1
Drugs Used in Food Animals: Background and Perspectives

Today’s society challenges the industries that make goods and products purchased by consumers to be open and accountable in their practices. Failure to do so raises questions, concerns, and, ultimately, fears about the decision-making processes that affect public health and public confidence. Public education and mass media communication has led the public to object to practices it perceives as threatening to human health. With a vast amount of data and rapid access to it (for example, through the Internet), some health professionals and consumers are asking legitimate questions about issues that range from environmental pollution to microwave radiation from recreational electronic devices. Agriculture and its food production practices are not immune to public scrutiny. On the one hand, consumers want a wide variety of products at reasonable prices. On the other hand, they demand safe, wholesome, and nutritious food products, and they question agricultural practices that are intended only to increase productivity and economic return for the farm.

In current agricultural practice, raising animals for food depends heavily on the use of pharmacologically active compounds: drugs. The use of drugs in food animals is fundamental to animal health and well-being and to the economics of the industry. However, drug use also is associated with human health effects.

There are five major classes of drugs used in food animals: (1) topical antiseptics, bactericides, and fungicides used to treat surface skin or hoof infections, cuts, and abrasions; (2) ionophores, which alter rumen microorganisms to provide more favorable and efficient energy substrates from bacterial conversion of feed and to impart some degree of protection against some parasites; (3) steroid anabolic growth promoters (whose mechanism of action resides in the interaction



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The Use of Drugs in Food Animals: Benefits and Risks 1 Drugs Used in Food Animals: Background and Perspectives Today’s society challenges the industries that make goods and products purchased by consumers to be open and accountable in their practices. Failure to do so raises questions, concerns, and, ultimately, fears about the decision-making processes that affect public health and public confidence. Public education and mass media communication has led the public to object to practices it perceives as threatening to human health. With a vast amount of data and rapid access to it (for example, through the Internet), some health professionals and consumers are asking legitimate questions about issues that range from environmental pollution to microwave radiation from recreational electronic devices. Agriculture and its food production practices are not immune to public scrutiny. On the one hand, consumers want a wide variety of products at reasonable prices. On the other hand, they demand safe, wholesome, and nutritious food products, and they question agricultural practices that are intended only to increase productivity and economic return for the farm. In current agricultural practice, raising animals for food depends heavily on the use of pharmacologically active compounds: drugs. The use of drugs in food animals is fundamental to animal health and well-being and to the economics of the industry. However, drug use also is associated with human health effects. There are five major classes of drugs used in food animals: (1) topical antiseptics, bactericides, and fungicides used to treat surface skin or hoof infections, cuts, and abrasions; (2) ionophores, which alter rumen microorganisms to provide more favorable and efficient energy substrates from bacterial conversion of feed and to impart some degree of protection against some parasites; (3) steroid anabolic growth promoters (whose mechanism of action resides in the interaction

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The Use of Drugs in Food Animals: Benefits and Risks of estrogen-, progesterone-, or testosterone-like compounds with specific classes of hormone receptors in animal cells) and peptide production enhancers (recombinant bovine somatotropin for increased milk production in dairy cows); (4) antiparasite drugs; and (5) antibiotics as used to control overt and occult diseases, and to promote growth. There are other drugs that modify the gastrointestinal environment to reduce the likelihood of rumen foaming and bloat in cattle, organic and inorganic water treatments that reduce the chances for water or fish infection in aquaculture, and miscellaneous drugs and compounds used with the advice of veterinarians to treat specific conditions. There are different ways to view the issue of how animal drug use affects health. Reported benefits are derived largely from the maintenance of good animal health, which lowers the chance that disease will spread to humans from animals. However, drugs used in food-animal production and drug residues in food products could increase the risk of ill health in persons who consume products from treated animals. The use of one class of drugs, antibiotics, could contribute to the emergence of antibiotic-resistant microorganisms in animals that could be transmitted to humans, causing infections that could be difficult to treat. The public has been concerned about the use of drugs in food animals for a long time. For example, in 1987, three out of five consumers viewed antibiotics in poultry and livestock as a serious health hazard, and an additional one-third of the people asked had some degree of concern about the hazard (Scroggins 1988). Using an historical database derived from frequency of specific topics in news articles and the amount of media attention paid to food safety between 1937 and 1991, the Economic Research Service (ERS) of the United States Department of Agriculture (USDA) reported that concern about pathogens in food was the issue most frequently cited (ERS 1994). The issue was of greater concern than others, including the effects of excess consumption of a food product, pesticide residues, toxic-waste residues, animal hormones, and “unsafe practices.” THE ROLE OF THIS REPORT The U.S. Congress instructed USDA, through authorizing legislation in the 1990 Farm Bill, to commission a study by the National Academy of Sciences to summarize use of drugs in food-animal production, the practices used to administer these drugs to animals, and the processes for monitoring the drug use and residues in the food chain. In 1992, with funding support from USDA, the Center for Veterinary Medicine of the Food and Drug Administration (FDA), the Pew Charitable Trust, the American Veterinary Medical Association, and the American Feed Industry Association, the National Research Council (NRC) established the Panel on Animal Health, Food Safety, and Public Health under the joint auspices of the Board on Agriculture and the Institute of Medicine’s (IOM) Food and Nutrition Board. The panel convened the Committee on Drug Use in Food

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The Use of Drugs in Food Animals: Benefits and Risks Animals. The committee was composed of private, public, and institutional stakeholders and experts in agriculture, veterinary medicine, human medicine, epidemiology, and economics. It was responsible for developing a strategy to identify the risks and benefits associated with the use of pharmaceutical products in food animals and for providing a report on these issues that included the following: Review of the role and uses of drugs in food-animal production. Summary of mechanisms of drug availability, accountability, and monitoring. Summary, evaluation, and progress report of the regulatory approval process for animal drug use. Summary of data regarding the effects of drug use in food animals on human health. Summary of mechanisms of antibiotic availability, accountability, and monitoring. Identification of emerging trends and technologies in food-animal production, and alternatives to antibiotic-drug use in food animals. Recommendations for research needs and priorities in animal health and drug use. Recommendations regarding antibiotic use, availability, and accountability and a strategy for the future. The issues surrounding the benefits and risks to human health attendant to the use of drugs, particularly antibiotics, in food animals have been the focus of many reports. The committee was faced with assessing risk for a large number of drugs and compounds in food-producing animals and with evaluating drug use and availability, accountability, and regulatory approval. To help accomplish the task, the committee conducted a review of the scientific literature to identify sources of problems. A search of scientific databases (AGRICOLA, maintained through the USDA National Agriculture Library, Beltsville, Maryland, 1970 to present; BIOSIS, Biological Abstracts, Inc., Philadelphia, Pennsylvania, 1980 to present) revealed that citations focused on antibiotic resistance to human health outnumbered by almost ten-to-one those related to drug and chemical residues and their effect on human health. For example, within these categories, 1,649 papers were published on antibiotic residues, topical antiseptics, steroid and nonsteroid growth promoters, antiparasitic drugs, animal-directed chlorinated hydrocarbons, sulfa drugs, and arsenical compounds as follows: (AGRICOLA) 585, 3, 110, 8, 48, 7, and 29, respectively; (BIOSIS) 490, 3, 90, 77, 51, 15, and 33, respectively. In contrast, there were 5,755 cited papers in BIOSIS that concerned antibiotic resistance and human health. These results strongly suggest that the greater public health concern with regard to drugs and health risk clearly resides with the use of antibiotics.

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The Use of Drugs in Food Animals: Benefits and Risks The committee also heard testimony on issues related to animal drug use, and it reviewed federal regulations that provide guidelines and list mandatory practices for drug use, monitoring capabilities for drugs and residues in foods, veterinary oversight in prescription drug use, rates of violations and incidences of documented human health problems. The committee concluded that most drugs and drug residues in animal-derived foods pose a relatively low risk to the general public when the drugs are used in a responsible manner consistent with labeling instructions. However, there were mixed concerns about the overall consequences of antibiotic use in food animals. These concerns were centered in conflicting data and views on the influence of antibiotic use on human health, the consequences of their use on animal health, and the economics of food animal production. Health experts expressed concern that animal and human health would be challenged in the future by a growing shortage of antibiotics to treat emerging pathogens that have acquired resistance to the killing effects of many antibiotics in common use today. After a brief overview of general practices of drug use in food animal agriculture, a summary of the processes through which drugs are approved and made available for use in animals, and a review of the drug residue-monitoring process, the report focuses mainly on the issue of antibiotic drug use in food animals. In later chapters, the potential economic effects of reducing use or banning some antibiotics are presented and alternative management practices to reduce the use of antibiotics in food-animal production are reviewed. REVIEW OF PREVIOUS REPORTS Major reports issued on antibiotic drug use in food animals and related topics have been somewhat inconclusive in their findings or are currently outdated. It has been 30 years since the Swann Committee Report (Swann 1969), 17 years since the Council on Agriculture and Science Technology (CAST) report (CAST 1981), and almost 10 years since the IOM report (IOM 1989). For one reason or another, the basic answer to the question of human health consequences of antibiotic drug use in food animals is still not known for certain. A summary of these and other reports is presented in Table 1–1. The Swann report recommended a ban on the subtherapeutic1 use of antibiotics in food-producing animals. The results of implementing the Swann report recommendations (where the definition of antibiotic class uses was established along with many of the subtherapeutic applications) on human health and antibiotic resistance (reviewed later in this report) are questionable (Dupont and Steel 1987). There does not appear to be any overall reduction in the rate of emergence of 1   Subtherapeutic concentration of antibiotics in the United States is defined as an amount added to feed at a concentration of <200 g/t (NRC 1980, IOM 1989).

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The Use of Drugs in Food Animals: Benefits and Risks TABLE 1–1 Summary of Previous Major Reports on Food-Animal Antibiotics Title Source Date Recommendation The Report to Parliament by the joint Committee on Antibiotic Uses in Animal Husbandry and Veterinary Medicine English Parliament 1969 Reclassification and use restriction of antibiotics into therapeutic (prescription) and nonprescription feed additives. Nutritional use banned. The Effects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds National Research Council 1980 “… literature … is insufficient for assessing the direct relationship between the use of subtherapeutic levels of antimicrobials in animal feeds and the health of humans.” “… data gathered in the U.K., Germany and the Netherlands do not indicate clearly [that the restrictions placed on these uses in these countries] reduced or averted the postulated hazards to human health.” Antibiotics in Animal Feeds Council for Agricultural Science & Technology, Report 88 1981 “Studies of long-term administration of antibiotics to humans indicate that infections due to bacteria resistant to antibiotics are dose-related. The literature reviewed showed no such infections with subtherapeutic dosages, but occasional infection with therapeutic doses. Thus it would be irrational to ban subtherapeutic use … without also banning therapeutic use.”

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The Use of Drugs in Food Animals: Benefits and Risks Human Health Risks with the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed Institute of Medicine 1989 Results demonstrate the selection for resistance to develop with the use of antibiotics on the farm in therapeutic and nontherapeutic dose applications. “[T]he committee was unable to find a substantial body of direct evidence that established the existence of a definite human health hazard in the use of subtherapeutic concentrations of penicillins and tetracyclines in animal feeds.” Likeliest estimates for mortality were formulated. The Medical Impact of the Use of Antimicrobials in Food Animals World Health Organization 1997 “The use of any antimicrobial agent for growth promotion in animals should be terminated if it is used in human therapeutics or known to select for cross-resistance to antimicrobials used in human medicine.”   Sources: Swann, 1969; NRC, 1980; CAST, 1981; IOM, 1989; WHO, 1997.

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The Use of Drugs in Food Animals: Benefits and Risks antibiotic resistance in the United Kingdom from the banning of subtherapeutic use of antibiotics. However, Wegener (Muirhead 1998), in a report to FDA, suggested that, in some European countries, there could be a decline in the occurrence of specific antibiotic resistance (vancomycin-like resistance) in chickens and humans attendant to the ban on avoparcin (a related antibiotic). Critics of the Swann report cite problems that could help explain the continued persistence of resistance after the ban on subtherapeutic antibiotic use in food animals. Some argue that the recommendations were not systematically and uniformly implemented as intended, and that instances of failure to comply with the recommendations allowed the rates of resistance emergence to continue. Others contend that the real problem resides in the therapeutic use of antibiotics in animals and that, unless there is a total ban on antibiotics in food animals, there will be no reduction in the emergence of resistance. Still others argue that effects do occur, but the use of antibiotics in food animals is largely insignificant in terms of their consequences for human health. The 1981 CAST report suggested that problems could be identified with the use of antibiotics in food animals (such as resistance development and zoonotic disease transfer in general), but the problems had so little effect on human health (the number of reported clinical cases versus the number of food animals in which antibiotics were used) that they were largely insignificant. The 1989 IOM report focused on the human health risks of penicillin and tetracyclines used subtherapeutically in animal feed. Several cases of human illness attributable to antibiotic-resistant pathogens that originated in livestock receiving antibiotics were discussed. However, the IOM (1989) committee could find no direct evidence to link subtherapeutic use of antibiotics to a definite human hazard. The report made some mathematical predictions of impact of human health consequences. Its model relied on several assumptions, and the committee that drafted the report readily acknowledged that estimates derived from these assumptions could be further refined, but that relevant data needed to be compiled to accomplish this task. In 1997 the World Health Organization (WHO) released findings that focused on the subtherapeutic use of antibiotics. Based on the report, WHO concluded that resistance to animal microbes arising from the subtherapeutic use of antibiotics is a high-priority issue. WHO would phase out the subtherapeutic use of antibiotics, particularly those used to treat humans, in food animals. The present report updates relevant information on the following three issues: (1) patterns of antibiotic use in food animals, (2) mechanisms underlying antibiotic resistance in bacteria, and (3) differentiation of relevant data from opinions that support or refute perceptions of health risks associated with the use of antibiotics in animals as well as particular aspects of antibiotic use in humans. It is important to cite both the data and the gaps in the data that limit a science-driven conclusion regarding the human health effects of antibiotic use in animals. Few projections are made in this report on human health consequences, largely

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The Use of Drugs in Food Animals: Benefits and Risks because such projections require the further use of extrapolations and assumptions, still might not answer the question, and could be used out of context. The report makes recommendations that should facilitate the collection and correlation of relevant data that can be accessed by all stakeholders to formulate decision-making policies based on good science and relevant statistics. THE ANTIBIOTIC ISSUE Antibiotics are used in food animals for treatment or prevention of disease and for increased production performance or increased efficiency of use of feed consumed by the animal for growth, product output, or modifying the nutrient composition of an animal product. Many times the drugs that improve the health of animals also enhance their growth and production performance because an animal can reduce that portion of the nutrition requirement associated with fighting subclinical diseases and bolstering health defense processes, thereby enhancing the portion of nutrients available for growth and production. Furthermore, there are uses for antibiotics to increase the growth response of animals that are apparently not related to their mechanism of action as drugs that can kill pathogens. The idea that medical discoveries will defeat whatever threat is posed to animals and humans by infectious pathogens and microorganisms is often taken for granted. Decisions on courses of action are made to obtain outcomes that are beneficial to public health, but the perceived benefits of some decisions often are obscure and in conflict with the priorities of others. The present report stems from concerns—expressed by professionals in human and animal health care, producers of food animals, and segments of the general population—regarding the beneficial and detrimental effects of using antibiotics in food-animal production. The consumables obtained from food-producing animals anchor much of the base of human protein requirements and the needs for other macro- and micronutrients in the United States and many parts of the developed world (NRC 1988). At the heart of the issue are opposing views on the appropriateness of antibiotic drug use in food-animal production. Legitimate questions about the practice are being raised by all sides. Concerns cover a wide spectrum, ranging from the concern that antibiotic use is too permissive to the concern that food production is in jeopardy if drug use in food animals is restricted. Many of the questions regarding this issue are not new, they have been raised before, and they remain largely unanswerable because of the difficulties associated with valid data collection, experimental designs that are nearly impossible to control, and the continuum of microbial adaptation that forces scientists to try to stay apace rather than address future needs.

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The Use of Drugs in Food Animals: Benefits and Risks A Possible Scenario A dairy farmer has worked for years breeding cattle to achieve the best genetics he can to obtain high-quality milk. A prize calf of the farmer is sick with a bacterial infection and is not responding to any of the traditional treatment strategies of the veterinarian. Elsewhere, a man’s immune system is weakened during treatment for a rare form of cancer. His susceptibility to infections is high. Unfortunately, the man has contracted a bacterial infection that must be controlled by antibiotics. The infection is initially unresponsive to “traditional” antibiotics; however, through culture and sensitivity testing, a new-generation antibiotic is found that will ensure the man’s longevity. For the farmer, such resources might not be readily available to save the calf, and questions arise as to whether all appropriate measures were taken to prevent the transmission of the organism to other animals on the farm or to the farmer himself. Questions regarding the appropriateness of antibiotic use in food-animal production and the risks and benefits to human health cannot and will not be answered soon. The issue might be too complex for experimental and epidemiological investigators to generate unbiased study results. Furthermore, some aspects of the research are so expensive that asking who should fund them is a valid question in itself. The data needed to address the issue are sparse, although more aggressive measures for reporting, tracking, and characterizing infections are being used. The lack of appropriate data and the extrapolation of poorly validated data sometimes allow illogical conclusions to be drawn, resulting in fears and demands for regulation that are not founded on scientific information. The Emergence of Antibiotics in Our Lives Throughout human history, people have sought remedies for their own ills and those of their animals. Largely through trial and error, and with no knowledge of the biological and biochemical processes at work, people developed herbal and folk remedies that used plants, plant extracts, and fermented food or beverages to relieve their ailments (Florey 1945; Brumfitt and Hamilton-Miller 1988). For example, one German folk treatment was to use the schaum or foam from the top of the fermenting vat of sauerkraut, as a drink to relieve pulmonary ailments. Most likely, what was consumed was a broth of penicillin, from the growth of penicillium mold that was effective against an organism causing bacterial pneumonia. The revelation that many diseases were transmitted by bacteria and microorganisms provided an observable explanation for many forms of disease. Serendipity and observation of biological phenomena provided early clues that the presence of some microorganisms prevented the presence or growth of others (Florey 1945; Fleming 1950). The middle decades of the twentieth century were an exciting time in human and animal medicine because of the scientific processes and new technologies

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The Use of Drugs in Food Animals: Benefits and Risks applied to antibiotics and the increased appreciation for their mechanisms of action. Not long after the introduction and widespread use of antibiotics such as penicillin, the realization came that these drugs might not be effective in all situations forever. The term “resistant” came into use to describe classes of bacteria against which an antibiotic was used effectively for some time but became ineffective. Derivatives of classic antibiotics, developed by chemists, provided a quick short-term solution to the resistance problem. Subsequently, bacteria were shown to adapt to these drug-related selection pressures and acquire resistance to multiple classes of drugs. Researchers in human medicine were not alone in their efforts to exploit the biochemical properties of antibiotics, and the veterinary community soon realized the benefits of using antibiotics to treat diseases in animals. From the 1940s through the 1950s, several reports in the peer-reviewed scientific literature clearly showed that the growth and productivity of animals intended for food were improved with the continuous use of antibiotics. The first true antibiotic with reported efficacy was streptomycin, followed soon after with tetracycline, chlortetracycline, penicillin, and bacitracin (CAST 1981). With the improved health and productivity of farm animals, intensive production practices were developed that allowed food-animal producers to operate more efficiently, as animals were raised more and more frequently in protected, albeit confined, quarters the year around. However, the added intensity and confinement have been partnered with the greater use of low concentrations of antibiotics to prevent or limit disease (CAST 1981; Roura et al. 1992) because of the somewhat higher incidences of naturally occurring diseases, such as respiratory infections in calves and chickens, and because of immune challenge in general. Research on the benefits of antibiotic use in animal feeds, as a disease prevention measure, demonstrated that the effects of these drugs were greater and more apparent in herds with few or no disease control measures (as reviewed by Zimmerman 1986). The higher incidences were not viewed as a problem, however, because continuous, low-concentration antibiotic use was found to maintain or restore the health of animals. As such, the economics of food-animal production depended on antibiotic and antimicrobial drug use in common animal production practices that facilitated the affordable, plentiful supply of meat and eggs, providing the quality, nutrition, and safety that consumers desired. Less than a decade after the first antibiotics were approved by the FDA for use in livestock (feed applications for enhanced production), concerns arose about the effects of this practice on human health. Initially, concern focused on the issues of antibiotic residues (the drugs themselves or metabolized degradation products of parent drugs) in the food supply and the potential for human pathogens to acquire the antibiotic resistance of animal pathogens. Subsequently, the focus shifted from residues to concerns for human health—specifically to the resistance to antibiotics developed by bacteria that were exposed to the drug in the animal, and survived.

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The Use of Drugs in Food Animals: Benefits and Risks Concern for the consequences of antibiotic resistance in animal agriculture on human health stems not only from what is known about the relationship but also from fear about what is not known. Given some limited facts, authoritative opinions, and some projections on possible—although not necessarily probable—biological events, scenarios can be quickly woven to paint a bleak picture of the future. Consumer interest in this sensationalism was reflected in the summary of popular literature coverage on the topic of antibiotic resistance between 1950 and 1994 in the Office of Technology Assessment (OTA) review of antibiotic resistance (OTA 1995). The OTA report correctly pointed out how synthesized scenarios (in which one is led from the initial use of an antibiotic on the farm, through the development of a resistant Escherichia coli, to the development of drug-resistant Salmonella by coliform plasmid transfer, to the farmer dying of drug-resistant salmonellosis) are questionably founded in reality. A comparison of the number of human disease cases confirmed as acquired from animals harboring infectious pathogens and the number of disease cases acquired in hospitals, hints that hospital care poses a greater risk to human health than does the use of antibiotics in food animals. OTA (1995) summarized data from the Centers for Disease Control and Prevention (CDC) supporting the observation that “1 out of 20 patients (2 million per year) acquire infection in the hospital … [at a cost of ] $4.5 billion a year in terms of extra treatment…. [The infections] directly cause 19,000 deaths … and [are] the eleventh leading cause of death in the U.S. population.” The number of drug-resistant, hospital-acquired bacterial infections increased close to 300 percent during the 1980s, even with CDC’s development and distribution of guidelines for antibiotic use in hospitals and human medicine by the CDC (OTA 1995). The number of cases of drug resistance in food animals receiving antibiotics is probably much greater than the number of humans developing drug-resistant bacterial disease, but there are fundamental differences in the way that the statistics should be interpreted. Although the use of antibiotics in food animals can cause resistance emergence, not all instances of resistance are clinically significant, not all involve resistance in pathogens, and not all cause actual illnesses. In contrast, because the occurrence of infection in hospitals is often considered life-threatening, the risk to human health of hospital-acquired infections might be thought of as a greater risk. Certainly, the development of hospital-acquired vancomycin resistance in pathogens is a major human health concern largely devoid of input from agricultural sources in the United States (Bingen et al. 1991; Frieden et al. 1993). Food-Animal Antibiotic Resistance and Human Health Direct literature citations relevant to instances of transferred antibiotic resistance from animals to humans and development of clinical disease are relatively few, but they do exist. In addition, state and federal public health statistics on

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The Use of Drugs in Food Animals: Benefits and Risks food-borne diseases provide useful information to make justified inferences about human health issues related to antibiotic resistance. Some criticisms have implied that public health department conclusions and recommendations on animal drug use are too conservative and that estimates of the effects on public health are unnecessarily high (AHI 1998). However, compiling these data and forming conclusions regarding effects on human health are significant parts of CDC’s mission. Human diseases caused by Campylobacter and Salmonella serve as a useful example for integrating many of the overlapping issues of animal antibiotic use and human health risk. Most frequently, people become ill after consuming food tainted with these organisms, which originate largely in food animals (ERS 1996b). The statistical databases for both diseases suggest that only a portion of the actual disease occurrences are reported, making the numbers used to state some aspects of risk erroneously low. ERS published a report on the medical and productivity losses associated with bacterial food-borne diseases (ERS 1996b) in which CDC statistics were collected for reported cases and projected unreported cases of salmonellosis and campylobacteriosis. Together, there are an estimated 6.5 million (upper end of the estimate) annual cases of disease occurring from Salmonella and Campylobacter infections in the United States. Of these, 93 to 95 percent recover fully and require no hospital or physician visit. Five to six percent visit a physician and recover fully. Two percent of the Salmonella cases and 0.6 percent of the Campylobacter cases require hospitalization. Of these cases, 94 to 95 percent recover fully; 2 to 6 percent die. The occurrence of death is presumed to be associated most frequently with invasive disease that becomes systemic and, to a smaller extent, is further associated with the failure of antibiotic treatment. A “modern” strain of Salmonella, DT-104, is resistant to multiple classes of antibiotics (Glynn et al. 1998). The death rate cited previously is largely affected by how treatable an infection with either of these bacteria is and the success in treatment is dictated by the susceptibility and relative resistance of the bacteria to the antibiotics used. Salmonella DT-104 and Campylobacter jejuni are becoming increasingly important to human health risk from antibiotic use in animals because with each additional occurrence of resistance to yet another class of antibiotics, the treatment of that infection becomes more difficult and the death rate, and thus, the risk to human health, becomes greater. These “special” pathogens (e.g., Salmonella DT-104) are important. They are among the bacteria that could cause great harm to humans as zoonotic pathogens because of the potential for widespread dissemination and difficulty in controlling infections that become invasive and septic. In the larger setting of the food-animal antibiotic issue, however, the view of several researchers is important in keeping the magnitude of the health threat in perspective. Shah et al. (1993) used in-patient and out-patient hospital infection data as well as in-patient hospital location data to assess some of the relationships between antibiotic health

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The Use of Drugs in Food Animals: Benefits and Risks risks to humans. Based on their data collection (incidence of life-threatening and difficult-to-treat infections and the patterns of bacteria and drug-resistant bacteria isolated) they concluded, “if use of antibiotics in the veterinary field [were] to lead to development of (ultimately untreatable) infections caused by multi-resistant bacteria in man, we should be encountering multi-resistant isolates with a higher frequency in community acquired infections than in nosocomial (hospital-acquired) infections.” The authors did caution, however, that because some difficult-to-treat pathogens can arise from the use of antibiotics in food animals (albeit at a much lower incidence than for hospital-acquired infections), there is no room for complacency in the use of these drugs in animals, and “close monitoring of antimicrobial susceptibility is warranted.” Human health is intrinsically linked to the health of food-producing animal populations. Factors that affect animal health also will affect human health. That link sometimes leads to conflicting concerns from different segments of the population. The public is concerned about the risks of drug use, residues, and microbial contamination of its food supply, but it also is concerned that the animals produced to supply the food are raised in healthful and humane conditions. The medical community is concerned about the threat of growing antibiotic resistance of human pathogens and about the contribution of antibiotic use in food-animal production to the emergence of resistance in human pathogens. Resistance problems are not solely a concern of the medical community. Animal producers and the veterinarians are concerned that resistance in bacteria in farm animals is interfering with the effectiveness of drugs. They also worry about an impending shortage of effective alternatives for use at therapeutic and subtherapeutic concentrations. What is the fundamental issue that brought about the commission of the present study? Furthermore, how can the positions of proponents and opponents of large-scale use of antibiotics in food-animal-production practices be summarized? Each question is based on conflicting perceptions: (1) Antibiotic use in animal agriculture is too great, too unregulated, and there is too little accountability—all of which perhaps contributes unnecessarily to a threat to human health. (2) Choices of antibiotics for use in agriculture to ensure animal health and productivity are too few. (3) The process of federal approval to use a drug for a specific purpose in animal agriculture is too rigorous, arbitrary, expensive, and lengthy—all of which impedes the development of new drugs. Antibiotics are the class of veterinary drugs most widely used in agriculture. However, the veterinary and animal production industries are concerned about the relative lack of approved drugs for use in food-producing animals across the entire spectrum of drugs compared with those for human therapeutic use. On the basis of interpretation of objective data and scientific expertise in the various fields, the committee presents recommendations in this report to improve harmony, understanding, and cooperation among all stakeholders. The magnitude of drug use in the food-animal industry in the United States is

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The Use of Drugs in Food Animals: Benefits and Risks large. The animal populations of various commodity producers are estimated at greater than 100 million beef cattle, 10 million dairy cattle, 10 million sheep, 60 million hogs, and 8 billion poultry. In 1995, those animals supplied 74 billion pounds of meat and poultry, 74 billion eggs, and 156 billion pounds of milk (ERS 1996a). Those commodities contributed more than $87 billion to the nation’s economy. To support the industries, 18 million pounds of antibiotics were used in major species in 1985; 90 percent of that was used for subtherapeutic dose applications (IOM 1989). In 1991, approximately 76 million pounds of antibiotics were used for treatment of disease in humans and animals (therapeutic, growth promotion, disease prevention); approximately 25 percent of that was used for food-animal production (treatment, disease prevention, growth promotion) (Carneval, R. 1997. Animal Health Institute, Alexandria, personal communication). Forty-five years after the initial approval of antibiotic-medicated feeds for livestock to improve overall health and increase productivity, the uses and applications for antibiotics are still growing in animal production facilities in the United States. Some new antibiotics have been developed and incorporated into animal use (for example, ceftiofur, efrotomycin, and a fluoroquinolone), and others have been removed (nitrofurans). Regardless, 60 to 80 percent of all livestock and poultry will receive antibiotics in feed or water or by systemic injection at some time during their production lifespan (IOM 1989). This practice is by choice of the producer (usually driven by economic incentive) where growth promotion is concerned, and by necessity with veterinary input where illness threatens animal well-being and management practices or human well-being. The practice is a strong indication that the economic and management benefits for the producer outweigh the cost of procurement and use. Concern over the public health consequences of animal antibiotic use, however, also grows steadily among practitioners of human medicine. The public perceives a risk to its health, but in general the perception is diffuse. Specific populations with health problems are more focused on the potential repercussions of antibiotic use in food animals. Risk is certainly greater among persons with immunodeficiency diseases (human immunodeficiency virus positive), patients who receive antineoplastic immunosuppression for cancer therapy, and among a large number of persons with diseases of the endocrine system that reduce natural immunity to infection (Telzak et al. 1991). Individuals who have direct contact with the food animals and the production environment also are identified at higher risk simply because of their increased contact with animals, carcasses, and excrement, for example. As determined by Wall et al. (1994) and Holmberg et al. (1984b), persons who came into contact with domestic or farm animals—especially ill animals—had more infections with the same organisms that affected animals. In fact, pathogen transfer from animals to humans and then from one human to another also can occur, as happened in an infant nursery outbreak in

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The Use of Drugs in Food Animals: Benefits and Risks 1980 (Lyons et al. 1980). Therefore, an emerging question is whether immunocompromised individuals with higher risk for exposure to food-animal microorganisms (such as farm families), pathogenic or not, constitute a sensitive population that should be monitored more closely for the emergence of antibiotic resistance from animals? Since the inception of this report, there have been important changes in perceptions and priorities of federal agencies regarding animal antibiotic use. Those changes are reviewed, and the current focus of several of the federal agencies with responsibility for human or animal health and food safety is described. It appears that some steps are being taken to obtain data to better assess the risks associated with antibiotic use. A prominent part of the process is consideration of active partnering of many agencies and industries to use reduced resources more efficiently for solving problems. There are risks associated with using antibiotics in animal production as well as not using them. The relationship between risks is dynamic, and the risks dealt with in this report could change, especially as more information is gathered. Through partnership and communication among stakeholders, the effect of the changing of risks inherent in the use of antibiotics can be identified and intervention strategies can be formulated before a true crisis develops.