Antimicrobial Resistance Issues and Options (1998) / Chapter Skim
Currently Skimming:
Workshop Report
Workshop Report
Pages 8-74
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 8... ...
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 dur ing a period when resistance was not generally seen as a major threat, and · funding for public health infrastructure.
|
From page 9... ...
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)
|
From page 10... ...
OTA emphasized that the estimate was a minimum, since it considered only inhospital 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.
|
From page 11... ...
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.
|
From page 12... ...
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
|
From page 13... ...
; · 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.
|
From page 14... ...
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.
|
From page 15... ...
Foodborne pathogens are Salmonella, Escherichia colt, and Campylobacter. SOURCE: National Center for Infectious Diseases, CDC.
|
From page 16... ...
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.
|
From page 17... ...
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.
|
From page 18... ...
A number of provincial and national surveillance programs are carried out across Canada at a number of universityaff~liated hospitals to study the epidemiology of antimicrobial resistance. As in the United States, these are industry driven and funded with specific marketing goals.
|
From page 19... ...
The former identify organisms, determine resistance rates, and provide characteristic strains for use by molecular biologists, who develop and streamline molecular fingerprinting methods and identify and track resistant genes. Scientific centers for this activity are, for molecular biology, the Institute of Biotechnology at the Universidade Nova de Lisboa in Portugal and the Laboratory of Microbiology at the Rockefeller University and, for clinical microbiology, the Microbiology Department at the National University Hospital in Iceland and comparable departments in other participating countries, currently 10 in number.6 Financial support is provided by the pharmaceutical industry, with in-kind support provided by participating institutions.
|
From page 20... ...
and the International Society of Infectious Diseases (ISID)
|
From page 21... ...
Additionally, the principal investigators provide consultations for susceptibility testing methods, molecular techniques, epidemiology and infection control, and skills in medical writing for peer-reviewed publications. The long-term durability and success of SENTRY and other resistance surveillance systems such as those described in Appendix A of this report will demand effective public- and private-sector partnerships, especially including the collabo ~Presented by Renu Gupta.
|
From page 22... ...
Because antimicrobial resistance surveillance data are, and will continue to be, highly laboratory dependent, laboratory quality is crucial. Moreover, although the accuracy of data is always an issue in research, there are a number of reasons to be concerned about the accuracy of the surveillance data currently coming from laboratory sources.
|
From page 23... ...
What Is Needed There is presently no single global or national surveillance system for monitoring antibiotic resistance that answers to the ideal described at the beginning of this section. There are multiple surveillance activities scattered across the
|
From page 24... ...
In 1995, an ASM Task Force recommended the immediate establishment of networks on a local, national, and global scale by the National Center for Infectious Diseases (NCID) at CDC and associated agencies, with the necessary fiscal support, for the surveillance of antimicrobial resistance in animals, humans, and food products.
|
From page 25... ...
This left 486 positions to be apportioned throughout the 50 states and one territory for the surveillance of all other infectious diseases.
|
From page 26... ...
As a consequence, each replication contains possibilities for change, a moment-to-moment capability to evolve so as to, for example, evade the human immune system or other potentially hostile forces. All this makes it surprising that antibiotic resistance is not actually an order of magnitude worse than it is.
|
From page 27... ...
TABLE 2 Federal, State, and Local Support for Infectious Disease Surveillance by Disease Category, United States, 1992 Dollars TO STDs Vaccine pre ventable All other1,535,059 diseases Antibacterial/ antiviral drug resistance6,260 48,795 400 55,455 < 1 7,478,557 2,987,606 2,967,790 1,193,222 5,830,516 Disease AIDS/HIV 25,794,280 4,085,098 7,819,550 2,921,175 Federal State Local Total Percent 1,317,359 34,590,196 2,884,901 9,957,605 2,412,700 13,200,040 1,116,091 5,230,488 46 13 18 4,193,480 11,559,055 15 Total 42,161,422 20,506,486 11,924,931 74,592,839 100 NOTE: Includes data from 50 states and one territory. SOURCE: Osterholm MT, GS Birkhead, RA Meriwether.
|
From page 28... ...
The reservoir of antimicrobial drug-resistant genes has been analyzed insuL ficiently. It is clear that genes have transferred not only between species within the same genus, but between genera and even across broader taxonomic boundaries.
|
From page 29... ...
In many instances, either sequencing or the use of probes, in a filter-based method or solid-state high-density array, is available, and much can be automated. Because such methods are also rapid, in theory and often in practice their use can generate real cost savings to clinical management because the necessary information is available in a timely fashion so that chances for truly appropriate care would be substantially enhanced.
|
From page 30... ...
In addition, when the chip is exposed to a target genome that is not Mycobacterium so that hybridization is therefore incomplete, it will produce a highly informative, reproducible, species-specific pattern, or "fingerprint," that permits species identification. In other words, these arrays can provide species identification of the Mycobacterium at the same time they provide information on the nucleotide differences in specific sequences that confer drug resistance.
|
From page 31... ...
Now, all the potential available targets can be evaluated more or less simultaneously and target selection is determined by relationships among genomes. At least nine biopharmaceutical companies are currently using genomic techniques to develop new antibiotic targets.
|
From page 32... ...
As the primary site of disease entry, infection, and pathogen replication, this extensive system is a potentially key locus of selection for antibiotic resistance and, furthermore, may be responsible for maintaining resistant alleles and transmitting them in the general population. This raises the question of whether there is a role for targeting preventive and therapeutic interventions at epithelial surfaces so as to evade or forestall problems of antimicrobial resistance.
|
From page 33... ...
Applications of Field Surveillance in the United States and Globally Surveillance for antibiotic resistance is dependent upon surveillance for infection, yet current global, national, and local systems are clearly inadequate for the detection of most infections and therefore woefully inadequate for tracking resistance in any coordinated way. Sexually transmitted disease is a useful example.
|
From page 34... ...
tuberculosis," as well as several multiplex assays, one of which detects herpes, syphilis, and chancroid from any genital ulcer and another that allows for detection of bacterial vaginosis, Chlamydia, gonorrhea, human papillomavirus, and trichomoniasis. These assays have much higher sensitivity and specificity than standard culture tests, can screen for both infection and resistant genes, and are cost-effective across a wide prevalence of infections and with different screening criteria.
|
From page 35... ...
The techniques used to test the samples gathered through such screening activities can also be used to assess resistance, an approach already in practice for HIV. The amplified DNA used to assess viral load in HIV-infected individuals in developed countries is probed for known resistant genes in the reverse transcriptase (RT)
|
From page 36... ...
One plausible strategy might be to select a set of sentinel hospitals that could serve as bases for global assessment of the prevalence and transmission of a few antibiotic-resistant genes, in other words, sites for the monitoring of gene flow and assessment of genetic diversity. This would surely require strengthening of the laboratories concerned and emphasis on effective data management to ensure that the proper responses occur in a timely manner.
|
From page 37... ...
These basic elements constitute what is, in effect, a "drug resistance equation." The ebb and flow of either component of the equation affects the magnitude of what may, or may not, become a resistance problem. If both elements of the equation are kept in check, the fact that drug-resistant organisms exist does not mean that they necessarily constitute a public health problem.
|
From page 38... ...
Yet even these patterns are not inevitable: In many parts of the developing world, drugresistant Salmonella are a nosocomial rather than a farm problem. At the same time, there is evidence that antibiotic resistance can be reversed or attenuated by reductions in antibiotic use.
|
From page 39... ...
Table 3 presents estimates of use in these different settings, the amount of use that is probably unnecessary, and the pathogens known to have developed antibiotic resistance in these environments. The Hospital The picture of the evolution of drug resistance in hospital settings clearly illustrates the fluidity of the resistance phenomenon as a whole.
|
From page 40... ...
40 ct Ha 'e v)
|
From page 41... ...
_ 41 - ~ c E ' C C ° ~ : ~.~, O'- ~ o ' -lo c = ~s:~ ~ 3 ~ ~ ~·~ cat '' ~ c~ ~ ~.~a ~ O ~ _ ~ I:: ~ ~ cat ~ 3._ g ~ · ~ ~ ,0 _ ~ C it, C ~ , ~ U AL JO E E ' A, ,, at' Hi ~L)
|
From page 42... ...
SOURCE: National Center for Infectious Diseases, Centers for Disease Control and Prevention. Adapted from McCaig LF and JM Hughes.
|
From page 43... ...
In 1993, the appearance of an epidemic strain (R-type ACSSuT) was conf~rmed with chromosomally encoded multiple drug resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline.
|
From page 44... ...
Antibiotic resistance among human Salmonella typhimurium DTI 04 isolates in the United Kingdom. NOTE: R-type ACSSut means that this strain of Salmonella is resistant to the antibiotics ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline at the concentrations commonly used for therapy of animal and human infections.
|
From page 45... ...
Strategies for Judicious Antibiotic Use In many crucial respects, a major contributor to many of the factors listed in Table 4 is inadequate knowledge. This implies that there has been inadequate education-of physicians and patients, of veterinarians and farmers, and of decisionmakers in managed care organizations about what antibiotics are, what they can do, when they are indicated, and the short- and long-term risks and costs of inappropriate antibiotic use.
|
From page 46... ...
46 CQ ._ o ._ ._ a: au Cal ._ o Ct I_ ._ Cal o Cal o C)
|
From page 47... ...
· The ASM, CDC, American Academy of Pediatrics, and American Academy of Family Practice have developed educational pamphlets and posters for patient education about antibiotic resistance and appropriate use. · Kaiser Permanente, Southern California Region, has a 24-hour pediatric and infectious disease support service to answer questions about the use of antimicrobials and provides feedback from its central laboratory to each medical center on local resistance patterns for E
|
From page 48... ...
48 c' ct ._ u, P~ ._ o ._ ._ sr ¢ ._ 3 o ._ c' ~: ._ c~ O O o s: ct u, o ._ ;> ct m ._ ._ ~o o o U
|
From page 49... ...
- 49 .= I o ·= Cd Cal ,c ~= (o C)
|
From page 50... ...
typhrmurium DT104 as an example of a specific reason for concern and on the more general concerns of selected entities for whom some aspect of antibiotic resistance is a current or potential issue. Concerns and Perspectives from Producers The National Pork Producers' Council (NPPC)
|
From page 51... ...
Strengthened Professional and Public Education The Council's Quality Assurance Program is an important educational vehicle. The program includes a Good Production Practices component, which provides a channel for professional veterinary input to the use of all drugs, including antibiotics.
|
From page 52... ...
Improved communication could help impede the spread of veterinary infections that, in epidemic form, demand extensive, high-volume uses of antibiotic therapy. Better education of producers and allied professions with respect to transmission of infectious diseases, basic prevention measures, and the nature of antibiotic resistance, particularly with respect to new findings, could reasonably be expected to affect farm management behavior in a positive direction.
|
From page 53... ...
and Center for Food Safety and Applied Nutrition, and the CDC. The activity is examining antibiotic resistance patterns in Salmonella, in cooperation with APHIS, USDA-ARS, FSIS, and animal diagnostic laboratories.
|
From page 54... ...
In the case of food production, the key stakeholders are the CDC, EPA, FDA, USDA, professional groups such as the AVMA and American Association of Swine Practitioners, and the commodity producer organizations. · Antibiotic resistance does not appear to be incorporated explicitly into discussions of food safety and the regulation and monitoring of imports, nor has the available scientific evidence inevitably been applied, suggesting the value of collaborative dialogue, perhaps led by WHO and including representation from
|
From page 55... ...
cold 0157 among domestic farm animals; · Exploration of the potential for competitive exclusion therapies or "probiotics," the constructive use of harmless or beneficial colonizing organisms in different areas of food production. Applied research in Europe might be instructive; · Exploration of off-label use in food production of antibiotics that retain critical roles in human health, most importantly, the quinolones, particularly given changes in the regulation of information on off-label use that are part of the FDA Modernization Act of 1997;26 · Exploration of whether management technologies can decrease subtherapeutic uses of antibiotics for growth promotion in animal husbandry as a consequence of more positive cost-benefit equations; and · Exploration of the prospects that new molecular diagnostics would be used in food production, particularly animal husbandry, were such tools to be developed.
|
From page 56... ...
Material is also taken from Fidler DP. Legal Issues Arising from the Development of Antimicrobial Resistance in the Era of Emerging Infectious Diseases.
|
From page 57... ...
As noted earlier in this report, although the CDC coordinates the national public health notifiable disease reporting system, the legal authority to require disease reporting and to specify which diseases are "reportable" is vested in state governments; reporting to the CDC is essentially voluntary. Although all states do participate, reporting is far from uniform.
|
From page 58... ...
This concern has proven especially acute in connection with sexually transmitted diseases, as the HIV/AIDS crisis amply demonstrated, but there are other sensitivities that have economic dimensions, for instance, the effects on tourism of published outbreak information. In the United States, the dissemination of health information gathered by public health agencies is regulated largely by the Constitution and state statutes; however, a recent survey of these statutes indicates that although most states have nominal safeguards on public health privacy, they are often incomplete or inadequate.
|
From page 59... ...
Were such duties to be accepted, requirements for monitoring and enforcement would be daunting and costs consequential. International legal issues also arise in relation to the misuse of antibiotics in food production, alluded to in an earlier section of this report.
|
From page 60... ...
, or whether it is a compound with possible development potential. One set of questions is raised when a new use is sought for an older product that has been on the market, whose patent protection may have expired, for which there may be a generic counterpart, and for which getting a new-use approval will require clinical trials, with associated costs in time and money.
|
From page 61... ...
One consequence of the explosion in genetic information is the possibility of more individualized therapies in other words, drugs that would take human polymorphisms explicitly into account. Researchers will be able to probe research targets in human disease, in this case infectious disease, and aim at molecules designed for a specific subset of patients.
|
From page 62... ...
Collaborative Research and Development It may be that in some circumstances, collaborative R&D efforts by several pharmaceutical companies might make scientific and economic sense, but companies point to difficulties posed by antitrust laws. In response to calls for collaborative R&D on a malaria vaccine, for instance, some companies have commented that such collaboration would be fraught with problems involving the sharing of intellectual property and the likelihood of falling afoul of legislation banning cartels.
|
From page 63... ...
Restricted Distribution* The issue here was whether the problem of inappropriate antibiotic use was not too serious to leave solely to provider and patient education and whether more formal, regulatory constraints on the distribution of new anti-infectives might have merit in terms of preserving the activity of such products and extending their usable life.
|
From page 64... ...
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 resis tance; · 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)
|
From page 65... ...
Detailed recommendations for implementation of a comprehensive resistance surveillance program are outlined in the 1995 ASM Task Force Report (see Appendix B)
|
From page 66... ...
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.
|
From page 67... ...
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.
|
From page 68... ...
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.
|
From page 69... ...
2. Intensified research into the effects of changes brought about by managed care on infection rates and antibiotic resistance patterns.
|
From page 70... ...
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.
|
From page 71... ...
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.
|
From page 72... ...
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.
|
From page 73... ...
Antibiotic use and antibiotic resistance worldwide. Review of Infectious Diseases 9(Suppl.
|
From page 74... ...
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.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.