantly, for optimal patient care; *   This section, which deals with the surveillance of antimicrobial resistance, includes a series of presentations by David Bell, Renu Gupta, David L. Heymann, Karl Kristinsson, Donald Low, Laurence McCarthy, Michael T. Osterholm, Fred Tenover, and Rosamund Williams. The general topic of surveillance was discussed by all of these presenters.

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to assess the public health burden imposed by a resistant pathogen, and its importance relative to other resistant infections, for the national and regional policymakers who must decide budget allocations and program priorities accordingly; to guide industry in new drug discovery, development, and marketing, and to provide the basis for drug licenser; and to target and effectively implement prevention and control measures, and to design advocacy and public education accurately and productively. These objectives dictate that much more needs to be known than simply which pathogens are becoming resistant to which drugs. For example, which patients have resistant infections? Are they randomly distributed across an entire population, or do they fall into certain risk groups, for instance, hospital patients, travelers returning from abroad, or individuals with high rates of past or current antibiotic use? Is the problem confined to a single group, or is it spreading into other groups and the population at large? Are there patterns to changes in the distribution of resistance, and how are these patterns instructive? What can be determined about trends in risk factors (e.g., drug use), and how do these differ by pathogen and location? As a general matter, response to these questions requires close monitoring of treatment and illness outcomes. The inevitable variability in these responses further requires that data be gathered locally, not only for local use but for systematic aggregation to determine larger dynamics. Historically, a number of problems have restricted efforts to monitor antimicrobial resistance. Since surveillance studies typically require the acquisition, shipment, and centralized testing of microorganisms, they are costly. Compromises are therefore made as to the number and types of institutions surveyed, demographics, the number and type of organisms studied, the geographic areas studied, and the frequency of assessments. There are other problems: the absence of standardized data to enable easy and rapid comparison of results; methodological differences between studies; delayed publishing and restricted availability of results owing either to proprietary sponsorship or to lack of interest among editorial boards; and poorly standardized methods for susceptibility testing and molecular epidemiology among nations. Characteristics of an Ideal Resistance Surveillance System The ideal system for surveillance of antimicrobial resistance would be prospective, active, timely, and affordable; be structured to permit the broadest possible access; provide accurate incidence and prevalence rates, which would in turn require both numerator and denominator information (e.g., the number of isolates

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tested and the number of resistant isolates), as well as a mechanism to permit exclusion of repeat isolates from the data pool; include information that identifies organisms causing infection and those involved in colonization (i.e., the ability of a bacterium to remain at a particular site and multiply there); gather data so as to permit categorization by region and locality, as well to discriminate between hospital or community and urban or rural sources; gather information on antimicrobial use and treatment outcomes, especially treatment failure (the outcome of resistance); be able to detect new resistance markers and therefore be dependent on standardized and reliable laboratory techniques, uniform criteria for determining resistance, appropriate specimens for culture, and adequate microbiologic validation; be a national network representing all regions and levels of care, thus including both hospital and outpatient facilities; computerize all participating laboratories, regularly collect electronic data, process and report in ongoing fashion, and integrate all databases at the national level; and make surveillance data available to practitioners at the appropriate regional and local levels so that problems at these levels could be managed appropriately. Local-Level Surveillance* It is critical here to underscore the importance of data from the local level, not only as the foundation of national and international comprehension of antimicrobial resistance, how it develops, and what it means, but as the basis for local ability to deal with disease emergence. Case material from Minnesota on Campylobacter (this state's most frequently isolated bacterial enteric pathogen) illustrates the importance of understanding "microtrends" within larger patterns. In 1992, the proportion of all Campylobacter isolates in Minnesota that were resistant to fluoroquinolones was 1.5 percent; by 1996, it was 6.4 percent. The point here is that this upward trend is actually a composite of two effects that have to be understood as independent phenomena, of comparable importance but with distinct dynamics. The first is an "indigenous" increase in the incidence of resistance—that is, an increase within the state—that is highest in summer months; the question of a possible relationship among the increase in the endemic rate of fluoroquinolone-resistant strains of Campylobacter, Food and Drug Administration (FDA) approval of fluoroquinolones for therapeutic use in poultry, and off-label use of fluoroquinolones remains unexamined. The second phenomenon is the increase in the first quarter of the year that comes from more *   Material on local-level surveillance was presented by Michael T. Osterholm.

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individuals' traveling outside the country, primarily to Latin America, who may acquire foodborne diseases due to widespread fluoroquinolone use in poultry in Latin America and then return with Campylobacter-resistant organisms—an ''exogenous" increase. Therapeutic use of fluoroquinolones in poultry has been prevalent in Latin America since the late 1980s; however, the FDA did not approve such use until 1994. Exogenous disease acquisition was also a factor in a complex dynamic involving the emergence in Minnesota of resistant Salmonella enteritidis, which proved to have been largely acquired through foreign travel in Europe, Africa, South America, and—in the great majority—Mexico. National Systems The United States Centers for Disease Control and Prevention* The CDC has two major approaches for conducting surveillance of antimicrobial resistance. The first is the National Notifiable Disease Reporting System (NNDS). Because the legal authority to require disease reporting in the United States is vested in state governments rather than in the federal government, this system consists of information reported by state health departments on a weekly basis. The Council of State and Territorial Epidemiologists, with guidance from the CDC, recommends to states what they should require in the way of reporting, but states are under no obligation to comply with these recommendations. Although most states do in fact comply, the completeness of reporting is highly variable, depending as it does on state-level resources, priorities, and legal codes. This system provides essentially no information on antimicrobial resistance. The second system, developed to compensate for some of the incompleteness and unevenness in the national system, consists of individual data collection efforts focused on individual diseases and involving direct reporting from different facilities. For example, data on gonococcal resistance are collected from a network of sexually transmitted disease (STD) clinics; on nosocomial pathogens, from a network of hospitals; on physician prescribing practices, from ambulatory care facilities; on foodborne pathogens, from a range of sources monitored by the CDC, FDA, and U.S. Department of Agriculture (USDA). There are defensible reasons for this variability: the differing epidemiology of each infection, the diversity of the prevention and control measures required, disparities in the research questions asked, and diversity in the partnerships needed to collect the data and address the particular problem at hand. *   Presented by David Bell.

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Figure 1. Centers for Disease Control and Prevention (CDC) "mosaic" of antimicrobial resistance surveillance systems. NOTE: Sources of nosocomial infections are primarily staphylococci, enterococci, and gram-negative bacilli. Foodborne pathogens are Salmonella, Escherichia coli,and Campylobacter. SOURCE: National Center for Infectious Diseases, CDC. At the same time, although each CDC system may gather a fair amount of epidemiologic, microbiologic, and clinical information, none provides anywhere close to national coverage, and the linkages and coordination among them thus far have been quite limited (see Figure 1). This raises several questions. One is how these different surveillance efforts might be integrated internally so as to provide a more solid and complete understanding of patterns and trends in resistance. Another is how these systems could be made to interact with the range of private-sector systems, including those implemented by universities, large managed care entities, or commercial enterprises, some of which may be funded by pharmaceutical companies and collect proprietary data. Other questions are how integration and expansion can be achieved and, very importantly, funded. The Surveillance Network* The Surveillance Network, or TSN, was developed by MRL Pharmaceutical Services, a private firm in Virginia specializing in diagnosis of infectious and immunological diseases. TSN is a U.S. national on-line network of 150 (by the end of 1997) hospital-based testing centers and independent laboratories chosen for their geographic, demographic, and methodological characteristics. MRL's philosophy was to incorporate these institutions in order to leverage existing testing capabilities and utilize data generated within the health care infrastructure. TSN has the ability to (1) assess and continuously improve testing; (2) detect the occurrence of antimicrobial resistance rapidly and analyze resistance *   Presented by Laurence McCarthy.

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trends in real time; and (3) analyze data, also in real time, at a strain-specific level, using multivariate techniques. TSN relies on the dynamic creation of two objective and interactive databases continuously expanded by the participating institutions. The first, the TSN database, contains more than 9.4 million strain-specific test results for 83 antibiotics tested against 649,000 bacterial isolates, representing more than 4,000 taxa and obtained from 426,000 patients; another 2.6 million records will have been added by the end of 1997. The size of this database relative to others is illustrated by Stenotrophomonas maltophilia: the largest study of this organism published to date contains information on approximately 170 strains; the TSN database currently has results for 4,331 strains. Data collected each day include selected patient information, microbial culture results, and quantitative and qualitative antimicrobial susceptibility test results. The second database, TSN Archives, contains more than 13.7 million test results from the same participating laboratories, as well as less precise antibiogram-based historic data for 1992-1995, the years preceding the database period. These archived data are used mainly to track historical trends. MRL plans to expand the network globally and increase the database to include antifungal, antimycobacterial, and antiviral agents. Plans also call for establishing systems to include clinical and pharmacy information and collaborating with national and international public health organizations and researchers. New software approaches were developed for collecting and analyzing TSN data and assessing their quality in an ongoing fashion. Data are automatically and electronically sent each day to MRL's data center in Reston, Virginia, where they pass through expert electronic systems that check for correctness, consistency, and epidemiologically significant events. They are then merged, at five-week intervals, into a national database. The databases can be queried from virtually anywhere via the Internet using proprietary software, but they are password-protected to ensure security and confidentiality for patients and participating hospitals, and all transmissions and Internet queries are encrypted. TSN has already produced the following findings for the United States. The frequency of resistance to oxacillin in S. aureus is 27.5 percent and in nonaureus staphylococci, greater than 60 percent; among oxacillin-resistant S. aureus, 86.3 percent are resistant to ciprofloxacin, 89.2 percent to erythromycin, and 49.8 percent to gentamicin. TSN findings have also reinforced the urgency of identifying organisms at the species level. For instance, in the case of VRE, although laboratory results for unspeciated enterococci fail to demonstrate a significant resistance problem, results for Enterococcus faecium demonstrate that more than 50 percent of strains are, in fact, resistant to vancomycin.

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The Canadian System* Canada has undertaken several initiatives in the surveillance of antimicrobial resistance, including two more or less formal systems and several ad hoc programs. The Canadian Hospital Epidemiology Committee (CHEC). The CHEC was initiated by the Canadian Infectious Disease Society and receives support from the Canadian counterpart of the U.S. CDC, the Laboratory Center for Disease Control (LCDC), and from industry. It consists of 23 hospitals in 9 of Canada's 10 provinces and will shortly include all 10. Detailed clinical data and information on organisms are collected, and all isolates are tested in a single dedicated center. The program has focused primarily on multidrug-resistant S. aureus (MRSA) infections, VRE, and Clostridium difficile. The Canadian Bacterial Disease Network (CBDN). The CBDN, part of the federally funded Networks of Centers of Excellence program, is a Canada-wide consortium of researchers on bacterial disease. In 1993, Mount Sinai Hospital, University of Toronto, a node of the CBDN, established an ongoing cross-Canada surveillance program to monitor and study drug resistance in hospital and community pathogens. It has a current enrollment of more than 100 laboratories that service hospitals and community physicians. Isolates under study are processed centrally at Mount Sinai Hospital to ensure the accuracy of testing and to enable further investigation of the epidemiology and mechanisms of resistance. For example, the fact of 2,000 to 3,000 isolates yearly of Streptococcus pneumoniae and Haemophilus influenzae has allowed the rapid emergence of multidrug resistance in these organisms to be recognized. Ontario Invasive Group A Streptococci Infections Surveillance Network. This program, which has been in place since 1992, monitors all invasive group A streptococcal infections in residents of the province of Ontario (population I I million). Each patient with an invasive infection of group A streptococci has the isolate, clinical information, and blood and tissue specimens, when possible and appropriate, forwarded to Mount Sinai Hospital as part of an ongoing study of the epidemiology and pathogenesis of this disease. This information is also forwarded to the Ontario Ministry of Health for the purpose of case follow-up and prophylaxis, where appropriate. The Laboratory Proficiency Testing Program (LPTP). Through an agreement with the Ministry of Health of Ontario, the Ontario Medical Association (OMA) has been identified as an agent to examine and evaluate of the proficiency of performance of tests in clinical laboratories. LPTP is the unit within OMA that carries out this mandate. Established in 1974, LPTP has focused on ensuring that laboratories are aware of the importance and implications of new *   Presented by Donald Low.

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and emerging multidrug-resistant pathogens, know how to detect them most accurately, and are able to identify them in blind surveys. LPTP has also conducted surveillance programs to monitor the emergence of such pathogens as VRE and methicillin-resistant S. aureus within the province. Toronto Invasive Bacterial Diseases Network (TIBDN). This is a population-based, prospective surveillance program that monitors rates of invasive cases of group A and B streptococci, S. pneumoniae, Neisseria meningitidis, and Listeria monocytogenes in Toronto (population 3.5 million) and allows the study of the epidemiology of these pathogens. Also operated out of Mount Sinai Hospital, the program is funded in part by the LCDC, Physicians Services Incorporated (PSI), and CBDN. Ad hoc surveillance programs. A number of provincial and national surveillance programs are carried out across Canada at a number of university affiliated hospitals to study the epidemiology of antimicrobial resistance. As in the United States, these are industry driven and funded with specific marketing goals. However, they also provide a valuable source of funding to allow point prevalence surveys to be carried out to determine prevalence and resistance rates of important hospital and community pathogens. The Icelandic Surveillance System* This small (population 270,000) homogeneous country is attempting to develop what might be considered a prototype of an ideal antimicrobial resistance surveillance system. It has been possible to develop uniform, standardized microbiological numerator and denominator data and information about antimicrobial use, as well as a national network. The system lacks merged databases, continuous processing and reporting, and the capacity for collecting outcome data, and is working on all three, independently and with other concerned entities. The original goal of the program was to monitor all pneumococci with reduced susceptibility to penicillin and now has been expanded to include methicillin-resistant S. aureus, vancomycin-resistant enterococcus, and multiresistant Mycobacterium tuberculosis. The Department of Microbiology laboratory at the National University Hospital in Reykjavik, serves as a reference laboratory in addition to setting all of the standards and methods to be used in Iceland (according to National Committee for Clinical Laboratory Standards [NCCLS] Guidelines). This facility is also the only laboratory in the country that trains all technologists and physicians in microbiology. Surveillance of resistance in Iceland is relatively easy because of its small homogeneous population and the relative isolation of the country. These factors also make it an ideal place to study the epidemiology of certain resistance traits. Close contact among the laboratories and a central laboratory that records all *   Presented by Karl Kristonsson.

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agency has very rarely used it. As noted above, prospective boundaries on market size could constitute a disincentive to industry R&D investment, disadvantaging companies whose product is narrowly restricted relative to companies whose products are not, especially at a time of increasing industrial effort to find new targets and develop new structural classes of drugs. Restriction could also compromise individual rights to therapy, partly because of limits on the user population and partly as a result of costs, because physicians might find themselves facing a choice between prescribing an inexpensive broad-spectrum drug and prescribing a costly drug of narrow spectrum. Thus, the sense of the workshop participants was that the concept of restriction was critical but would most effectively embrace a range of interventions aimed toward the objective of preserving the efficacy of products already in use: using postmarketing surveillance as fully as possible to identify resistance; exploring the potential of formularies used by managed care organizations to limit the use of drugs for which there already exist worrying levels of resistance; quantifying the risks of inappropriate antibiotic use and developing descriptive models of the differences that could result from reduced use; attempting to anticipate resistance by using enrichment procedures in the early stages of drug development to identify plasmids in the pertinent ecosphere that might become sources of resistance and their in vivo potential for "exchangeability" from natural sources; more profoundly exploring broad ecological areas where resistance is known to be developing (e.g., fluoroquinolone and gentamicin use in food production); raising existing levels of knowledge about actual drug usage in humans and animals; exploring with WHO the use of its Essential Drugs List as a tool in dealing with the unrestricted availability of antimicrobials in some countries; conducting research responsive to pressures for the approval of antimicrobials for over-the-counter use; expanding outcome research on utilization (and nonutilization) of antibiotics, with a major objective incorporation of its findings into managed care policies. SUMMARY OF AREAS FOR CONSIDERATION Many areas, topics, issues, and options surfaced in the course of this workshop. Following is a summary of the key issues and options discussed.

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Surveillance Information Systems ISSUE: No country, including the United States, has a reliable, longitudinal, full-service antimicrobial resistance surveillance program with comprehensive focus, nor is there a comprehensive database for monitoring trends in antimicrobial usage. Multiple surveillance activities around the globe are attempting in different ways and at different speeds to move toward the ideal depicted in this report, but these systems, as a group, are uncoordinated and unstandardized. Thus, the magnitude of the resistance problem and its impact are really unknown. OPTION: The qualities needed are presented in the section of this report dealing with surveillance. Detailed recommendations for implementation of a comprehensive resistance surveillance program are outlined in the 1995 ASM Task Force Report (see Appendix B). These recommendations await funding, implementation, assumption or assignment of leadership, and formation of partnerships. ISSUE: Research and information on the impact of rapidly increasing antimicrobial resistance in the community are lacking. OPTION: Inclusion of information about the effects of resistance on the outcome of infections in systems of data collection. Laboratory Systems ISSUE: Some currently available molecular methods are clearly applicable only to research and reference laboratories; their feasibility for most commercial or clinical laboratories is at best limited. OPTIONS: Selection and strengthening of the laboratories in a set of sentinel hospitals to serve as bases for global assessment of the prevalence and transmission of the most critical antibiotic-resistant genes (i.e., sites for monitoring gene flow and assessing genetic diversity). Design of categories and pathways for reducing data sets into comprehensive packages for use by clinicians and researchers. ISSUE: The NCCLS Guidelines seem not to be as widely and regularly available as would be useful, and the processes and criteria for their development are not clear.

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OPTIONS: Expand distribution of NCCLS Guidelines and, if necessary, increase the frequency with which they are updated. Train laboratory personnel in sentinel hospitals in standardized methodologies. Law and Regulation ISSUE: CDC cannot mandate states to reform laws regarding reporting, but must rely on education, persuasion, and invitation. OPTIONS: Exploration of whether increased resistance and rapid diminution of effectiveness of existing antibiotics might justify awarding greater authority to CDC to monitor and enforce legal duties regarding resistance, and consideration of the means by which this might be accomplished. Consideration of ways to integrate issues of resistance into formulary development processes in pivotal managed care organizations, as well as the potential for inclusion of pharmaceutical industry representation on such committees for review and implementation of programs. ISSUE: A global antimicrobial resistance network might require many countries to import equipment, software, and reagents. OPTION: Drafting language for international agreement. Response: Prolonging Effectiveness Education ISSUE: Many needs related to the modification of attitudes and behaviors among providers, patients, parents, managed care organizations, and the pharmaceutical industry may be most usefully considered as an integrated global strategy. Not the least of these is the need for ongoing education concerning infection control, hygiene, and sanitation in health facilities and the community in general. OPTIONS: Table 5 of this report provides a listing of strategic areas for interventions meant to modify attitudes, behaviors, and, where applicable, policies among the major parties to the antimicrobial resistance problem.

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Law and Regulation ISSUE: Many groups are compiling practice guidelines for antibiotic use, possibly generating confusion and complicating their value to providers, for whom such guidelines might afford some protection from liability. OPTIONS: Speedy implementation of a joint project involving all pertinent professional societies in developing unitary guidelines (including checklists for providers to use in clinical settings) for antimicrobial use, perhaps analogous to the Report of the Committee on Infectious Diseases of the American Academy of Pediatrics (''Red Book"), implementing their extensive dissemination, and very importantly, updating them periodically based on annual data from longitudinal studies. Greatly expanded research into outcomes of antibiotic misuse, nonuse, and prudent use in health care facilities and in the community, as the foundation for the articulation and revision of guidelines, the policies of the health professions and the full range of health care facilities, and the formularies of such facilities, including the WHO Essential Drugs List. ISSUE: Some existing products seem to have activity against resistant pathogens but because this particular efficacy has not been documented, these indications do not appear in the labeling. OPTIONS: Development of alternative ways to define efficacy, for example, surrogate markers, in vitro technologies, and animal models to address lack of a well-defined population for clinical trials. Exploration of the possibility of congressional authorization to extend patents for such products and the relevance of recent legislation adding six months of exclusivity when DHHS requests pediatric studies of an existing product, with the recognition that this topic is complex and difficult. ISSUE: Shorter courses of full therapeutic levels of antibiotics may in some cases be feasible and perhaps encouraged, with a positive effect on volumes of selective pressure. The issue is complex since there is also evidence that subtherapeutic doses may select for resistance. OPTION: Design and implementation of research on clinical outcomes from shorter courses of therapy, as the basis for subsequent updating of new practice guidelines and revisions to labeling. ISSUE: The FDA is increasingly pressed to approve some prescription antibiotics and antifungals for over-the-counter use.

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OPTION: Research and/or systematic marshaling of existing research to inform agency response. ISSUE: Antibiotic use is widespread in hospital, community, and farm settings, yet knowledge of the magnitude of these uses depends largely on estimation and extrapolation. OPTION: Improved data gathering and analysis, perhaps through national systems that would continuously monitor antimicrobial usage. Response: Developing New Products Incentives for Industry ISSUE: There is said to be a perception in the pharmaceutical industry that collaborative development of new antimicrobials might be constrained by U.S. antitrust laws, although to what extent this is the case is unknown and the evidence is contradictory. On the one hand, both U.S. antitrust law and European Union competition law permit collaborative joint ventures within certain parameters; on the other, dispute about ownership of gene sequences is current and heated. OPTION: Exploration of the extent to which these factors constitute disincentives explicitly for the development of new antimicrobial products and, if this should prove to be the case, further exploration focused on alternative solutions for the dilemmas identified. Research ISSUE: Resistance is so complex and dynamic at the genetic level that more work is needed to understand the diversity and prevalence of resistant gene families, both in nature and in the animal microflora that are the bridge to human contact, and to discern the origins of these genes and how they spread from one organism to another. OPTIONS: Studies of gene flow. Research using enrichment procedures in the early stages of drug development to identify plasmids in the pertinent ecosphere that might become sources of resistance and their in vivo potential for "exchangeability" from natural sources.

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Education ISSUE: Limited data are available to describe the difference that prudent antibiotic use would make. Without such data, public education and advocacy are constrained. OPTION: Quantification of the risks of injudicious antimicrobial use and development of descriptive and predictive models of the differences judicious use of antimicrobials would make, for purposes of policy development, advocacy, and action. ISSUE: The community antimicrobial resistance equation is being affected to an unknown degree by proliferation of household and personal-use products with added antibacterial properties and by changes in hospital discharge patterns. OPTIONS: Intensified research into the effects of incorporating antimicrobials into items of daily personal use. Intensified research into the effects of changes brought about by managed care on infection rates and antibiotic resistance patterns. Agricultural Use Research ISSUE: Historically, there has been a paucity of hard data on the development and transfer of resistance produced by animal husbandry, aquaculture, and agricultural uses of antibiotics, particularly solid quantitative data with well-described etiologic pathways and data on trends in antimicrobial usage in veterinary settings. Lack of ready access to data from veterinary reference laboratories has been a limitation in this regard. OPTIONS: Collaboratively designed, implemented, and analyzed research on these dynamics, perhaps beginning with case studies (e.g., DT104, fluoroquinolones, gentamicin). Collaborative access to data from veterinary reference laboratories. ISSUE: An ecological understanding could help in a number of aspects of animal husbandry, including conditions that foster the enhancement of antimicrobial resistance.

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OPTIONS: Systematic, collaborative development, by the USDA, AVMA, FDA, and producer organizations, of strategies and educational materials to expand such understanding. Development of cost-benefit and cost-effectiveness models of different on-farm antibiotic usages to enhance the public health community's understanding of farmer perspectives. ISSUE: Applied research suggests that there is potential in using competitive exclusion therapies or "probiotics," that is, the constructive use of harmless or beneficial colonizing organisms in different areas of food production. OPTION: Additional applied research. ISSUE: There is ambiguity as to whether requests for registration of antibiotics for use on agricultural products that are exported are governed by the environmental clauses or the food safety requirements of NAFTA and/or GATT. Nor does antibiotic resistance appear to be incorporated explicitly into discussions of food safety and the regulation and monitoring of imports. OPTION: Collaborative dialogue, perhaps led by WHO and including representation from the World Trade Organization, European Union, and U.S. Departments of State and of Commerce. FINAL COMMENTS Since the introduction of sulfonamides and penicillin more than 50 years ago, the world has become accustomed to the availability of antibiotics that are promptly and reliably effective, relatively free of side effects, and inexpensive compared to other medical and surgical interventions. The initial treasure trove is, however, all but exhausted. Yet, like cheap petroleum, the habit interferes conceptually and practically in market-incentive structures with the development of successors, and there is high risk that what remains of the treasure will be wasted by its imprudent use. The transition period as the market makes the necessary adjustments will be painful, and it is possible to imagine a scenario in which antibiotics with lower therapeutic indexes at thousands of dollars per course of treatment could instill a need for rationing and special development incentives, to great consumer distress, particularly in populations whose financial resources are constrained. The evidence and opinions presented at this workshop suggest, nevertheless, that the transition from a historically generous armamentarium to one at least temporarily much less lavish could be mitigated by wiser policies, both to conserve what remains and to plan for what is to come; policies for the most cost-

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effective use of antibiotics; evidence-based regulation, with transparent balancing of risks and benefits; and as already exemplified in genome projects, social investment in the underlying science needed to develop new antimicrobial agents. Also, because antimicrobial drug resistance is increasingly known to be a global problem, it can be addressed only with international cooperation, at a minimum in the acquisition and sharing of information. Whatever frictions might ensue from shaping and implementing such policies would be more than offset by the savings in medical and hospital costs and, most importantly, by the deaths and disability avoided. NOTES 1.   American Society for Microbiology. New and Reemerging Infectious Diseases: A Global Crisis and Immediate Threat to the Nation's Health, The Role of Research. Washington, D.C.: American Society for Microbiology, 1997. 2.   Finland M, et al. Occurrence of serious bacterial infections since introduction of antibacterial agents. Journal of the American Medical Association 170:2188-2197, 1959. 3.   Phelps CE. Bug/drug resistance. Medical Care 27:194-203, 1989. As reported in Levy SB. The Antibiotic Paradox: How Miracle Drugs Are Destroying the Miracle. New York: Plenum, 1992. 4.   Martone WJ, WR Jarvis, DH Culver, et al. Incidence and nature of endemic and epidemic nosocomial infections. In Hospital Infections, Third Edition. JV Bennett and PS Brachman, eds. Boston: Little Brown, 1992. 5.   U.S. Congress, Office of Technology Assessment. Impacts of Antibiotic-Resistant Bacteria (OTA-H-629). Washington, D.C.: U.S. Government Printing Office, 1995. 6.   Current and past members are Argentina, Brazil, Bulgaria, Chile, Colombia, Greece, Hungary, Iceland, Italy, Japan, Mexico, Poland, South Korea, Spain, Sweden, Taiwan, Turkey, and Uruguay. 7.   There is some improvement in the funding picture for global activities related to surveillance, including the surveillance of antimicrobial resistance. In December 1997, the United States Agency for International Development (USAID) announced the allocation of an additional $50 million for the control of infectious diseases in countries other than the United States. Priorities for splitting the allocation are the "control of tuberculosis, control of malaria, improved surveillance of disease outbreaks, and a broad effort to detect and limit drug-resistant microbes. The latter is an area of particular concern because it does not yet have a coordinated global program in place." Decisions on specific allocations are scheduled for the first part of 1998, with enhancement or expansion of existing programs of WHO, CDC, and other organizations the most likely use of the funds (ProMEDa-mail 97[309], December 22, 1997).

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8.   Bioinformatics is the use of software, databases, and networks for gene and open reading frame identification; database homology and pattern searching with both DNA and protein sequences; comparative sequence analysis and multiple sequence alignment; protein structure prediction and mapping of functional sites; protein homology modeling and inverse folding as a means of probing protein structure and function; and the discovery or design of drugs against genes or their products. 9.   Winner L, et al. New model for analysis of mucosal immunity: Intestinal secretion of specific monoclonal immunoglobulin A from hybridoma tumor protects against Vibrio cholerae infection. Infectious Immunity 59(3):977-982, 1991; Burns JW, et al. Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science 272:104, 1996. 10.   Institute of Medicine. The Hidden Epidemic: Confronting Sexually Transmitted Diseases. TR Eng, WT Butler, eds. Washington, D.C.: National Academy Press, 1997. The contents of the category "sexually transmitted disease" are not always the same. As noted, WHO categories include only the four curable STDs cited in the text. The U.S. cost figures cited include cervical cancer, chancroid, chlamydial infection, gonorrhea, pelvic inflammatory disease, syphilis, and herpes simplex, human papillomavirus, and hepatitis B virus infections. The burden of disease data cover chlamydial infection, gonorrhea, pelvic inflammatory disease, and syphilis. All of the sources, however, treat sexually transmitted HIV/AIDS as a discrete category. 11.   In addition to PCR and LCR assays, there are transcription-mediated amplification (TMA), self-sustaining sequence amplification (3SR), QB replicase-based amplification (QRA), strand displacement amplification (SDA), and branched DNA amplification (bDNA). 12.   Jaschek G, CA Gaydos, LE Welsh, TC Quinn. Direct detection of Chlamydia trachomatis in urine specimens from symptomatic and asymptomatic men by using a rapid polymerase chain reaction assay. Journal of Clinical Microbiology 31(5): 1209-1212, 1993. 13.   Levy SB. The Antibiotic Paradox: How Miracle Drugs Are Destroying the Miracle. New York: Plenum Press, 1992. 14.   From 1975 to 1990, the annual visit rate to office-based physicians for otitis media more than doubled; for children under 15 years of age, the rate increased almost 150 percent (SM Schappert. Office visits for otitis media: United States, 1975-90. Advance Data from Vital and Health Statistics of the National Center for Health Statistics, No. 214 (PHS) 88-1250. Hyattsville, Md., September 1992). 15.   Kristinsson KG. Effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci. Microbial Drug Resistance 3(2):117123, 1997.

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16.   Levy SB. The challenge of antibiotic resistance. Scientific American 283(3):46-53, 1998. 17.   A glycopeptide chemically related to vancomycin, avoparcin has been used as a growth promoter in animal feeds in Europe since the mid-1970s. There are now indications that avoparcin use is selecting for vancomycin resistance in enterococci so that in Europe, VRE are found in community populations, waste water, farm animals, and some food products, unlike the United States where VRE are found largely in hospitals (U.S. Congress, op. cit., note 4). 18.   Dowell S and B Schwartz, unpublished data. Atlanta: Centers for Disease Control and Prevention, 1997. 19.   There is a considerable literature on the extent to which guidelines provide protection from liability, for example: National Health Lawyers Association. Legal Issues Related to Clinical Practice Guidelines: Colloquium Report. Washington, D.C.: National Health Lawyers Association, 1995. 20.   The Alliance for the Prudent Use of Antibiotics, P.O. Box 1372, Boston, MA 02117. 21.   Report of a study sponsored by the Fogarty International Center of the National Institutes of Health, 1983-1986. Antibiotic use and antibiotic resistance worldwide. Review of Infectious Diseases 9(Suppl. 3):S23 1-316, 1987. 22.   The subject of off-label use of antibiotics, including its implications for the development of drug resistance and its regulatory aspects, is very large and very complex but was not addressed at the workshop. 23.   Furthermore, two major activities are engaged in different processes for obtaining a more systematic understanding of this large problem. The Committee for Veterinary Medicinal Projects (the body responsible for evaluating documentation related to applications for licensing drugs for veterinary use in the European Community) established an ad hoc group charged with carrying out an epidemiological analysis of the status of antimicrobial resistance in animals and humans, as a basis for subsequent risk assessment. In addition, a major WHO workshop on "The Medical Impact of Use of Antimicrobial Drugs in Food Animals" recently reviewed this subject and will make recommendations regarding different aspects of the rational use of anti-infective drugs in food animals. 24.   Feinman SE. Antibiotics in animal feed—drug resistance revisited. ASM News 64(4):24, 1998. 25.   Milk is removed from each quarter of the cow's udder through the "streak canal" in the end of each teat. The canal is kept closed by a circular muscle (sphincter) that prevents milk from escaping and bacteria from entering. The cells lining the canal make keratin, which traps organisms that attempt to invade through the teat end, keeping them from gaining access to immune cells in the teat epithelium lining. If the sphincter muscles are weak, the teat will leak milk and is more likely to become infected.

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26.   The FDA Modernization Act abolishes the long-standing prohibition on dissemination by manufacturers of information about unapproved uses of drugs and medical devices. The act allows a firm to disseminate peer-reviewed journal articles about an off-label indication of its product, provided the company commits itself to file, within a specified time, a supplemental application based on appropriate research to establish the safety and effectiveness of the unapproved use. The act also allows drug companies to provide economic information about their products to formulary committees, managed care organizations, and similar large-scale buyers of health care products. The provision is intended to provide such entities with dependable facts about the economic consequences of their procurement decisions. The law, however, does not permit the dissemination of economic information to individual medical practitioners that could affect their prescribing choices. 27.   Institute of Medicine. Orphans and Incentives: Developing Technologies to Address Emerging Infections. Workshop Report. PF Harrison, J Lederberg, eds. Washington, D.C.: National Academy Press, 1997. The FDA Modernization Act of 1997 was passed in November and includes measures that may be of particular help in encouraging and expediting the development of new antimicrobial products. The most pertinent measures are the following: Measures to modernize regulation of biological products by bringing them into harmony with regulations for drugs, by eliminating the need for establishment license application as well as the batch certification and monograph requirements for insulin and antibiotics, by streamlining approval processes for drug and biological manufacturing changes, and by reducing the need for environmental assessment as part of a product application. Codification of FDA's regulations and practices to increase patient access to experimental drugs and medical devices and to accelerate the review of important new medications. Reauthorization of the Prescription Drug User Fee Act of 1992, which had made possible the $329 million in user fees paid by the pharmaceutical industry that helped FDA significantly shorten the duration of its drug review processes through managerial reforms and the addition of 696 employees to its drugs and biologics programs. An FDA Talk Paper (January 14, 1998) reports that in 1997, FDA's Center for Drug Evaluation and Research (CDER), supported by user fees, achieved a median approval time of 12.2 months for 121 new original drugs, which was 18 percent shorter than the year before. Of these drugs, 39 were new molecular entities containing an active substance never before approved for marketing in any form in the United States. The CDER also approved 431 generic products and antibiotics, which are not supported by user fees, 80 more than in 1996 and the highest number of generic approvals in the decade.