8
Approaches to Minimizing Antibiotic Use in Food-Animal Production

Historical data demonstrate that the intensification of food-animal production in the United States increased with the finding that antibiotics used in one form or another increased productivity by decreasing the incidence and severity of disease (Hays 1986; Cromwell 1991). However, researchers in some European countries suggest that a shift to less intensive rearing and increased attention to hygiene can resolve many of the situations where the disease and stress load on animals might warrant the use of antibiotics and augment the risk to human health (WHO 1997; Witte 1998). There are many differences in the magnitude and scale of animal agriculture between the United States and many European countries. A goal of producing food animals in the United States devoid of antibiotic use might not be realistic now. It would in fact require a total change in the philosophy and the economics of how production animals are raised (Swann 1969; Hays 1986; Walton 1986; ERS 1996c) and a major overhaul of the interactions and interdependencies between animal producers and crop producers (ERS 1996c).

Concerns about the linkage of antibiotic use in food animals to the development of drug resistance in pathogens in animals and, ultimately, in humans have prompted attempts to limit the use of antibiotics in animal production whenever feasible. The use of antibiotics is considered necessary by many proponents to ensure optimal animal health and growth or production efficiency. The therapeutic applications are obvious when faced with the potential losses that can be incurred with the re-emergence of active infection and disease in a herd, flock, or school. If a goal of animal production specialists is to reduce overall use and, certainly, inappropriate use of antibiotics in food animals (NRC 1989a), strate-



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The Use of Drugs in Food Animals: Benefits and Risks 8 Approaches to Minimizing Antibiotic Use in Food-Animal Production Historical data demonstrate that the intensification of food-animal production in the United States increased with the finding that antibiotics used in one form or another increased productivity by decreasing the incidence and severity of disease (Hays 1986; Cromwell 1991). However, researchers in some European countries suggest that a shift to less intensive rearing and increased attention to hygiene can resolve many of the situations where the disease and stress load on animals might warrant the use of antibiotics and augment the risk to human health (WHO 1997; Witte 1998). There are many differences in the magnitude and scale of animal agriculture between the United States and many European countries. A goal of producing food animals in the United States devoid of antibiotic use might not be realistic now. It would in fact require a total change in the philosophy and the economics of how production animals are raised (Swann 1969; Hays 1986; Walton 1986; ERS 1996c) and a major overhaul of the interactions and interdependencies between animal producers and crop producers (ERS 1996c). Concerns about the linkage of antibiotic use in food animals to the development of drug resistance in pathogens in animals and, ultimately, in humans have prompted attempts to limit the use of antibiotics in animal production whenever feasible. The use of antibiotics is considered necessary by many proponents to ensure optimal animal health and growth or production efficiency. The therapeutic applications are obvious when faced with the potential losses that can be incurred with the re-emergence of active infection and disease in a herd, flock, or school. If a goal of animal production specialists is to reduce overall use and, certainly, inappropriate use of antibiotics in food animals (NRC 1989a), strate-

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The Use of Drugs in Food Animals: Benefits and Risks gies must be implemented that offset the potential for increased severity and incidence of animal infection. Reducing the use of antibiotics in food animals must benefit human and animal health in reducing the incidence and severity of disease. Strategies to reduce the extent of therapeutic antibiotic use fall into two categories: prevention of disease and infection and documented diagnosis of the presence of a pathogen and selection of an antibiotic that is effective and thorough in eliminating infection. To end repeated trial-and-error batteries of antibiotics, the bacteria must be sensitive to the antibiotic prescribed. In addition, viral disease should never be confused with bacterial disease. Curbing the use of antibiotics in subtherapeutic disease prevention and growth promotion might offer the greatest opportunity to reduce the amount of antibiotics used in food animals. Alternative strategies largely will be manifested in the application of appropriate management practices. Appropriate practices will maximize genetic growth or productivity of food-producing animals and provide dietary nutrients in optimal amounts, in proper sequence, and in correct timing to prevent the demands and strains in one physiological system from compromising the functions of others. The need for antibiotic use in food animals is unlikely to be obviated totally, and strategies involving the prudent and judicious use of antibiotics can have a positive influence on the animal industries. However, what is possible through the integrated use of strategies that are less dependent on antibiotics is an overall reduction in disease incidence. When disease does occur, the duration and severity of illness can be reduced and perhaps more readily managed by selective and appropriate use of antibiotics. The added benefit of maintaining sound immune competence in animals is that the clearance of invading microorganisms can effectively be increased when therapeutic intervention agents are indicated. Ultimately, the hope is that the safety of the food supply will be improved by reducing the adverse consequences of antibiotic overuse, while maintaining high standards of animal welfare, production, and food quality. Management strategies and preventive-medicine programs that can be used to reduce disease incidence and thus drug use in food-producing animals are as follows: (1) providing stringent controls on hygiene, population dynamics, feed quality, and environmental conditions to prevent or reduce stress; (2) eradicating specific diseases; (3) optimizing nutrition to enhance natural immunity or feeding nutrient regimens as a preventive measure to lessen the consequences of abrupt changes in conditions for animals (for example, transport to feedlots or release onto fresh pasture); (4) breeding for genetically disease-resistant livestock (Axford and Owen 1991); and (5) in some instances, using alternative growth promotants such as cattle anabolics (Rumsey 1988) or somatotropins (NRC 1994), which pose few or no detectable residue problems (Henricks et al. 1983). Some procedures to aid in disease prevention are easily implemented, such as the addi-

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The Use of Drugs in Food Animals: Benefits and Risks tion of lime to sawdust bedding to reduce bacterial counts and guard against udder infection in dairy cows (Hogan et al. 1997). The process of disease eradication is often costly in the short run, but it can be economically justified in specific situations—generally when a public health risk is substantial. The national eradication programs for brucellosis and tuberculosis are examples in which this approach was warranted and successful. However, the eradication of one pathogen might simply lead to its substitution by another (Axford and Owen 1991). In addition, disease that has been eradicated should not be regarded with complacency. Although hog cholera and bovine tuberculosis were successfully controlled in this country, recent data from the U.S. Department of Agriculture’s Animal and Plant Health Inspection Service and the Agricultural Research Service suggest that new forms of cholera and tuberculosis might again become a threat to U.S. animal production; they are already a threat abroad. New population dynamics between domestic and wild animals similarly pose a threat to animal production and challenge management strategies. Extensive research is under way in the agricultural community, which is exploring and refining strategies to maintain or enhance animal productivity and health while decreasing the need for and use of antibiotics. Many of the approaches mentioned below are still being validated with the hope of successful transfer of the technology into animal production. ANIMAL MANAGEMENT Management practices encompass a large realm of procedures implemented at various stages in animal production. Although management practices might be considered routine, many have evolved as specific preventive measures to inhibit pathogenic infections and improve animal health and well-being (Swanson 1995). Management practices that have implications for reducing the need for drug use focus on manipulating the animal’s environment to reduce stress, introducing hygienic measures to reduce exposure to disease, and developing methods to enhance immunity. Ambient Temperature and Heat Stress Animals are more susceptible to disease during periods of environmental stress (Smith and Hogan 1993). Controlling environmental factors can promote host resistance, thereby reducing dependence on antimicrobial agents. Consideration must be given to numerous factors, such as minimizing extremes of temperature and humidity and minimizing social stresses. Fighting with pen-mates, continuous introduction of new animals into a herd or flock, and inadequate space for feeding or sleeping can weaken animals. (Minton et al. 1995; Swanson 1995; Hyun et al. 1998).

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The Use of Drugs in Food Animals: Benefits and Risks Animals subjected to temperature and humidity extremes are less able to resist bacterial challenge. For example, dairy cattle subjected to high temperatures have increased incidences of mastitis. Mastitis is expensive not only because infected cows produce less milk but also because the milk of cows in treatment must be discarded. Dairy animals, which originated in temperate climates, have increased mastitis and somatic-cell counts (SCCs) in tropical environments (Oliver et al. 1956; Roussel et al. 1969; Wegner et al. 1976). Additionally, chronic, perhaps subclinical, infections erupt into obvious disease states more readily in heat-stressed cows than in animals kept in thermoneutral environments (Nelson et al. 1967; Bishop et al. 1980). Therefore, strict mastitis control procedures must be integrated with heat stress management to avoid disease and drug use. The strategies implemented will vary by season and location. Numerous strategies have evolved to compensate for heat stress, and they are aimed at providing relief to animals to prevent production losses. Evaporative coolers are used to cool poultry, cattle, and swine in areas of low humidity. Design of poultry and swine buildings has evolved to maximize heat loss during high-temperature extremes and to regulate heat loss during cold periods. Moreover, building design can provide uniform distribution of air through all areas of an animal facility. Novel approaches, such as misting the animals with fresh water or providing cooling ponds, relieve animals from heat stress. Persistent hot weather will cause a drop in milk production, but the decrease will not be as severe if the cows are protected from the sun and provided with high-quality forage. Feed intake varies with ambient temperature, decreasing substantially for animals in hot and humid conditions and resulting in commensurate declines in growth or performance. Animals should be protected from heat as much as possible with natural or artificial shade, especially during persistent hot weather. In field and corral systems, providing shade only over feed mangers and waterers can result in the feeding areas becoming overloaded with manure, because animals remain there for shade. The animals can then become dirty, which for dairy cows can result in mastitis (Smith and Hogan 1993; Roberson et al. 1994). Therefore, additional shaded areas should be provided away from feed. The use of water mist on heat-stressed cows in corrals was studied for 20 consecutive days at 100°F and above (Shultz et al. 1985; Shultz 1987). In herds with average daily production of 59.4 lb of milk per cow, production losses due to heat were significantly less for misted cows than for cows without access to mist. The use of feed-manger water in California resulted in a marked reduction in deaths of fresh cows that had recent cases of mastitis. It is essential to avoid creating sites that support the growth of mastitis-causing organisms in the environment where cows lie down. Sprinklers and fanning stations adjacent to milking parlors have been used quite successfully. This method provides evaporative cooling with just enough water to keep the cows’ bodies wet, although their udders must be dried before

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The Use of Drugs in Food Animals: Benefits and Risks milking to prevent the development of mastitis. The fans help to remove warm, humid air from the body surfaces of cows and help to dry them (Beede et al. 1987). The sprinkler and fan system also was found to reduce body temperature and increase milk yield of cows in Arizona, Florida, and Israel. Cows can be wet down again in the exit lane of the milking parlor. Spray should cover only the top and sides of the cows so that the germicidal teat dip used after milking is not washed off. Thus, the cows are temporarily relieved from the effects of the sun, and instead of returning immediately to the shade, they follow their normal cool-weather practice of eating and drinking after each milking. That keeps animals on their feet and allows time for teat-duct closure before contact with soil and manure, which can result in intramammary infection. Although the effectiveness of this method of cooling depends on evaporation, it also should work for dairies in more humid areas where evaporative coolers are not practical. Nutritional measures to alleviate heat stress in ruminants include feeding high-energy rations to reduce excess physiological heat generated by digestion of high-fiber rations. In addition, it is important to avoid handling and milking cows during the hottest part of the day; early-morning and late-evening moving and feeding encourage consumption. One heat-stress-management strategy for cooling cows and reducing incidence of mastitis involves the use of cooling ponds (Shearer et al. 1987). Florida researchers studied a 1,400-cow dairy that elected to use ponds after comparing costs with other cooling methods and the success of other dairies using them. In the study, 1 group of cows was located in lots with cooling ponds and permanent shade, and the groups with no pond had access to shade structures only. Results showed that cows with access to cooling ponds had significantly less clinical mastitis (9.8 percent vs. 18.6 percent). The authors suggested that the reduction in mastitis was due to enhanced resistance to infection resulting from reduced heat stress as well as to improved udder preparation. Water quality and availability can offset some of the adverse effects of heat stress. Cows drink about 50 percent more water at 80°F than at 40°F, and they require water to cool themselves in the form of respired moisture and body sweat (Graves 1986). Chilling the drinking water for milking cows during hot weather can help rid cows of the large heat load that they produce and receive from their environment (Lanham et al. 1986). Under conditions of high relative humidity, chilling drinking water to 50°F has helped alleviate heat stress, resulting in increased feed intake, milk yield, and rumen motility, and in decreased respiration and body temperature (Baker et al. 1988). Similarly, evaporative cooling significantly increased reproductive performance and milk production in cows in a hot, dry climate (Ryan et al. 1992; Chen et al. 1993). A practical application of management strategies and changes to equipment design to combat heat stress in animals is illustrated through management practices being implemented in the broiler industry to facilitate easier drinking for

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The Use of Drugs in Food Animals: Benefits and Risks overheated birds. Poultry deaths in the southeastern United States can be devastating during the summer months, and heat stress increases the incidence of disease. The design of poultry waterers can have a significant effect on how heat-stressed birds are able to drink water (May and Lott 1996; May et al. 1997). The consumption of water is not constant during the day and affects the bird’s feed consumption patterns and the ability to thermoregulate. In poultry houses, birds need to pant to shed heat. The positioning of waterers, the height of drinking nipples, the drinking process, and panting can become a major problem of coordination for the birds that can result in insufficient intake of water. The problem is associated with reaching for and triggering the nipple waterers, swallowing the water, and panting vigorously. Overcrowding and Behavioral Stress Overcrowded animals often must compete for feed, water, and sleeping space and so are more susceptible to disease. Animals that harbor subclinical infections can become chronic shedders of pathogens, which can be transmitted to other animals or to humans through direct contact or through food. Often, constant vigilance by animal caretakers is essential to prevent timid animals from being crowded away from feed and water or from being subjected to fighting. To avoid such problems, animals must be given appropriate space and should be commingled as little as reasonably possible. Sick or weak animals should be housed separately from healthy pen-mates. In some situations, group feeding results in higher consumption rates than does individual feeding; as a result, overall body-weight gains can be increased. However, competition can result in gorging, particularly by calves fed high-concentrate feeds, which can cause bloating, acidosis, and bacterial imbalances in the rumen and gut. These animals are predisposed to illness and are often treated with additional medicinals and antibiotics. Vaccination Strategies to Prevent Disease Traditionally, vaccination has been used to control pathogens that affect agricultural animals. However, the use of vaccines for controlling food-borne pathogens (for example, Salmonella in poultry products and Escherichia coli O157:H7 in bovine products) is a relatively unexplored method for reducing or eliminating pathogenic bacteria from the food chain. Vaccination can be a reliable alternative to drug use in the prevention of some diseases in animals. Attenuated live vaccines delivered orally have several distinct advantages over injected vaccines. The vaccine is usually delivered by spray or in drinking water, so needles are not required and animals need not be handled individually. In addition, depending on the life cycle of the parent

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The Use of Drugs in Food Animals: Benefits and Risks pathogen, some live vaccines induce humoral, cellular, and mucosal immune responses, because they invade and stimulate the gut-associated lymphoid tissue. Control of Salmonella in poultry with vaccines could be useful for two reasons. First, resistance to antibiotics could be better controlled (Cohen and Tauxe 1986). Second, live attenuated Salmonella administered orally elicit cell-mediated mucosal and humoral immune responses, thus making them excellent vaccines (Clements 1987; Curtiss et al. 1993; Griffin and Barrow 1993). Attenuated bacteria also have shown great promise as delivery vehicles for heterologous antigens, such as virulence determinants and epitopes from a variety of mucosal pathogens. Stable expression of heterologous surface-exposed antigens has been achieved in Salmonella typhimurium (Curtiss and Kelly 1987; Hassan and Curtiss 1994). Recent advances in molecular biology and understanding of microbial physiology and pathology have facilitated the development of several well-defined gene deletion mutations in Salmonella that result in a virulent immunogenic phenotype. The current approach to attenuation in Salmonella species is to introduce mutations that decrease virulence while maintaining the ability to colonize lymphoid tissue, elicit immune response, and maintain genetic stability. This strategy is being used to produce patented live virulent Salmonella vaccines to control Salmonella enteritidis and Salmonella typhimurium in many animal species (Cooper et al. 1994; Hassan and Curtiss 1994, 1996). Salmonella typhimurium and other species have been used successfully in model systems to deliver antigens from a variety of mucosal pathogens (Clements 1987; Cardenas and Clements 1993). In addition, several molecular systems have been developed to stabilize the expression of heterologous antigens in vaccine strains (Strugnell et al. 1990a,b, 1992; Morona et al. 1991). Although most studies have been done in mice with antigens to human pathogens, the results indicate that animal vaccination has significant merit. One important pathogen needing further investigation in this regard is E. coli. Various strains of this organism cause economic losses to poultry and swine producers. The O157:H7 strain is a well-known food-borne human health hazard. Morona et al. (1994) showed that Salmonella typhimurium vaccine strains expressing relevant E. coli fimbrial antigens can elicit antibody responses in pigs comparable to those seen with injected killed vaccines. Other potential pathogen targets for this technology include species of Campylobacter, Bordetella, Pasteurella, Erysipelothrix, Clostridium, Mycobacterium, Mycoplasma, and Eimeria. A short list of other pathogens from which relevant antigens have been cloned and expressed in Salmonella species includes Salmonella (Strugnell et al. 1990b) Echinococcus multilocularis (Gottstein 1992), and Bordetella pertussis (Guzman et al. 1991).

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The Use of Drugs in Food Animals: Benefits and Risks DNA Vaccination A challenge to animal health experts is the development of proper antigens to use in vaccination programs to prevent the development and spread of disease. Often the use of whole-organism preparations is ineffective because of the similarity in protein antigens among many organisms. In addition, proteins and peptides that are unique to specific pathogen species are often poorly antigenic and ineffective in producing antibodies to protect an animal from a pathogen-specific disease. Recently, experiments were summarized at the International Meeting on Nucleic Acid Vaccines for the Prevention of Infectious Diseases at the National Institutes of Health. In the technique of nucleic acid vaccination, plasmid DNA from a specific pathogen gene is introduced into a host by direct injection, by high-velocity injection using the gene gun, or by oral administration (IMNAVPID 1996). The gene gun is a device in which a 0.22 caliber ammunition blank is used to insert genetic material intracellularly by high-velocity dispersion and cell membrane penetration. Antibodies to the proteins encoded by these DNA fragments that code for the protein are efficiently produced, and the antibody concentration (titer) is roughly proportional to the mass of DNA injected. An important feature of this approach is that the antibody responses are easily manipulated either by coexpression or by the administration of cytokines, such as interleukin-4 (IL-4), IL-6, and interferon-γ (IF-γ). Oral DNA administration is effective in eliciting localized mucosal immune response, where the first site of pathogen interaction might be the mucosal surface itself. The DNA vaccination, and particularly the use of gene hybrids, presents the opportunity to obtain site-specific immune expression. For example, by fusing a site-specific promoter gene to a desired structural gene, a relatively high expression of the desired antigen can be obtained at a specific site where only the promoter region is activated. Such strategies also could be used in situations where gut-specific antibody production would serve as a first line of defense against a gut pathogen in an animal. An advantage of this approach is that specific base sequences of DNA can be easily and cheaply made to serve as specific antigen stimuli without the need to grow active cultures of organisms and extract proteins (for further detail, see IMNAVPID 1996). Beneficial Microbial Cultures, Probiotics, and Competitive-Exclusion Alternatives The disease ramifications associated with microbial contamination of foods are not taken lightly and are the major focus of President Clinton’s food safety initiative (CFSAN 1997). As the president stated in a radio address January 25, 1997, We have built a solid foundation for the health of America’s families. But clearly we must do more. No parent should have to think twice about the juice they pour their children at breakfast, or a hamburger ordered during dinner out.

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The Use of Drugs in Food Animals: Benefits and Risks The chief targets of the initiative are related to bacteria and organisms that enter the food chain from gut and fecal origins from domestic animals. The majority of gut-derived organisms are readily controllable through standard and routine measures established for the food production industries; however, concern heightens when conditions within the animal are right for the emergence of organisms of greater virulence and pathogenicity. Most of the time, proliferation of these undesirable organisms is held in check by the nature of gastrointestinal ecology. This is sometimes called the principle of “competitive exclusion,” the ability of a population of beneficial microorganisms to condition the gut and intestinal environment with regard to pH, ionic balance, and selective microbial excretion products and to prevent establishment of pathogenic microorganisms in the gut. An in-depth review of the homeostatis established and maintained in the gut through the proper balance in microbial ecological factors is beyond the scope of this report. However, it is worthwhile to restate that the normal gut microbial population provides a good measure of assurance that inappropriate bacteria find it difficult to establish a clinically significant presence. Under normal circumstances, pathogenic organisms cannot proliferate and are outcompeted by normal flora. Research is demonstrating the effectiveness of feeding live beneficial microorganisms to animals to maintain or reintroduce balance into gut ecology that might have been challenged by the emergence of pathogens (Stark and Wilkenson 1988). The food-animal industry is experiencing an increase in the development of antibiotic-resistant bacteria as well as bacteria that have increased pathogenicity, particularly Salmonella, coliforms, and Campylobacter. As a result, there is renewed interest in the use of normal gut flora, probiotic, and competitive-exclusion products (CEPs) to reduce gastrointestinal stress and its effects on the animal’s performance without resorting to the use of antibiotics. Some proposed benefits of normal gut flora and probiotics are improved survival of newborns, reduction or prevention of diarrhea, increased growth rate, improved feed efficiency, and enhanced immune response (Stark and Wilkenson 1988). The administration of beneficial microorganisms to animals started in the 1920s, and the name “probiotics” (defined as “for life”) was introduced in the 1970s. Feeding beneficial microorganisms to chicks is intended to protect them against colonization by such pathogenic bacteria as Salmonella and enterotoxigenic E. coli (ETEC) (Nurmi and Rantala 1973). The resident host flora can exclude the newcomer by several mechanisms. Volatile fatty acid production, pH effects, toxic metabolite production, or simple occupation of attachment sites within the gut have been studied and reviewed (Bailey 1987). The most commonly used probiotics are live cultures of 3 to 5 species of lactic-acid-producing bacteria, such as Lactobacillus acidophilus or Streptococcus faecalis. In 1989, the U.S. Food and Drug Administration (FDA) required manufacturers of these products to use the term “direct-fed microbial” (DFM) instead of probiotic. DFMs are used to control and promote the proper environmental

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The Use of Drugs in Food Animals: Benefits and Risks conditions for establishing an ideal microbial population in an animal’s digestive tract. They do not establish or provide the normal gut flora; the animal must obtain flora from its environment. DFM products are regulated by the FDA Center for Veterinary Medicine as food, under the provisions of the Compliance Policy Guide 689.100. Unlike CEPs, the microorganisms administered to animals in DFMs are defined and specified. The organisms used in these products are listed by the Association of American Feed Control Officials. CEPs are unspecified mixtures of live microorganisms isolated from the intestinal tract of animals of different species. Because some of the claims of these products are therapeutic, CEPs are listed as drugs and are regulated as such (CVM 1997a). Successful antimicrobial plus beneficial microorganism programs have been developed in Europe using quinolone therapy followed by competitive-exclusion microbial cultures to produce Salmonella-free broilers. The administration of the proper mix of competitive microorganism cultures also appears beneficial in the control of Campylobacter fetus subspecies jejuni in young chicks (Soerjadi et al. 1981, 1982). Scientists researching this interesting form of bioremediation of pathogenic microorganisms suggest that, in animals subjected to stress, the balance between normal and potentially pathogenic bacteria in the intestine is altered (Abe et al. 1995). As a result, the pathogens might proliferate to a population density that permits their emergence within the animal as a disease or be of sufficient numbers to pose a threat to human health if they are contaminants of food. Probiotics, built up by strains of lactic-acid-producing organisms, promote digestive balance by supplementing intestinal microflora with beneficial bacteria, thus creating conditions unfavorable for pathogen growth. Additional mechanisms of action of probiotic microorganisms include production of antimicrobial substances, competition for adhesion receptors in the intestine, competition for nutrients, and immunostimulation, all of which create an environment incompatible for pathogens. Probiotics are used in dairy calf ration supplements as a prophylactic disease control tool against digestive disorders (Stark and Wilkenson 1988). Probiotics also have been shown to improve production performance by increasing average daily gain, feed consumption, and feed efficiency (Abe et al. 1995). Biosecurity Biosecurity techniques should be based on an understanding of pathogen transmission. A knowledge of all potential entry routes for pathogens to a herd is an essential prelude to developing a comprehensive biosecurity program. If multiple pathogens with different routes of transmission are listed according to priority for exclusion from a group of animals, a multiple-point biosecurity program is warranted. Dial et al. (1992) summarized several sources in formulating biosecurity policies for swine, but they could be applied to all food animal species:

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The Use of Drugs in Food Animals: Benefits and Risks Locating herds away from potential sources of infection, including other production facilities, slaughterhouses, sale barns, and roadways. Enclosing herds in bird-proof facilities. Placing fences around the farm boundaries and placing locks on doors and windows to prevent entry of visitors. Prohibiting entry of vehicles used to transport animals, unless they are empty and have been cleaned and disinfected before arrival at the facility. Providing secure loading areas that prevent animals from returning to buildings once they have been exposed to trucks. Aggressively controlling rodent and fly populations, including the use of weed control and gravel borders to discourage rodents from approaching facilities. Excluding cats and dogs from farm complexes. Excluding people, including visitors, who are nonessential to farm operations. Ensuring that farm personnel do not come in contact with animals outside the herd. Establishing a minimum quarantine time for people before they come in contact with livestock. Requiring all people to shower before entering farms and providing clothing to wear on farms. Ensuring pathogen-free feed sources and instituting methods of delivering feed to farms that closely control the access of potentially contaminated trucks. Cleaning outside feed spills to avoid attracting rodents and birds. Providing secure manure storage and disposal. Promptly disposing of dead animals. Moving incoming stock to isolation areas that have separate ventilation and manure removal systems. Placing sentinel animals with incoming stock and using diagnostic tests (serological tests or postmortem examination) to detect infection. Ensuring that feeds, water, bedding, equipment, and supplies are free of infectious agents. Restricting the use of manure-disposal equipment. Testing replacement herds for the presence of pathogens. Using high-health technologies (for example, artificial insemination, embryo transfer, surgical derivation, and medicated early weaning) to introduce new genetic stock. Many of these options are based in common sense, but some of the specific elements are difficult to control or implement. The seasonality of biosecurity calls for different measures to be taken at different times of the year. In the fall, wild-animal populations begin to seek additional shelter, warmth, and food, and

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The Use of Drugs in Food Animals: Benefits and Risks domestic animal facilities offer much of what those animals seek. In those situations, wild animals can spread disease to domestic populations. Similarly, quarantine, disinfection, and clothing changes are often highly effective measures to counter the spread of potential pathogens. Realistically, few producers have the resources or time to increase their operations to provide for showers and change of clothes every time they enter a different animal facility. If these measures are to be effective, the ease of implementation must be balanced with the return. Fly Control Flies are important vectors of bacterial diseases, and biting flies contribute greatly to the stress in cows. Stress can cause a reduction in milk production (Richardson 1987) and a spread in mastitis during warm summer months. Preliminary studies at the Hill Farm Research Station at Louisiana State University, Homer, Louisiana, indicated that flies are instrumental in establishing coagulase-negative staphylococcal teat-canal colonizations in young dairy heifers (Richardson 1987). Such colonizations result in intramammary infections at freshening and persist into lactation. Therefore, fly control is especially important during hot, humid weather when conditions are optimal for multiplication. The overall presence of ectoparasites can establish conditions in which the stresses on animals are so great that the natural partitioning of nutrients for growth or production is significantly perturbed, and conditions for further disease stress and microbe emergence can be established. Experiments conducted by Cole and Guillot (1987) demonstrated that the excess in energy expenditure of cattle infected with Psoroptis ovis was proportional to the area of body surface infected. The data further showed that it was impossible to account for the entire increased energy expenditure by higher feed consumption. Increased energy expenditure from fighting the infection coupled with decreased intake resulted in excessive energy wasting and loss of weight. This is a problem in the modern context of nutrition because it is now realized that the total concept of nutrition is not only what the animal eats, but also how the nutrients are absorbed from the gut and partitioned to different tissues to accomplish specific physiological tasks. This nutrient partitioning is mediated via a complex interaction between the nutrients, the endocrine system, and the immune system, referred to as the endocrine immune gradient (Elsasser et al. 1995, 1997; NRC 1995). Moisture, Mud, and Manure If there is a single physical environmental factor that predisposes animals to constant infection and reinfection, it is moisture. Moisture facilitates the development of a proliferative medium to support most microorganisms. Under hot and humid conditions, such factors as rain, mud, manure, and bedding become

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The Use of Drugs in Food Animals: Benefits and Risks even more important, because they can increase the number of mastitis and disease-causing organisms present on animals. In this type of environment, disease must be prevented by decreasing exposure to pathogens and increasing animals’ resistance to infection. If disease caused by environmental pathogens is a problem, it is imperative that bedding materials be kept as clean and dry as possible. Finely chopped organic bedding materials, such as sawdust, shavings, recycled manure, pelleted corn cobs, peanut hulls, and chopped straw, frequently contain coliforms and streptococci in excess of 1 × 106 colony-forming unit (cfu) per gram and might exceed 1 × 108 cfu/g, a number that often increases mastitis and airborne respiratory disease incidence. Inorganic materials, such as sand or crushed limestone, are preferable to finely chopped organic materials and are recommended to reduce the bacterial load (Hogan et al. 1997). Enhancing Natural Mediators of Immune Function Cytokines, the so-called hormones of the immune system, also work in disease prevention and therapy. Cytokines are chemical (peptide) signal molecules that are released from specific or generalized immune cells and nonimmune cells throughout the body to function either at sites remote from the point of origin or locally at the site of origin (Babiuk et al. 1991; Elsasser et al. 1995). Resistance to disease is mediated in part by leukocytes that are directed against microorganisms that enter the body. Cytokines are produced naturally in all animals and function by regulating the activity of leukocytes, monocytes, macrophages, and neutrophils involved in protecting animals from the effects of invading organisms. For example, INF-g modulates phagocytic leukocyte populations. Because INF-γ has been shown to greatly enhance leukocyte ability to destroy bacteria, studies have been conducted to determine whether this cytokine is effective in controlling mastitis in dairy cows. In one investigation (Sordillo and Babiuk 1991), dairy cows given intramammary INF-γ had fewer infected mammary gland quarters, exhibited milder clinical symptoms, and experienced infections of shorter duration (Table 8–1). Success of treatment was attributed to the ability of this cytokine to enhance leukocyte activity and minimize the deleterious effects of bacterial endotoxin. Likewise, Quiroga et al. (1993) found that INF-γ promoted bovine milk neutrophil phagocytic activity in vitro. Prophylactic use of INF-γ shortly before or after calving could reduce the incidence of coliform mastitis, which now occurs frequently in many herds. Colony-stimulating factors (CSFs) are cytokines required for the proliferation and differentiation of bone marrow stem cells into functional mature leukocytes. Administration of CSFs increases blood leukocyte counts and increases cellular ability to phagocytose and kill disease-causing bacteria. Granulocyte and macrophage colony-stimulating factor (GMCSF) induces maturation of bone marrow cells into neutrophils and macrophages, and subcutaneous administration to cows before the dry period was found to enhance the

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The Use of Drugs in Food Animals: Benefits and Risks TABLE 8–1 Efficacy of Recombinant Bovine IFN-γ against E. coli Mastitis Treatment Group Eligible Quarters Percentage Showing Clinical Signs of Mastitis Clinical Scorea Percentage of Infected Quarters Percentage Reductionb IFN-γ 24 16.7 1.8 21.4 71.1 Placebo 23 70.0 2.3 74.1   aClinical scores range from 1 to 5:1 is normal milk with no quarter swelling; 2 is questionable milk with no quarter swelling; 3 is obvious abnormal milk with no quarter swelling; 4 is abnormal milk with a swollen or tender quarter; and 5 is acute mastitis with systemic involvement (Smith et al. 1985). bCompared with placebo-treated group. Source: Adapted from Sordillo and Babiuk (1991). TABLE 8–2 Effect of GCSF on Blood and Milk Leukocyte Profiles and Efficacy against Staphylococcus aureus Mastitis Treatment Blood Leukocytes (mm3) Blood Neutrophils (%) Milk SCCa (1000/ml) Milk Neutrophils (%) Reductionb (%) GCSF 30,213 81.3 582 64.4 47 Control 8,675 21.3 261 45.3   aSCC = Somatic cell count. bCompared with control group. Source: Adapted from Nickerson et al. (1989). antimicrobial activity of neutrophils (Babiuk et al. 1991). These leukocytes might be more competent in defending the udder during periods when cellular activity is normally compromised; thus, GMCSF might be useful as an alternative to conventional dry-cow antibiotic therapy. The administration of granulocyte colony-stimulating factor (GCSF) to lactating dairy cows also was found to markedly increase total leukocyte and neutrophil concentrations in blood and milk (Table 8–2). The resulting reduction in new intramammary infections was due to the recruitment of neutrophils that provided a phagocytic line of defense (Nickerson et al. 1989). In addition to enhancing phagocyte activity, other cytokines regulate the activity of lymphocytes. Local administration of IL-2 to cows at the beginning of the dry period was found to expand lymphocyte populations in mammary tissues and secretions during involution, stimulate the local production of antibodies,

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The Use of Drugs in Food Animals: Benefits and Risks and accelerate the involution process, all of which promote resistance to invasive bacteria during the dry period (Nickerson et al. 1993). Killed Bacterial Adjuvants: Biomodulation of Cytokine and Immune Function Further biomodulation of immune system functions might be manipulated by the selective use of specific preparations of bacteria that have inherent adjuvant properties when injected into animals. Propionibacterium acnes serves as a general immunostimulant of leukocytes involved in nonspecific resistance to disease. For example, heat-killed cultures and soluble factors of these bacteria stimulate chemotaxis, phagocytosis, and intracellular degradation of bacteria by macrophages and neutrophils (Hogan et al. 1993). The soluble factors produced by Propionibacterium acnes can interact directly with cell membranes to alter cellular metabolism or to release cytokines that potentiate defense mechanisms of phagocytes. Cytokines released in response to Propionibacterium acnes include INF-γ, GCSF, tumor necrosis factor, IL-1, and IL-2. There are realistic complications and concerns with the implementation of cytokine biomodulation. The endogenous peptides possess considerable cytotoxicity as well as cachectic character when elaborated in states of overproduction (Elsasser et al 1995; 1997). However, modulation effected through localized paracrine (cell-to-cell) cytokine activities could provide the desired immunomodulatory response with minimal toxicity. NUTRITION A relationship between nutrition and resistance to infection is becoming increasingly evident (Chandra 1992). Macronutrients and protein and energy relationships are important to proper health status; however, research suggests that the greatest breakthroughs in nutrition and stress management will occur in defining specific micronutrient (trace mineral and antioxidant) requirements (Tengerdy et al. 1981, 1983; Burton and Traber 1990; Burton 1994). The literature contains many reports of altered (improved) immune function associated with changes in dietary components, but much of the work is unrepeatable and, therefore, questionable with regard to the stated conclusions. In addition, the complexity of immune system functions and interactions that appear to be affected by some aspect of nutrition are so extensive that studies performed in vitro on isolated cells or nonspecific blastogenic responses of immune cells do not reflect the nature of the in vivo interactions. In addition, there are few if any substantive in vivo studies that have investigated the relationship between nutrient requirements for optimal animal growth and productivity and those that satisfy the needs of the immune system. Knowledge of how antioxidants work in nutrition and disease resistance is

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The Use of Drugs in Food Animals: Benefits and Risks rapidly increasing. To optimize disease resistance, animal diets should be balanced and formulated for the appropriate stage of growth or production. Although supplementation with antioxidants might reduce adverse cell responses to infection, the therapeutic benefits of nutritional management of clinical disease are not well documented. The relationship between proper nutrition and resistance to infection is well illustrated in the dairy cow and underscores the need to supplement animal rations with specific micronutrients that promote optimal immune cell function and disease resistance. Finally, management practices must alleviate the detrimental additional effects of the environment to avoid immunosuppression, increased incidence of infection, and, therefore, drug use. Refined nutrient management could improve growth, feed efficiency, and host response to disease (Elsasser et al. 1995). Diet appears to influence resistance to infection, because specific nutrients are important in endocrine regulation, immune and somatic cell function, antibody production, and tissue integrity. In particular, micronutrient interactions might increase disease resistance through regulating cellular and molecular processes, including membrane flux and integrity, superoxide formation, and leukocyte function (Tengerdy et al. 1981, 1983). Bovine mastitis is among the most costly diseases to the livestock industry and provides an excellent example of the interaction between nutrition and animal health. Consequently, the potential to modulate mammary resistance to disease by nutritional supplementation has gained widespread interest, aided by the heightened focus on nonantibiotic approaches to infectious-disease control. In dairy cattle, micronutrients increase mammary resistance to infection and therefore decrease the incidence of mastitis (Erskine 1993). Antioxidants, such as selenium and vitamin E are important in immune response to bacterial challenge. Smith et al. (1984) and Hogan et al. (1993) found that dietary supplementation with vitamin E and selenium decreased the incidence and duration of clinical mastitis by producing a more rapid influx of neutrophils into infected mammary glands and increasing intracellular killing of ingested bacteria. Leukocytes are a major defense mechanism of the bovine mammary gland, and nutritional effects on leukocyte function can have a profound effect on mammary immunity. Antioxidants have been shown to be critical to promoting efficient mammary phagocyte killing, and their effects provide evidence of a link between nutrition and mastitis resistance. Experimental evidence suggests a critical need for antioxidants to support proper bovine phagocytic function. Neutrophils collected from cattle fed diets deficient in copper or selenium have impaired antioxidant enzyme activity and therefore impaired ability to kill ingested bacteria. Vitamin E supplementation of dairy cattle diets enhanced the ability of blood neutrophils to kill ingested Staphylococcus aureus and E. coli. Likewise, selenium supplementation in dairy cows resulted in mammary neutrophils’ increased killing of Staphylococcus aureus and E. coli, and decreased extracellular hydrogen peroxide production compared

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The Use of Drugs in Food Animals: Benefits and Risks TABLE 8–3 Blood Selenium, GSH-Px, and Serum Vitamin E of Cows from Low- and High-SCC Herds Component Low SCC High SCC Blood selenium (mg/ml) 0.133 0.074a Blood GSH-Px (mU/mg of hemoglobin) 35.6 20.2a Serum vitamin E (μg/100 ml) 484.6 421.3 a Significantly different (P <0.01) Source: Adapted from Erskine et al. (1987). with neutrophils from selenium-deficient cows (Reddy et al. 1986; Hogan et al. 1990; Eicher-Pruiett et al. 1992). As discussed in Chapter 2, dairy farmers and veterinarians use the presence of immune somatic cells in milk as an indication of the presence of udder infections and mastitis in lactating animals. In 32 Pennsylvania dairy herds, whole-blood concentrations of selenium and activity of the selenium-dependent enzyme glutathione peroxidase (GSH-Px) were higher in herds with low SCCs than in herds with high SCCs (Table 8–3) (Erskine et al. 1987). Herd prevalence of infection was negatively correlated with blood GSH-Px activity, that is, the higher the GSH-Px activity the lower the prevalence of infection. Weiss et al. (1990) also found that plasma selenium and GSH-Px were negatively correlated with bulk tank milk SCC, and the rate of clinical mastitis was negatively correlated with plasma selenium concentration and vitamin E concentration in the diet. These data suggest that general health of animals can be affected by deficiencies in some aspects of nutrition that compromise an animal’s natural ability to fight off invading microorganisms. Smith et al. (1984) supplemented diets of pregnant heifers with vitamin E (50 to 100 ppm) and selenium (0.3 ppm) 60 days prepartum and throughout lactation. Dietary supplementation reduced staphylococcal and coliform infections at calving by 42.2 percent, and duration of infection by organisms other than Corynebacterium bovis was reduced 40 to 50 percent. Clinical mastitis was reduced in early lactation (57.2 percent) and throughout lactation (32.1 percent), and mean SCC was lower. In addition, injection of 50 mg of selenium 3 weeks prepartum decreased new infections at calving. Likewise, Hogan et al. (1993) observed that dietary selenium supplementation resulted in a more rapid influx of neutrophils into infected mammary glands and increased intracellular killing of ingested bacteria. Dietary supplementation with vitamin E resulted in an increased bactericidal activity of neutrophils. Vitamin A and its precursor, ß-carotene, are necessary for the proper function of epithelial cell membranes, and they stimulate cellular and humoral immunity. Chew et al. (1982) showed that cows with lower concentrations of vitamin

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The Use of Drugs in Food Animals: Benefits and Risks A and ß-carotene in the blood had more severe mastitis. Vitamin A and ß-carotene also reduced the incidence of mammary infection during the early dry period (Dahlquist and Chew 1985) and reduced SCC (Chew and Johnston 1985), although a more recent study (Oldham et al. 1991) found no effect from vitamin A and ß-carotene supplementation at concentrations above those recommended by the National Research Council (NRC 1989b). Leukocytes, particularly activated phagocytes, require antioxidants to achieve efficient performance. The ability of antioxidants to enhance leukocyte function might explain partially their beneficial effect on mammary resistance to disease. The in vitro killing of Staphylococcus aureus by blood neutrophils was enhanced by adding ß-carotene to the diet of cows fed rations with low concentrations of ß-carotene and no supplemental vitamin A (Erskine 1993). The use of inorganic trace minerals or organic-complexed minerals to boost health is of considerable interest to producers and feed additive manufacturers. Many reports have been issued on the health benefits of the use of selenium, zinc, copper, and iron. Seldom, however, has research been performed that critically differentiates between the addition of these elements to diets, where the aim is to supplement and remedy a deficiency, and their use in excess of, for example, National Research Council recommendations. However, research examples such as those cited below and previously in this chapter do support the view that mineral supplementation can affect health status of food animals. Selenium alone or in combination with vitamin E has been effective in reducing the incidence and severity of several reproductive problems in livestock, such as retained placentas, metritis, and other dysfunctions thought to reflect abnormal immune function or a predisposition to infection resulting from the stress of parturition and shift in metabolism to support lactation (Barnouin and Chassagne 1991; Jankowski 1993). Copper and zinc are essential to immune cell function as the enzyme copper–zinc superoxide dismutase, which is important for production of hydrogen peroxide to destroy engulfed bacteria. Zinc deficiency leads to increased susceptibility to infections in dairy cattle (Miller 1978), and use of organic zinc complexes in the diet has been found to decrease SCC. Kellogg (1990) summarized research with zinc–methionine and showed a significant decrease in SCC with an increase in milk production. Research indicates that supplemented chromium also might have immunostimulating properties and some production-enhancing abilities. Initial effects of supplemental chromium on the immune system were observed in stressed feedlot calves, in which chromium supplementation was associated with lowered morbidity and improved weight gain, feed efficiency, and immune responsiveness. Mallard et al. (1994) showed that cows fed supplemental chromium had a significantly higher number of antibody responses to several antigens and higher lymphocyte proliferation upon mitogen stimulation as compared with nonsupplemented controls. Cows receiving chromium also exhibited higher concentrations

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The Use of Drugs in Food Animals: Benefits and Risks of immunoglobin G1 in serum and colostrum. Chromium supplementation was associated with increased milk yield, particularly among primiparous cows. The use of chromium supplementation as a means of increasing animal health must be viewed with some caution. A recent summary of the function of chromium in animal nutrition (NRC 1997) suggests that the data are not strong enough to warrant generalized conclusions regarding chromium and animal health. Micronutrients also affect optimal disease resistance in pigs (Peplowski et al. 1980), beef cattle (Chew 1987; Erskine et al. 1989), and fish (Durve and Lovell 1982). Pigs fed higher concentrations of vitamin E had increased serum antibody titers against E. coli (Ellis and Vorhies 1976). Immunocompetence in beef cattle is enhanced by dietary selenium, iron, copper, and zinc (Chandra and Dayton 1982). Vitamin E has also been found to improve disease resistance in cattle (Erskine 1993). Vitamins have been found to increase immune response in fish (Webster 1991). Additional research on basic and applied nutritional modulation of animal health should be pursued and research funding should be increased where applicable. Where possible, much of this research should focus on whole-animal approaches to nutritional modulation of health because of the complex interconnectedness of the various components of the immune system. It becomes difficult to assess cause-and-effect relationships where individual components of the immune system are isolates, for example, in in vitro systems, and lose the capability of being modulated by other components of the system. DISEASE ERADICATION Some livestock and poultry diseases are so devastating or present such a great public health risk that eradication becomes a viable option. Tuberculosis and brucellosis are approaching complete eradication after many years of testing and slaughter or depopulation programs and long-term national surveillance. More short-term eradication programs, involving complete slaughter of poultry flocks, have made significant progress in eliminating Salmonella enteriditis and avian influenza. Other diseases have been virtually eradicated through intensive vaccination programs and the development of breeding stock that is free of specific diseases such as Salmonella. In swine, a program of depopulation and repopulation has been used to improve herd health and productivity and to lower medication use and drug costs (Leman 1988, 1992; McNaughton 1988; Deen 1992). This technique results in an approximate 10 percent improvement in feed efficiency and average daily gain and a 10 to 20 percent increase in pounds of pork marketed annually from each sow (Leman 1992). However, this technique disrupts an enterprise’s cash flow and it can be expensive (Kavanaugh 1989; Deen 1992).

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The Use of Drugs in Food Animals: Benefits and Risks GENETICS Molecular biology approaches can be applied to genetic strategies to enhance selection for advantageous traits, including resistance in livestock to disease. Traditionally, breeding strategies have not been designed to select for host resistance and desirable production traits at the same time. One alternative to the traditional approach is the use of genetic-marker-assisted selection, which offers an opportunity for simultaneous improvement in all the traits. Selection pressure applied to livestock for economically important traits is often accompanied by increases in stress and disease problems in production environments. Knowledge of the genetic correlation between disease resistance and immune responsiveness traits and production traits will be required to include these traits in livestock selection (Rothschild 1991). Because of the difficulty in measuring disease resistance and immune responsiveness, these traits have been ignored in most selection programs. Breeding for disease resistance also is difficult because resistance is regulated by genes at numerous loci and is greatly influenced by environmental factors. Heritability estimates (the percentage of variation controlled by genetics) for resistance to most livestock diseases that have been studied are low (Warner et al. 1987; Rothschild 1989). However, genetic variation among animals for disease traits is reasonably large, making breeding for disease resistance possible and justified. New tools of molecular biology make it possible to simultaneously improve production and disease resistance traits. Molecular genotyping techniques allow the detection of DNA polymorphisms. Such polymorphic marker loci can be used in marker-assisted selection. For example, selection for a disease resistance gene, for which there is no direct method of genotyping, can be effected by selection for the appropriate alleles at linked marker loci (Archibald 1991). A few examples of successful genetic selection strategies already exist for disease resistance in most food-animal species. Broilers are mostly free of Marek’s disease and avian leukosis as a result of genetic screening of breeding stock. The use of restriction fragment length polymorphisms to breed for desirable production characteristics and disease resistance is being tested in poultry (Marini 1995). A new DNA test for the porcine stress syndrome (a noninfectious congenital defect) is widely used in the pork industry to eliminate animals with that syndrome from the breeding herd. Dairy breeders can use a DNA-based test to detect and remove carriers of bovine leukocyte adhesion deficiency. The Ndama breed of cattle in West Africa is resistant to trypanosomiasis, and genetic research is under way to transfer this trait to other cattle. Research on the major histocompatibility complex in humans and laboratory animals has been fruitful. In the cow, that complex is known as the bovine lymphocyte antigen (BoLA) complex, and much progress has been made in understanding how it promotes disease resistance. Associations between specific BoLA alleles and mastitis, tick

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The Use of Drugs in Food Animals: Benefits and Risks resistance, enzootic leukosis, milk fat, milk protein, and weight gain have been reported (Stear et al. 1985). A Canadian study reported a significant influence of specific BoLA class I alleles on traits with economic importance, such as disease-treatment costs (Batra et al. 1989). Breeding programs for dairy cows have resulted in great genetic improvement for milk yield but have led to increased susceptibility to mastitis, because thus far, the correlation between milk yield and disease resistance is negative. Simulation studies showed that breeding programs based on milk and butterfat production increased the number of cases of clinical mastitis per cow per year by 0.02, resulting in a loss of 180 kg of milk per lactation and a cost of approximately $50.00 (Standberg and Shook 1989). Genetic variation in resistance of cows to mastitis can be used in selection programs to improve disease resistance. However, it is long-term process that must be cost effective if it is to be a part of disease control programs. Shook (1989) organized the approaches to disease control according to priority and, within a category of preventive measures, listed genetic improvement last—after eradication, sanitation, and enhancement. Biochemical markers can be used to predict susceptibility to mastitis. For example, the M-blood-group system might be closely linked to the BoLA system, and the presence of the M-blood-group system was found to be associated with increased incidence of mastitis (Larsen et al. 1985). Jensen et al. (1985) observed that cows carrying the M-factor (M/M and M/–) appeared to exhibit higher frequencies of mastitis than did cows that lack that factor. Likewise, Walawski et al. (1993) found higher SCCs in M-positive cows than in M-negative cows. Enhancing immunity also could offer alternatives to the use of antibiotics in food animals. Animals vary in their ability to resist, control, or reject infections. The complex interactions between a pathogen, the environment, and the host are controlled by many genes. Only a small number of the genes that control the variations and the specificity or quality of immune responses have been identified and characterized. Strains selected for resistance to one pathogen or for a high immune response potential are not necessarily resistant to all pathogens. Genetics can control the response to infection in 3 ways: by controlling innate immunity, by determining the specificity of acquired responses, and by affecting the magnitude of the acquired immune response (Doenhoff and Davies 1991). Those mechanisms and the genetics controlling them can be exploited with the use of molecular biology approaches to develop more effective biological products and immune-enhancing strategies. RECOMMENDATIONS • The committee recommends increased investment of research funds on the influence of nutrition and other management practices on immune function and disease resistance in all species of food animals. Such investment, aimed

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The Use of Drugs in Food Animals: Benefits and Risks particularly toward whole-animal studies, could significantly increase our understanding of this complex issue. Specifically, there is great need to define the effect of meeting requirements in states of deficiency, to refine the effect of supplementing beyond the state of adequate growth requirement, and to further refine the requirements for growth and productivity in contrast to those needed for optimal immune function. Of particular importance is the identification of feeding strategies that decrease or prevent the development of stress-related disease opportunities by specific use of diets or diet ingredients in anticipation of stresses—such as shipping, weaning, and group penning—that animals might experience. In addition, increases in private and public funding and conduct of research in the identification of nutrient–gene interactions that modulate immune function will enhance our ability to determine how nutrient components can be helpful in mitigating challenges to animal health. • The committee recommends increased research funding for development of new vaccination techniques and a better understanding of the biochemical basis for antibody production and manipulation in vivo. New strategies for vaccination regimens offer promise to allow the host animal to develop its own biological response to control pathogens, and research funding should underwrite this approach. Likewise, research on integrating the immune and production responses, including genetic selection, will benefit the quest to reduce dependence on drug use to maintain production capabilities. Genetic selection, molecular genetic engineering of food animals for disease resistance, and immune enhancement could increase the efficiency of milk and meat production. However, use of such strategies will not reduce the reliance on drugs in livestock production in the immediate future. Research efforts also are needed in gene mapping, development of molecular techniques, and genetic evaluation of food-producing animals.