5
Factors Contributing to the Emergence of Resistance

OVERVIEW

Although microbial resistance results primarily as a consequence of selection pressure placed on susceptible microbes by the use of therapeutic agents, a variety of social and administrative factors also contribute to the emergence and spread of resistance. The focus of this session of the workshop was to examine these factors and to describe potential ways to minimize their role in promoting antimicrobial resistance.

In the United States and other developed countries, one leading factor is the over-prescription by physicians of antimicrobials, particularly antibiotics, even in the absence of appropriate indications. Such inappropriate physician practices are often fostered by diagnostic uncertainty, lack of opportunity for patient follow-up, lack of knowledge regarding optimal therapies, and patient demand. In many developing countries, problems typically arise because 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.

Some common types of human behavior also play a role in promoting resistance. Of particular importance, for example, are patient self-medication and noncompliance with recommended treatments. Noncompliance occurs when individuals forget to take medication, prematurely discontinue the medication as they begin to feel better, or cannot afford a full course of therapy. Self-medication almost always involves unnecessary, inadequate, and ill-timed dosing. In some countries, problems of noncompliance and



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5 Factors Contributing to the Emergence of Resistance OVERVIEW Although microbial resistance results primarily as a consequence of selection pressure placed on susceptible microbes by the use of therapeutic agents, a variety of social and administrative factors also contribute to the emergence and spread of resistance. The focus of this session of the workshop was to examine these factors and to describe potential ways to minimize their role in promoting antimicrobial resistance. In the United States and other developed countries, one leading factor is the over-prescription by physicians of antimicrobials, particularly antibiotics, even in the absence of appropriate indications. Such inappropriate physician practices are often fostered by diagnostic uncertainty, lack of opportunity for patient follow-up, lack of knowledge regarding optimal therapies, and patient demand. In many developing countries, problems typically arise because 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. Some common types of human behavior also play a role in promoting resistance. Of particular importance, for example, are patient self-medication and noncompliance with recommended treatments. Noncompliance occurs when individuals forget to take medication, prematurely discontinue the medication as they begin to feel better, or cannot afford a full course of therapy. Self-medication almost always involves unnecessary, inadequate, and ill-timed dosing. In some countries, problems of noncompliance and

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self-medication are magnified because significant amounts of the available antimicrobials are poorly manufactured, counterfeit, or have exceeded their effective lifetimes. Various practices common in hospitals contribute to the resistance problem as well. Indeed, hospitals are especially fertile grounds for breeding resistant microbes. They deal regularly with large numbers of patients (many with suppressed immune systems) in relatively close proximity to each other, and they frequently treat their patients with intensive and prolonged antimicrobial therapy. 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. Transmission of drug-resistant organisms among patients may be airborne, from a point source (such as contaminated equipment), or by direct or indirect contact with a contaminated environment or the contaminated hands of staff. Failure of health care workers to practice simple control measures (e.g., hand washing and changing gloves after examining a patient) is a leading contributor to the spread of infection in hospitals. Hospitals typically rely on two major forms of intervention to minimize resistance problems. One approach involves limiting antimicrobial use as much as possible; the other involves implementing intensive infection-control programs. Important components of these programs include surveillance; outbreak investigation and control; sterilization and disinfection of equipment; and implementation of such patient-care practices as handwashing, isolation, and barriers between infected patients. Although much is known about how hospitals can minimize the spread of infection, research is still needed to fill some important gaps in knowledge. One need is for development of rapid, reliable diagnostic methods for identifying the presence of infection, the specific infecting organism, and the susceptibility of the microbe to various therapeutic agents. Diagnostic precision is the key to effectively modifying the current approach of widespread empiric antimicrobial use in ill patients with suspected infections. A further need is to develop materials for use in medical devices, such as catheters, that are resistant to colonization by microorganisms. In addition, continuing development of new antimicrobial agents remains a priority. Another factor that is widely believed to contribute to resistance problems is the use of various antimicrobial agents in animals raised commercially for food, such as poultry, pigs, and cows. Participants debated just what contribution such agricultural use makes to the spread of antimicrobial resistance among human pathogens. While some participants maintained that the problem is minimal and being effectively managed by various public and private programs, others described a greater level of risk. They expressed concern that use of antimicrobials in animals, either for

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therapeutic use or to promote growth, 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. In response to the workshop presentation, “The Use of Antimicrobials in Food-Producing Animals,” a paper was prepared to address the public health consequences of antimicrobials in agriculture and can be found in Appendix A. ANTIBIOTIC USE AND RESISTANCE IN DEVELOPING COUNTRIES Iruka N. Okeke, Ph.D. Department of Biology, Haverford College, Haverford, PA “The ways and means for putting medicine in order must take account of the conditions of life and work among the people whom it must serve.” Walton H. Hamilton, 1932 Antimicrobial resistance adversely affects the outcome of community-and hospital-acquired infections in developing countries. For example, mortality in recent cholera and dysentery epidemics has been significantly increased by antibiotic resistance (Goma Epidemiology Group, 1995; Sengupta et al., 2000; Okeke et al., 2001). Other cases in point include tuberculosis, respiratory tract infections, infectious diarrhea, sexually transmitted diseases, and malaria. These conditions account for most of the illness in the developing world. In these countries, the infectious disease burden is typically high, whereas the options available to prescribers are few—often limited to older, cheaper, and non-patent protected drugs. Studies that have monitored resistance rates over time have documented a rising prevalence of resistance to these commonly used antimicrobials (see Figure 5-1) (Hoge et al., 1998; Okeke et al., 2000; Hsueh et al., 2002). Drugs that have been rendered ineffective or for which there are serious concerns include the broad-spectrum antibacterials tetracycline, ampicillin, trimethoprim-sulfamethoxazole chloramphenicol and streptomycin, anti-tuberculosis drugs as well as the antimalarial chloroquine. Resistance to these drugs has promoted an upsurge in the use of previously second-line, more expensive agents that are, in many cases, agents of last resort. The fluoroquinolones and sulfadoxine-pyrimethamine are two such examples, and with both, an upward trend in the proportion of resistant strains has already been identified (Okeke et al., 2000; Winstanley, 2001; Mwansa et al., 2002). Although there are other agents, currently in routine use in

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FIGURE 5-1 Trends in the proportion of Escherichia coli from healthy subjects resistant to three or more and six or more of seven antibacterial drugs. SOURCE: Okeke et al., 2000. industrialized countries, the cost of these precludes their use by poor patients in the developing world. The extent and determinants of microbial resistance vary considerably from one geographic area to another but the current globalization trend means that the consequences transcend geographical borders (Okeke and Edelman, 2001). In some developing countries, unprescribed antibiotic use is relatively uncommon so that antibiotic use and resistance patterns may mirror what is seen in the industrialized world (O’Connor et al., 2001). In others, regulations that would encourage appropriate antibiotic use are in place but the infrastructure or the will to enforce them is not (Djimde et al., 1998; Chuc and Tomson, 1999; Okeke et al., 1999; Chatterjee, 2001; Siringi, 2001). Although there are many generalizations in this report, it must be emphasized that it is impossible to paint a picture of the current situation or draw a model for intervention that would fit every developing country. Examples are taken from different countries, but the principal focus here is on sub-Saharan Africa where the burden of infectious disease is highest and antibiotic use is commonly under-regulated (Djimde et al., 1998; Siringi, 2001). Emergence of Resistance Studies conducted in industrialized countries have correlated antibiotic consumption with the prevalence of antibiotic resistance. Per capita expenditure on antibiotics is lower in developing countries in spite of a greater burden of infectious disease, and microbial resistance is often highly prevalent. Some of the reasons for this are that cheaper agents are used, agricul

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tural and veterinary consumption is often lower, and alternative (or no) therapy is common. However, a significant reason for high selection pressure in the face of modest antimicrobial expenditure is inappropriate antibiotic use. Antibiotic Prescription by Health Professionals Some of the types of antibiotic misuse in clinical practice include unjustified prescription (in such conditions as diarrhea and the common cold), under-prescription (for example, in urinary tract infections and sexually transmitted diseases), under-dosing, and short duration (Calva, 1996; Nizami et al., 1996; Paredes et al., 1996; Bartoloni et al., 1998). Antimicrobial prescription in many developing countries is almost entirely empirical and based on surveillance data obtained from locations or at a time that it is unlikely to be relevant to the ensuing situation. Broad-spectrum agents are frequently employed because susceptibility data is unavailable. In addition, the rising number of HIV-positive people increases selective pressure for resistant organisms by increasing the need for prophylactic and curative antimicrobial use. As in industrialized countries, prescribers are subjected to pressure from patients (Paredes et al., 1996). In addition, health professionals rarely have the opportunity to review cases and are often dealing with life-threatening disease. Hence, antibiotics are often prescribed when unnecessary. Advocates of appropriate antibiotic use advise the prescriber to weigh the benefits to the individual against the risk to public health. This presents a dilemma even to those health professionals that are aware of the long-term consequences of antibiotic abuse. This is because many of the benefits to the individual actually impact public health. For example, the untreated, or improperly treated, but surviving, patient serves as a reservoir of resistant pathogens. Secondly, treatment failures in health centers will lead to lowered confidence by patients and consequent upsurge of visits to unorthodox practitioners, encouraging unsanctioned antibiotic distribution. Since health professionals frequently have only one opportunity to administer therapy, there is the inclination to use broad-spectrum therapy to increase the chances of successful treatment. These factors serve to dissuade health professionals who are aware of the consequences of inappropriate antimicrobial use from putting their knowledge into practice (Larsson et al., 2000). The dilemmas faced by prescribers are further complicated by the practices of patients in developing countries, who are more likely to fail to complete a prescribed course of antibiotics or to admit to reserving part of it for future use (Calva, 1996; Pechere, 2001).

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Multiplicity of Sources Patients in many developing countries will often seek care for the same ailment from multiple sources, a practice that prevents follow-up and confuses case history (Needham et al., 2001). This is a function of the wide variety of sources for antimicrobial drugs and the fact that many of these sources will dispense antibiotics without prescription (Chuc and Tomson, 1999; Wachter et al., 1999). Djimde et al. classified the sources of antimalarials in Malian villages as including sanctioned (physicians, pharmacists, nurses, pharmacy sellers, and midwives) and unsanctioned (stall keepers, itinerant vendors, and tradesmen dealing in clothing, confectionary, cosmetics, and motorcycle parts) (Djimde et al., 1998). The situation is similar in many other developing countries, and pharmacy premises, although sanctioned, often serve as an outlet for unprescribed antibiotics because of the competitive pressure from unsanctioned providers (Chuc and Tomson, 1999; Okeke et al., 1999). Unsanctioned providers tend to have shabbier premises and a smaller range of medicines but they flourish because they are often cheaper due to lower overheads. They are more accessible to the majority of the population than doctors and nurses and will accept a non-physiologic cause of disease. Unfortunately, they may supply poor quality medicines (but these are often dispensed by sanctioned providers) and could serve as an outlet for illicitly sourced drugs. As they often lack basic training on drug handling, they are often unaware or incapable of storing their wares appropriately. They have been known to ignore or are unaware of expiry dates and to mix batches, brands, and even different drugs. They also have limited (if any) clinical training and therefore offer diagnosis and prescription that may be incorrect (Wachter et al., 1999). Antibiotic choice is based on experience, folklore, or customer preference usually in complete disregard of the long-term consequences of antibiotic misuse. These providers supply antimicrobials to a varied but significant proportion of the populaces they serve. They are therefore a crucial target group for optimizing antibiotic use. Antibiotic policies directed at medical services alone will only affect a minority of treatments when unsanctioned persons are major providers. It is however difficult to integrate unsanctioned providers into official policies because they are often technically illegal. Another category of health providers that must be taken into account is the traditional medicine practitioners. In a Malian study 23 percent of rural antimalarial consumers preferred herbs or traditional medicines (Djimde et al., 1998). Indeed, many herbal remedies have demonstrated some antimicrobial activity in vitro, and traditional medicine represents a potential alternative to antibiotic therapy, which could reduce selective pressure to orthodox antibiotics. To date, very few of these natural products have been

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subjected to scientific or clinical evaluation. The majority remain unevaluated and recipes are often held as family secrets akin to a trade secret (Sofowora, 1982). Traditional practitioners receive years or decades of apprenticeship in traditional medicine and herbs but have no training in Western clinical methods. Importantly, one traditional practitioner recently admitted adulterating his concoctions with antibiotics, and the extent to which this practice occurs is not known (Okeke et al., 1999). If traditional practitioners are using Western medicines, there is a need to ensure that they receive appropriate training in diagnosis, treatment, and undesirable effects, including antibiotic resistance. In some developing countries, patients prefer to seek care from sanctioned providers, even though it is available from other sources (O’Connor et al., 2001). In many other countries, unsanctioned and traditional providers are more commonly frequented by the unwell. We have sought to identify reasons why patients seek care from unorthodox sources. In a study designed to determine the health-seeking practices of educated Nigerians, a cohort of university undergraduates was followed for one year. The students were all entitled to free medical care provided by physicians at the University Health Center and drug supply from an attached pharmacy. Within the year, of 43 students who had diarrhea, only 16 percent sought treatment at the health center. Twelve percent did not seek treatment at all but 72 percent resorted to self-medication, at their own expense, even though they could obtain medical care at no cost. Furthermore, 80 percent of the self-medicators took at least one antibacterial medicine and 45 percent took more than one antimicrobial (see Table 5-1). Clearly, factors other than cost and health care availability influence antibiotic misuse. Another relatively affluent population we studied were West Africans resident in Nigeria that had traveled by air to another country. Most of the travelers had visited Europe or North America. Of the 424 travelers to TABLE 5-1 Use of Unprescribed Antibiotics by Students with Diarrhea Antibiotic or combination No. (%) of self-medicated cases Tetracycline alone 7 (22.6) Metronidazole alone 7 (22.6) Pthalyl sulphathiazole alone 3 (9.7) Tetracycline + Metronidazole 10 (32.3) Tetracycline + Pthalyl sulphathiazole 3 (9.7) Tetracycline + Metronidazole + Pthalyl sulphathiazole 1 (3.2) Total taking at least one unprescribed antibiotic 25 (80.6) Loperamide 1 (3.2) Herbals 3 (9.7)

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whom a questionnaire was administered, 52.4 percent traveled with at least one antimalarial and 30.4 percent with at least one antibacterial drug. Only 19.8 percent said that they would visit a doctor or clinic if they fell ill during their travels. The rest preferred to take medicines they had brought with them or obtain medicines from friends (Okeke et al., in press). These findings appear to suggest that the reasons why antibiotics are abused in sub-Saharan Africa are not entirely economic. Working in Zambia, Needham et al. (2001) have identified barriers to tuberculosis diagnosis, which give some insight of factors that lead patients to self-medicate or obtain treatment from unorthodox sources. Significant factors they identified included female sex (p < 0.02) and education (p < 0.04), but not economic or health factors. There was considerable delay in diagnosis if a patient made prior health seeking encounters, particularly to unsanctioned and traditional providers (p < 0.001). Sub-Standard Medicines Even when antibiotic prescription and use is optimal, sub-therapeutic dosing and consequent resistant selection can arise from poor quality antibiotic preparations. A recent survey of tablets claiming to contain the antimalarial Artesunate from Cambodia, Laos, Myanmar, Thailand, and Vietnam found that as many as 38 percent of the samples did not contain the drug (Newton et al., 2001). Multiple reports have described the dispensing of medicines in Nigeria that contain as little as half of their label content (Okeke and Lamikanra, 1995, 2001; Taylor et al., 2001). Some of the medicines are counterfeit—they were intentionally formulated with less than the stated content (Chatterjee, 2001; Newton et al., 2001), but significant proportions contain degraded drugs (Okeke and Lamikanra, 1995, 2001). Degradation of heat- and moisture-labile antibiotics occurs very readily in tropical developing countries where ambient temperatures may approach 40°C and humidity is high enough to distort capsule shells and soften tablets. The packaging of many pharmaceuticals may be insufficient to protect them in tropical developing countries, and in some cases it may be desirable to reformulate them for this environment or modify shelf life recommendations. One rationale for employing uniform shelf lives in temperate and tropical countries is that labels indicate that medicines are to be stored under controlled conditions. Indeed, local regulations usually stipulate that pharmacy premises in the tropics must be air-conditioned. In reality, frequent power cuts may mean that the air is only intermittently conditioned, warehouses and unsanctioned premises are almost never air-conditioned, and imported drugs may languish for many months at ports.

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Dissemination The warm moist climate and close proximity of non-human vectors in tropical countries increase the likelihood that pathogenic and commensal bacteria will survive in the environment and be transmitted to humans (Rosas et al., 1997). In many developing countries, these factors combine with poor sanitation and shortfalls in infection control to create havens for the amplification and dissemination of resistant strains in the community (Graczyk et al., 2001). Overcrowding, a direct consequence of urban migration, increases the chance that this dissemination will occur. The world’s fastest-growing cities are in developing countries, many of which cannot provide potable water or safe sanitation for a majority of their residents (McMichael, 2000). Antibiotic misuse also tends to be more common in crowded areas and may be a feature of urban social change (Bojalil and Calva, 1994; Chuc and Tomson, 1999). Separate studies have suggested that cities serve as havens for the exchange of pathogenic and antibiotic-resistant organisms. In contrast to a Dutch study, which found that there was very little difference in the carriage of E. coli resistant to antibiotics in a rural and an urban area (Bonten et al., 1992), studies in Nigeria and Nepal have demonstrated that urban residents are more likely to harbor resistant bacteria than people residing in rural or provincial areas (Lamikanra and Okeke, 1997; Walson et al., 2001). The capacity of laboratories in developing countries to conduct susceptibility testing and to diagnose infections needs to be strengthened. Not only is resistance surveillance insufficient or lacking, the ability to diagnose many infections and thereby prescribe appropriate and timely treatment is hampered by inadequate laboratory support. In many localities, the extent of the antibiotic resistance problem is not known and empirical antibiotic prescription is akin to guesswork. Similarly, evidence about resistance is of necessity commonly anecdotal. Even if interceptive strategies to control resistance are implemented, there are no local means of measuring the success or otherwise of such policies. Conclusion This report attempts to highlight a number of factors that predispose the emergence and spread of antibiotic resistant organisms in developing countries. Implementation of the World Health Organization’s (WHO) Global Strategy for Containment of Antimicrobial Resistance will potentially address all of these issues (WHO, 2001). Priority should be given to education, 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 insti

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tution of functional and sustainable laboratories for antibiotic resistance surveillance. The real challenge however will be implementing this strategy on a country- and sub-country-specific basis, taking the special features of each developing country into account to ensure sustainability. For example, in some countries, targeting educational intervention at physicians may reduce inappropriate use (O’Connor et al., 2001). In particular, it would be desirable to present incentives for prudent antibiotic use in order to address the gaps between knowledge and practice seen in health professionals and lay-people. In other areas, the approach must be different because of the extensive prescription of antibiotics by unsanctioned providers and patients themselves; antibiotic policies that target orthodox clinical practitioners and premises will have only limited impact. In these cases, policies and interventions that reach unconventional distributors and the patients themselves are more likely to have a broad and sustained effect. Most importantly, interventions will have to be tailored to specific countries and communities since the factors that determine their success will be to a large extent cultural. HEALTHCARE-ACQUIRED INFECTIONS: HOSPITALS AS A BREEDING GROUND FOR ANTIMICROBIAL RESISTANCE Lindsay E. Nicolle, M.D., F.R.C.P.C. Department of Internal Medicine and Medical Microbiology University of Manitoba, Winnipeg, Manitoba, Canada Hospitalized populations are more likely to be colonized or infected with resistant microorganisms compared with community populations (Datta, 1969; McGowan et al., 1974). This association of acute care hospitalization with antimicrobial resistance was recognized soon after the introduction of antimicrobial therapy (McGowan et al., 1975). Widespread outbreaks of penicillin-resistant Staphylococcus aureus in the late 1950s reinforced this observation (LaForce, 1993). Repeatedly, review articles from 20–30 years ago identified the problem and the association of resistance with widespread empiric antimicrobial use (Jackson, 1979; Weinstein and Kabins, 1981; McGowan, 1983). While antimicrobial resistance is more frequent in acute care hospitals, the prevalence of resistance across hospitals is highly variable. Some of this variability mirrors geographic variation in prevalence of resistant organisms. Large hospitals providing tertiary care and teaching hospitals have a higher prevalence of resistance than smaller community hospitals and have repeatedly been the site where new resistance is first described. This is the experience of methicillin-resistant Staphylococcus aureus (MRSA) emer

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gence in U.S. hospitals (Haley et al., 1982), and was repeated in the 1990s with the emergence of vancomycin resistant enterococci (VRE) (Fridkin et al., 2001). Determinants of Resistance The high prevalence of antimicrobial resistance in acute care facilities, and repeated emergence of new resistance, is attributable to both patient and facility characteristics (see Table 5-2). Persons at highest risk of acquiring infection are found in hospitals. These include patients at extremes of age with biologically impaired immune systems, such as premature neonates and the very old. Other patients have acquired immunodeficiency, which is often therapeutically induced. These include the increasing numbers of solid organ and bone marrow transplant patients and profoundly neutropenic patients, as well as patients with severe trauma or extensive burns. These highest risk patients are primarily cared for in large, tertiary care, teaching hospitals. Hospitalized patients experience repeated interventions for monitoring or therapy which further impair normal host defenses and increase the risk of infection. Indwelling urethral catheters, central vascular lines, endotracheal tubes, and surgical wounds permit access of microorganisms to normally sterile body sites. Recent evolution in health care delivery with shortened hospital stay and increased patient acuity means patients now hospitalized are at even greater risk for infection. TABLE 5-2 Variables Which Promote the Emergence and High Prevalence of Resistant Organisms in Acute Care Facilities Patient variables Inherent immunocompromised status e.g., neonate, very old Acquired immunocompromised status e.g., transplant patients, profound neutropenia, extensive burns Therapeutic interventions which compromise normal defenses e.g., indwelling urethral catheters, central lines, endotracheal tubes, surgical procedures Intense antimicrobial use Systemic: 30–50% of patients • Therapeutic • Prophylactic Topical use Institutionalization Increased opportunities for transmission • Shared equipment • Shared staff • Airborne

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States in 2000, the food animal population totals were 8.4 billion chickens, 97 million cattle, and 98 million pigs. In order to raise this quantity of animals in today’s commercial livestock and poultry operations, efficiencies of scale include grouping hundreds to tens of thousands of animals together on a single farm. This necessitates the application of herd health measures, applied on a population basis, to maintain a high level of herd (or flock) health status, since an epidemic disease outbreak would decimate the population. Measures such as vaccination, limited commingling, adequate ventilation and temperature controls for minimizing environmental extremes, biosecurity, appropriate nutrition and housing, and producer quality assurance programs and practices are currently used in modern agriculture. However, these measures are not always sufficient to prevent or control disease. The use of antimicrobial agents as a strategic tool to maintain animal health remains an essential component of today’s food animal production system. Antimicrobial agents are used in food animal production to prevent disease in high-risk animals and to control or treat disease; or to improve the ability of the animal to convert feed to muscle. Unlike the situation in human medicine where individual patients can be treated, food animal medicine is often practiced on a population basis for reasons of animal welfare, logistics, and efficiency since it is impractical to individually treat each animal in a group that consists of hundreds to tens of thousands. Herd health medicine also relies heavily on preventive medicine strategies to control or prevent disease in high risk populations. Addition of antimicrobial agents to feedstuffs, or by water, or parenteral administration to groups of animals by injection to prevent or control disease progression is done strategically when certain criteria are met. These criteria include prior experience of a disease outbreak associated with animal movement or weather extremes, or a noticeable increase in clinical signs of disease in a few animals in the group. This early therapeutic administration to the entire group is warranted, since many animals will have been exposed to the index cases and are now “incubating” the pathogens. Left untreated, as time elapses, more animals will “break” with clinical signs. Strategic application of an antimicrobial agent at the right time can minimize the pathogen load within a sufficient number of animals in the group (by allowing the host immune defenses to control the infection) and ultimately restore the group to an acceptable health status. Thus, preventive medicine, as a part of a herd health program, is in some cases the best way to maintain healthy animals. It is not appropriate to allow the majority of animals to suffer or die unnecessarily before beginning treatment (which is likely to fail at that late stage of the disease course). Many critics of this well-established practice incorrectly refer to the administration of “subtherapeutic” doses of antimicrobial agents in this instance, when in fact, the doses were developed to be

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therapeutic for those animals exhibiting signs of disease and are sufficient to benefit those animals that are incubating the pathogen and would soon break with disease. Routine administration of antimicrobials to healthy animals, with the intention of doing so as “insurance” or to “cover” poor management or hygiene is not a practice used by the leading production companies because it would be expensive, unsuccessful, and an unsustainable method of animal production. The administration of antimicrobials to enhance performance or growth of the animals may reflect the intention of the producer, but frequently the antimicrobial agents are in reality controlling an unrecognized subclinical disease exposure in the animals. With respect to specific animal species, the use of antimicrobial agents is quite diverse (GAO, 1999; NRC, 1999; Prescott et al., 2000; Muirhead, 2001). Most poultry production requires the use of ionophores to prevent coccidia (intestinal parasites) infections, which otherwise would devastate a flock. Some antibiotics are administered at hatching, to reduce the prevalence and/or severity of infections that occur in day-old chicks due to vaccination stress on the immature immune system. In poultry house situations, rapid onset of respiratory or enteric diseases requires that antimicrobial agents be administered at the earliest opportunity to prevent significant morbidity and mortality in the flock. For the most part, poultry are medicated via feed or water because it would be impractical to individually treat thousands or tens of thousands of birds. Swine production can be divided into several stages from gestation, to farrowing, to nursery, to grower and finisher. Each stage has its own unique needs for antimicrobial usage, but in particular respiratory disease and enteric disease can frequently spread rapidly throughout a herd and require antimicrobial intervention. Thus strategically timed oral medications in groups of high risk pigs to prevent disease at times of movement, high stress, or waning maternal antibody may be needed. Injectable products are used when needed for therapy to individual sick sentinel pigs of the herd, that is, those showing the most and earliest clinical signs. Beef cattle that are affected by respiratory disease are usually treated with injectable antibiotics. Liver abscesses, coccidiosis and metabolic diseases are also common in feedlot cattle and are prevented or controlled by administration of antimicrobial agents in feed (Nagaraja et al., 1996; McGuffey et al., 2001; Muirhead, 2001). Infections in dairy cattle are usually cases of mastitis which are treated in acute cases or at “dry off” by intramammary infusion of antimicrobial agents. The use of antimicrobial agents in aquaculture is minimal (only tetracycline and a sulfa are approved), with applications done only in certain situations via medicated feed. The antimicrobial agents that are used in food animal production are similar to those used in human medicine, but with several key exceptions (GAO, 1999). The Food and Drug Administration (FDA) or their equiva

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lent in other countries has approved all of these products for use after a thorough review of the drug manufacturers’ data that demonstrate efficacy, safety, and quality of the medicinal product. The common classes of antibiotics used in both humans and animals are: beta-lactams (including cephalosporins), tetracyclines, macrolides, aminoglycosides, lincosamides, sulfonamides, streptogramins, and fluoroquinolones. Examples of compounds not used (or minimally used) in humans, but important in food animals include: ionophores, avilamycin, bacitracin, carbadox, flavomycin, and pleuormutilins. It should be noted that some antimicrobial agents such as chloramphenicol and vancomycin are banned from use in food animals in the United States and other countries (Payne et al., 1999). Some of the antimicrobial agents used in food animals are approved for delivery by both a parenteral and an oral route, but in many cases only a feed administration route is approved and/or feasible for a variety of reasons. A detailed compendium of the technical aspects of feed additives is available (Muirhead, 2001). The actual amount of antimicrobials distributed by manufacturers in the U.S. animal sector has been reported (but doesn’t include the amount of generic products distributed) (Muirhead, 2002). Of the total amount of 10,936 tons of active antimicrobials reported sold in 2001, 35 percent was classified as ionophore/arsenical, 33 percent was tetracycline, and 18 tons (<1 percent) was fluoroquinolone. Overall, 83 percent of the total was used for disease and 17 percent used for performance improvement. A separate estimation of U.S. usage, based on many assumptions, was calculated to be 12,300 tons just for a non-traditionally defined designation of “non-therapeutic” uses (Mellon et al., 2001). Antimicrobial use in food animals has been a subject of discussion for over 30 years. A large number of reports, conferences, meetings, research studies and other communications have been produced. It is outside the scope of this short paper to review all of the key literature on this subject; however, a number of recent reviews and reports are provided for further information (IOM, 1998; Bezoen et al., 1999; Commonwealth of Australia Government, 1999; GAO, 1999; Barton, 2000). The primary concern has been that the use of antimicrobial agents in food animals will select for resistance to those agents in intestinal bacteria, and via foodborne transmission, an infection in humans will develop that is untreatable. A newer variation on this theme has been that foodborne commensal bacteria might transfer their resistance genes to existing susceptible normal human flora, and thereby set the stage for a non-treatable infection at a later time in the person’s life. The bacteria at issue are limited to salmonella, campylobacter and enterococci, and vary with the animal species. Additional areas of concern include environmental contamination with excreted antimicrobials or their metabolites; residue concentrations of antimicrobials in edible tissues; and direct zoonotic transmission.

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Some antimicrobial classes and routes of administration generate more concern than others. For example fluoroquinolone water medication use in poultry has resulted in a Notice of Opportunity for Hearing for the sponsor from the FDA, but the use of an injectable fluoroquinolone in cattle has not. In Europe, use of fluoroquinolones in animals is not considered to put human health at undue risk, but should be monitored (WHO, 1998; CVMP, 2001). Feed additive uses for efficiency claims and disease prevention have also come under scrutiny by some government officials, physicians, microbiologists, and others. The antimicrobial agents involved primarily include tetracyclines, beta-lactams, sulfonamides, macrolides, lincosamides, streptogramins, and bacitracin. The European Union Commission has legislatively removed the efficiency claim authorizations of several antimicrobial agents, and plans to remove the authorizations for the remaining agents in a few years. In the United States, the Center for Veterinary Medicine (CVM) is conducting a risk assessment on E. faecium and virginiamycin use. Since foodborne bacterial transmission is an essential component of the issue, it represents a critical control point for ensuring food safety from all pathogens, not just those with antibiotic resistance genes. If one looked at a short list of the chain of events that are needed to “go wrong” in order for an antibiotic-resistant foodborne disease to result in an adverse outcome for a typical patient, it would include the following: Antibiotic-resistant bacteria are present in a particular group of animals. Selection of pre-existing strain with resistance gene(s) or a resistance mutation in the presence of an antibiotic. Strain maintains itself in the presence of other gut flora until slaughter (with or without continued antibiotic selection pressure). Fecal contamination of the carcass occurs during processing leaving bacteria on the meat. Carcass decontamination measures are ineffective or incomplete. Food product processing, shipment, or storage may result in the growth of the contaminating bacteria. Cooking at an inadequate temperature and duration fails to kill the bacteria or the food is recontaminated after cooking by improper handling. Human consumption of food results in resistant bacterial colonization or infection. Infection severity requires physician care or hospitalization; antibiotic prescribed that is of the same class as was used on the farm. Clinical resolution of infection may not be as rapid or complete as with a susceptible strain; culture and susceptibility testing in lab compel change in antibiotic.

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Outcome is that the treatment period is prolonged or the patient may possibly die. It should be obvious that not all foodborne bacteria are antibiotic-resistant. Each stage of the chain of events represents a decrease in the total number of “chances” for something to “go wrong” in the subsequent stage. For example, at step 7 only improperly cooked or recontaminated food is likely to result in cases of foodborne disease. Of the fraction of people exposed in step 7, not all will get sick in step 8. In essence, this is the type of rationale that comprises a risk assessment. One could use this approach to identify key steps to direct interventions to minimize bacterial transfer or impact from all foodborne pathogens, not just those with antibiotic resistance genes. Thus the central issue is not whether antibiotic use in food animals can select for resistance in particular types of bacteria which can then cause foodborne disease in people that is more difficult to treat. The real issue is what is the frequency at which this occurs and to what extent should resources be used to intervene? In other words, should 50 percent of the available resources be directed to the use of antibiotics in food animals if the “resistance contribution” is 5 percent? Many intervention recommendations have already been made (and are currently in the implementation phase) to minimize the contribution of food animal antibiotic use to the overall concern in human medicine. Additional reports with such guidance are cited here for reference (WHO, 2000; OIE, 2001; Torrence, 2001; U.S. Government, 2001; FDA, 2002a; FDA, 2002b). In general, the following themes can be found across these reports: Risk assessment. This approach seeks to objectively evaluate the likelihood of an adverse effect through hazard identification, hazard characterization, exposure assessment, and risk characterization; and could potentially be used predictively to evaluate the effect of proposed intervention strategies as a part of the risk management phase. Reduction in antibiotic usage. This approach seeks to reduce the need to use antibiotics by emphasizing improved hygiene, vaccination, housing, etc., in an effort to avoid disease outbreaks in the first place. In some recommendations, elimination of certain antibiotics or uses is advocated. Rational or responsible antibiotic use. The development and implementation of a series of guidelines to veterinarians and other animal care specialists on the proper use of antibiotics is strongly advocated. Indeed, many veterinary organizations have already done so and producers are now incorporating them into their quality assurance programs. Regulatory reform to address resistance. Regulatory reform is ongoing in the United States, the European Union, Australia, and many other coun

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tries with respect to the requirements that antibiotic manufacturers will have to meet in order to maintain their products or have new ones approved. Resistance and usage monitoring. Monitoring of foodborne pathogens, principally campylobacter, salmonella and E. coli, and the “indicator” E. faecium for changes in antibiotic susceptibility patterns is ongoing in many countries, although test methods, isolate collection schemes, etc., are not optimal or consistent. Monitoring of the quantities of drug usage to assess reduction in antibiotice use is done in several small countries, and is being done on a self-reporting basis by the veterinary pharmaceutical industry in the United States and the European Union. In conclusion, the use of antibiotics in food animals is essential to maintain a consistent supply of healthy animals entering the food chain. Although some antibiotic-resistant foodborne bacteria do make their way through the food chain to cause disease in consumers, the magnitude and clinical impact of that event remains unclear. In the larger context of human antibiotic resistance, antibiotic-resistant foodborne bacteria are a minor component compared to hospital- and community-acquired infections and antibiotic use. Nevertheless, the food animal production sector is doing its part to minimize antibiotic resistance by participating in the five activities above while continuing to deliver a safe, abundant food supply to the nation. In response to this paper, “The Use of Antimicrobials in Food-Producing Animals,” a paper was prepared to address the public health consequences of antimicrobials in agriculture and can be found in Appendix A. REFERENCES Alford RH and Hall A.1987. Epidemiology of infections caused by gentamicin-resistant Enterobacteriaeceae and Pseudomonas aeruginosa over 15 years at the Nashville Veteran’s Administration Medical Center. Reviews of Infectious Diseases9:1079–1086. Austin DJ and Anderson RM. 1999. Transmission dynamics of epidemic methicillin-resistant Staphylococcus aureus and vancomycin resistant Enterococcus in England and Wales. Journal of Infectious Diseases179:883–891. Bartoloni A, Cutts F, Leoni S, Austin CC, Mantella A, Guglielmetti P, Roselli M, Salazar E, Paradisi F. 1998. Patterns of antimicrobial use and antimicrobial resistance among healthy children in Bolivia. Tropical Medicine and International Health3:116–123. Barton MD. 2000. Antibiotic use in animal feed and its impact on human health. Nutrition Research Reviews13:279–299. Bezoen A, van Haren W, Hanekamp JC. 1999. Emergence of a Debate: AGPs and Public Health Human Health and Antibiotic Growth Promoters (AGPs): Reassessing the Ris k. [Online]. Available: http://www.euronet.nl/~ssf/hanagp1.html. Bojalil R and Calva JJ. 1994. Antibiotic misuse in diarrhea. A household survey in a Mexican community. Journal of Clinical Epidemiology47:147–156.

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