1 Antibiotics Use in Agriculture: An Overview Richard H. Gustafson Downloaded via 148.251.232.83 on October 16, 2018 at 00:12:00 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. Agricultural Research Division, American Cyanamid Company, Princeton, NJ 08540 Antimicrobial agents and antibiotics in particular have been utilized in livestock rearing for more than thirty years. This has allowed the production of meat, eggs, and milk at levels of efficiency significantly higher than that seen in the pre-antibiotic era. In terms of current kilogram amounts in the U.S., the feed additive uses far surpass all other uses in agriculture and approach the total amount utilized in human medicine. Starting in the 1960's, the use of antibiotic feed additives has been questioned by some as a potential threat to human health. This long standing controversy has been a difficult one for regulatory officials, scientific advisory groups, and legislators who must decide whether directed changes in current agricultural uses are justified. The use of antibiotics in agriculture is a subject of wide variety and complexities. It is also a subject of considerable controversy. It was in the years surrounding 1950 that Dr. Jukes and his colleagues demonstrated that chlortetracycline at low levels, i.e. 20 ppm and lower, could improve performance in livestock (J.). By performance we mean the rate of gain and the amount of feed per unit of gain. Antibiotics, particularly penicillin, had been used in animals prior to that period, but only as an injectable in sick livestock or as mammary infusions in lactating dairy animals suffering from mastitis. After Stokstad and 3ukes opened the door and many agricultural researchers walked in, the development of antimicrobials as feed additives developed at a rapid pace (2). Registration and Commercialization Today, in the United States, the FDA is responsible for examining safety and efficacy data before an antibiotic or synthetic chemical may be commercialized for livestock use. This includes studies on formulations, product stability, conventional and genetic toxicity, environmental safety, metabolism, residue studies in target animals, studies on antibiotic resistance in gut microflora and on salmonella shedding in target animals. Similar requirements are part of registering these products in overseas markets. In general, after a product is discovered in the laboratory, many 0097-6156/86/0320-0001$06.00/ 0 1986 American Chemical Society
2 AGRICULTURAL USES OF ANTIBIOTICS years and millions of dollars are required to bring it to commercialization. Extending registrations of existing products to other livestock species is also a time-consuming and expensive proposition. The big three meat species are poultry, swine, and cattle. The potential markets for these groups of animals may support the required industrial research if the probability of registration and commercial success are high. On the other hand, the minor species, goats, sheep, turkeys, cultured fish often do not support large expensive programs. The dairy industry is also large and antibiotics for the control of mastitis must be considered a significant market. Antibiotics to be used as feed additives must also be inexpensive and fermentation yields often need to be improved before commercialization is possible. Some feed additives are used as biomass products. They are marketed this way because the high costs of extensive purification would make any other course impractical. A biomass product contains the inert spent products of fermentation, remnants of the producing organism, media, precipitation products, etc. The following demonstrates the number of registered feed additives according to category. Table I. The Number of Registered Feed Additives According to Category Synthetic Antibiotic 13 Anticoccidials 3 Anticoccidials 5 Antibacterials Antibacterials Histomonastats 1 Anthelmintic 8 Anthelmintics 9 Miscellaneous Antibiotic is defined here as a chemical produced in whole or in part by a microorganism in large scale fermentation. Definitions after that are somewhat grey. For example, two of the three ionophore anticoccidials currently used by the poultry industry are also used to promote feed efficiency in cattle, and that effect is certainly a consequence of antibacterial activity in the rumen. Many of the narrow spectrum gram positive antibiotics are poorly absorbed from the gut and registration claims are confined to growth promotion and feed efficiency, particularly at the commonly used levels. Other antibiotics are well absorbed and provide a significant measure of protection against bacterial disease, in addition to promoting growth and feed efficiency. It should be noted that although the summary table provides information on the variety of products which are available, the list doesn't necessarily reflect current uses. For example, synthetic chemicals dominated the anticoccidial market during the 1950's and 60's. With the introduction of monensin, the first ionophore antibiotic used for this purpose the anticoccidial market shifted away from synthetic chemicals and toward antibiotics, where it exists today. Nevertheless, the older synthetic products are still registered and are still part of the armamentarium of anticoccidials. There are more than twice as many synthetic chemicals as antibiotics registered for feed additive use. Table II lists antibacterial drugs, fermentation products and synthesized chemicals approved for use in food animals.
1. GUSTAFSON Antibiotics Use in Agriculture: An Overview 3 Table II. Antibacterial Feed Additives Synthetic Carbodox Furazolidone Nitrofurazone Sulfamethazine Sulfathiazole Antibiotic Bacitracin Methylene Disalicylate Bacitracin Zinc Bambermycins Chlortetracycline Erythromycin Lincomycin ineomycin Novobiocin Nystatin Oxytetracycline Penicillin Streptomycin Tylosin Virginiamycin The nitrofurans and sulfa drugs are antibacterial feed additives that occupy a continuing important position in the prophylaxis and treatment of livestock disease. These are products which are well absorbed and have good activity against a variety of respiratory pathogens. Carbadox, another synthetic feed additive, has been used extensively in the swine industry for performance improvement and the control of swine dysentery. Uses of Antibiotics in Animal Agriculture The antibiotic feed additives era started with the tetracyclines and this class continues to dominate the field. Chlortetracycline and oxytetracycline were initially used at fairly low levels as promoters of growth and feed efficiency. As the market for these products increased rapidly, production efficicency and fermentation yields also improved. Eventually costs came down and it was economically feasible to use them at higher levels in poultry, swine and cattle, i.e. prophylactic levels which controlled endemic bacterial diseases. A combination for swine was introduced in the 1960's, consisting of chlortetracycline at 100 g/ton, sulfamethazine at 100 g/ton, and penicillin G at 50 g/ton and it was the rapid acceptance of this product by swine producers which was partially responsible for an upsurge of antibiotic use in livestock production. At the same time tetracyclines became increasingly useful in protecting feedlot cattle from the bacterial component of respiratory diseases, as well as reducing the prevalence of liver abscesses caused by Fusobacterium. Anaplasmosis is controlled by tetracyclines in those areas where this disease is endemic in cattle. The poultry industry has also used tetracyclines at higher levels to protect flocks against respiratory diseases as well as controlling certain enteric infections. These prophylactic uses are used particularly at times and in animals in which the risk of bacterial disease is highest. This high risk situation tends to operate in young animals, or when livestock, particularly cattle, are exposed to the stresses of shipment or severe weather. It should be noted that injectable antibiotics are also used extensively in feedlot cattle with a penicillin-streptomycin combination and injectable oxytetracycline used rather extensively for respiratory disease.
4 AGRICULTURAL USES OF ANTIBIOTICS The current uses of tetracyclines in the poultry industry are almost entirely at the higher levels for the control of bacterial disease. This includes both feed additive and drinking water formulations. Tylosin and erythromycin are commonly used in the livestock industry. These macrolides show wide spectrum activity against gram positive organisms with particularly useful activity against mycoplasma in poultry, swine, and cattle. The combination of tylosin and sulfamethazine is used in swine feed. Erythromycin, the first commercialized macrolide and long the flagship of this group in human medicine, is also registered for use in poultry, swine, and cattle but is used far less than tylosin. Both erythromycin and tylosin are also used therapeutically as injectables and in drinking water for treatment of a variety of infections. The only beta-lactam antibiotics used in food producing animals are penicillin G, ampicillin, amoxicillin, hetacillin, cloxacillin, and cephapiron. Of these, only penicillin G is used as a feed additive, most of it as a combination product in the swine industry. Penicillin feed additives are also registered for use in poultry, but not in cattle. Although penicillin has negligible activity against most gram negative organisms, later generations of beta-lactams have had a much broader spectrum. This group of antibiotics has been the subject of a great deal of pharmaceutical company research, primarily because of the existence in nature of a wide variety of beta-lactamases and cephalosporinases, enzymes which break down various members of this class. Beta-lactam antibiotics continue to be in the forefront of human medicine and as mammary infusion products in the dairy industry. Aminoglycosides registered for feed additive use include streptomycin and neomycin although these antibiotics currently are not being used extensively. Gentamicin and kanamycin are not registered for feed use but are approved as injectables. Gentamicin is also used in an egg dip solution to control specific pathogens in the turkey industry. The general group of antibiotics characterized by gram positive activity and poor absorption from the gut are used principally for growth promotion and feed efficiency in the swine and poultry industry. These include bacitracin, the bambermycins, and virginiamycin. In addition, two products of this type used freqently in Europe and the Far East are avoparcin and nitrovin. The growth promoters major claims are for improved rate of gain and feed efficiency, although occasionally claims at high levels for disease control have been allowed. For example, virginiamycin is registered at 25 to 100 grams/ton for control of swine dysentery in the United States. In the European Economic Community, these growth promoters are used free sale, strictly for performance purposes and disease claims are not made. Therapeutic and prophylactic feed additives for the control of bacterial infections are used by veterinary order. Although the feed additive uses of antibiotics have been emphasized, it should be noted that the uses as injectables for therapy, mammary infusions for mastitis, boluses, pills, capsules, medicated blocks, and drinking water formulations include a wider variety of antibiotics than are added to feeds. Many of these are currently used at the discretion of the meat producer or dairyman, others must be used under the direction of a veterinarian. For example, chloramphenicol is an antibiotic which the veterinarian has access to, but which the FDA has indicated should not be used in livestock destined for human consumption, primarily because of the
1. GUSTAFSON Antibiotics Use in Agriculture: An Overview 5 Agency's concern about the potential for toxic residues in humans. This antibiotic is used in European livestock. Extent of Antibiotic Use A question which should be considered here is the extent of antibiotic use in meat production. It's difficult to obtain market figures on individual antibiotic products since the industry considers this information proprietary. It is also unclear how to best express the extent of agricultural uses. Should we be talking about dollars or kilograms? There is no doubt that in terms of kilograms, feed additive use is by far the most significant. The National Academy of Sciences in their 1980 report on feed antibiotics (3) cited figures obtained from the U.S. International Trade Commission, showing non-medical uses to be between 5 and 6 million kilograms in 1978. Unfortunately reporting by weight tends to blur the distinction between growth promoters which are used at 3 or 4 grams per ton such as the bambermycins, and coccidiostats such as monensin, which are used at 100 g/ton. The differences in feed consumption by chickens, swine, and cattle also compound the difficulty of examining antibiotic use. According to figures released by the Animal Health Institute, 1983 sales by American companies of pharmaceuticals, biologicals, and feed additives for animal agriculture exceeded 2 billion dollars (4). These figures represent sales at the manufacturers level. The total feed additive market for 1983 was about half of that total. Pharmaceutical antibacterials sold for $210 million and animal feed antibacterials at $271 million that year. In terms of value to the consumer, the Council of Agricultural Science and Technology reviewed six economic studies and concluded that feed additives save the U.S. consumer approximately $3.5 billion per year in meat prices (5). Antibiotic use accounts for most of this. Although specific figures are proprietary, the tetracyclines have dominated the product lists in terms of total use but tylosin, sulfa drugs, nitrofurans, the gram positive growth promoters and the ionophore antibiotics are also highly significant. The Public Health Question The long controversy surrounding antibiotic feed additives is principally concerned with selection of antibiotic resistant bacteria in livestock. The public health significance under consideration may be reduced to the following questions: "Do the uses of antibiotics in meat animals interfere with the continued efficacy of antibiotics in human medicine?" and secondly, if there is a connection, "would stricter controls on certain feed additive uses help maintain antibiotic effectiveness?" In the United States, the controversy has currently settled on feed additive uses of tetracyclines and penicillin. In response to similar concerns in England in the 1960's, the Swann Committee recommended that feed additives used only for growth promotion and feed efficiency continue to be permitted free sale but that antibiotics used for prevention or control of disease be used only on veterinary prescription. These regulations were implemented in England in 1971 and a few years later, by several other European countries. Most observers agree that these regulations have not altered antibiotic resistance levels in livestock and that antibiotics having disease claims continue to be widely used in these countries, even though veterinary prescriptions are required. The veal calf industry overseas uses antibiotics in milk replacer in
6 AGRICULTURAL USES OF ANTIBIOTICS order to protect the health of these young animals which are particularly susceptible to stress and bacterial infections. The FDA and industry have both been embroiled in the antibiotic resistance controversy for more than 15 years and a resolution of the dispute remains elusive. Part of the reason is that the subject is highly politicized with pressures on the FDA from a variety of sources anxious to introduce new restrictions. The communications media, TV, newspapers, periodicals have also turned their attention to this subject in recent years. Agricultural groups, industry manufacturers, and congressmen with agricultural constituencies have tended to remind the FDA that restrictions are not justified so pressure on the Agency comes from both sides of the issue. It f s my opinion that most microbiologists, infectious disease experts, and epidemiologists believe that further government restrictions on the agricultural use of antibiotics would accomplish nothing in the way of public health benefits. This overview has presented an introduction to the subject of antibiotics in animal agriculture and provides a general view of the extent of antibiotic use. The manuscripts to follow will offer more details and provide additional food for thought. Certainly the current efficient production of meat and dairy products is dependent on a wide variety of antibiotics and this will continue to be true in most Western countries in which livestock production is an important part of the economy. Literature Cited 1. Stokstad, E. L. R.; Jukes, T. H., Proc. Soc. Exptl. Biol. Med., 73; 523-528. 2. Gustafson, R. H.; Kiser, J. S., In "The Tetracycline"; Hlavka, J. J.; Boothe, J. H., Eds; HANDBOOK EXP. PHARM.; Springer-Verlag: Heidelberg, 1985; pp. 405-446. 3. "The Effects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds". National Academy of Sciences, National Research Council; Washington, March 1980. 4. Animal Health Institute; 119 Oronoco St., Alexandria, VA. 5. "Antibiotics in Animal Feeds"; Council for Agricultural Science and Technology, Report No. 88, March 1981. RECEIVED February 19, 1986