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APPENDIX K ANT IBIOT ICS IN ANIMAL FEEDS Committee on Animal Health and the Committee on Animal Nutrition Board on Agriculture and Renewable Resources National Research Council 317

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CONTENTS EXE CUT IVE SUMMARY CHAPTER 1 INTRODUCT ION ClIAPTER 2 SUBTHERAPEUTIC USE OF ANTIBIOTIC S Animal Management Swine Poultry Cattle and Sheep Amount Used and Feed Preparation Swine Poultry Ruminants Effects of Restrictions Swine Poultry Ruminants Economic Effects of a Ban on the Use of Antibiotics Future Changes in Antibiotic Use Alternatives Environmental and Management Changes Selection for Genetic Resistance in Natural Immunity Development of Vaccines Adaptation of Minimal Disease Programs Development of New Antibiotics CHAPTER 3 EFFICACY OF ANTIBIOTICS IN ANIMAL FEEDS Swine Poultry Cattle and Sheep CHAPTER 4 RESTRICTIONS ON ANTIBIOTICS IN EUROPE Background Antibiotic Use Performance Resistance CHAPTER 5 EFFECTS ON ANIMAL DISEASE OF SUBTHERAPEUTIC USE OF ANTIBIOTICS 319 321 325 328 328 328 331 332 332 332 333 336 338 338 338 339 339 341 343 344 345 345 345 346 347 347 350 350 354 354 355 357 357 360

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320 CHAPTER 6 THERAPEUT IC USE OF ANT IBIOT ICS Background Control and Regulation Epidemiological Considerations CHAPTER 7 VOIDS IN KNOWLEDGE AND SUGGESTED RESEARCH Effect of Tetracycline Feeding on Animal Therapy Poult ry and Swine Cattle Relation of Antibiotic Feeding to Human Health Mechanisms of Action of Antibiotics in Growth Promot ion REFERENCES 363 363 366 366 368 368 368 369 370 370 372

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EXECUTIVE SUMMARY The food-producing animal and poultry industries have under- gone a dramatic change that began around 1950. What was an ex- tensive industry became extremely intensive: units increased in animal concentration, both physically and numerically. Utiliza- tion of the beneficial responses of feed-additive antibiotics in improved growth and feed efficiency developed concurrently with the intensification of the animal industry. It has been proposed that feed-additive antibiotic usage was an integral part of this revolution in animal-production technology. It is estimated, at present, that 40 percent of the antibiotics produced are used for feed additives. Estimates allocate 0.5 million kg to the cattle industry, 1.0 million kg to poultry, 1.4 million kg to swine, and 0.4 million kg to other animals such as companion animals. The animal producer can obtain antibiotics in the form of balanced the feed-manufacturing industry. The producer also has access to and can purchase antibiotic products from farm and veterinary supply centers. Administration of antibiotics in the drinking water is becoming increasingly important in both poultry and swine production. . supplements and premixes that are processed and sold by Feedlot systems for beef cattle and sheep would not change if low-level antibiotic feedings were not permitted, but it is likely that disease problems and therapeutic use of antibiotics would increase. The discontinuance of low-level (5 to 10 g/ton) usage of penicillin and tetracyclines would have little effect on the - ~ the elimination of higher levels (100 to 200 g/ton) would make it very difficult to control bac- terial disease in young chickens and turkeys. If all tetracy- clines and penicillin were banned as feed additives for poultry, the effective alternative antibiotics and sulfa drugs would likely maintain present production and efficiency standards. However, the problem of selective pressure for some multiple ~ ~ ~ ~ ~ by plasmids may still persist DoultrY industry. However. antibiotic resistance mediated with alternative antimicrobials. 321

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322 If only tetracyclines and penicillin were banned as feed- additive antibiotics for swine, there would be little if any effect on swine productivity or efficiency. There are other promising antibacterial agents that could serve the industry well. If subtherapeutic use of feed additive antibiotics is banned, future changes in disease control will include preventing exposure to infectious agents, treatment of disease after an outbreak has occurred, and control of infectious disease by immunological means. Preventing exposure to infectious agents will be extremely diffi- cult and will result in a slowing down of animal production. Post-outbreak treatment has had variable effectiveness, but would certainly be less effective than the present use of subtherapeutic levels of antibiotics. The control of infectious disease by immun- ological means would be an ideal way to safeguard against subclini- cal infection. However, thus far there has been limited success in protecting animals against bacterial pathogens that affect the intestinal and respiratory tracts. Antibiotics have been effective in improving the rate and efficiency of gain in swine, cattle, and poultry. The responses in poultry and swine are generally greater in younger animals than in those reaching the end of the growing-finishing period. There is some evidence that the improved farrowing rate of swine is asso- ciated with the use of antibiotics. Responses in cattle have not been as great as those in swine and poultry. Improvement in rate of gain and feed efficiency in cattle has averaged about 5 percent. Evidence indicates that the effectiveness of antibiotics has not decreased over time. Antibiotics in feed have also been used in animal production in Europe since 1953. The British have monitored microbial resist- ance to antibiotics and have conducted some basic and applied re- search concerning this aspect. Although the use of antibiotics in the United Kingdom has been restricted as a result of the Report of the Joint Committee on the Use of Antibiotics in Animal Husbandary and Veterinary Medicine (referred to in this report as the Swann Report; Swann et al. 1969), the total tonnage used in animal pro- duction in 1975 was at an all-time high. Although the amount used in animals was only about 15 percent of the total usage, the ratio of the human population to the livestock population receiving anti- biotics is substantially higher than in the United States. Ingestion of antibiotics results in the development of resist- ance in bacteria such as in the E. cold and Salmonella species. The resistance appears to be related to usage patterns. British research

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323 has shown that resistance persists longer following long-term use, compared to short-term use. There is strong evidence that development of resistant strains of bacteria in humans is closely related to antibiotics used in humans. No concrete evidence has been reported in the United Kingdom showing that antibiotic re- sistance has decreased since cne use has decreased. Swann Report, or that antibiotic The wise use of antibiotics is not a substitute for, but a complement to, good sanitation and husbandry practices. Ex- tensive use of low-level antibiotics in feeds has brought about concern for potential harmful effects due to development of resistant strains of organisms in host animals that might cam- promise animal as well as human health. Drug resistance in bacteria was observed soon after the introduction of antibiotics. Antibiotics have been used extensively in animal feeds for nearly 30 years. Questions and discussions concerned with the potential human health hazards from subtherapeutic antibiotic feeding to animals have been aired for nearly 30 years. Yet, it is difficult - ~ - ~ ran he Tori hi .~n~r; fist lv to cite human health problems that ~ rid to meat animals fed antibiotics or that can be associated with contact with animals fed low levels of antibiotics. There have been incidents of salmoneDlosis in humans involving antibiotic- resistant strains of animal origin but there is no evidence of any relation to low-level antibiotic feeding. Surveys of the use of drugs for therapeutic purposes indi- cate that antibacterial agents account for almost 50 percent of drugs used by practicing veterinarians. In vitro testing has sometimes been questioned in that infections associated with organisms that seem to be resistant In vitro are quite respon- sive to antibacterial therapy In viva in clinical use. Scattered reports, published and unpublished, attribute failure in drug therapy to low-level antibiotic feeding. Others claim continued effectiveness of drugs previously fed for long periods at subtherapeutic levels. Carefully controlled studies exploring possible relationships between antibiotic feeding and subsequent drug effectiveness are needed. Critical experimental studies on the effect of low-level antibiotic feeding on animal therapy and human health are de- finitely needed. It is proposed that studies be conducted in the following areas:

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324 1. Does Feeding of Tetracycline and Penicillin Compro mise Animal Therapy?--This research should be done with swine, poultry, and cattle. In swine and poultry, conditions should be closely controlled. In cattle it would seem essential that re- search be conducted in commercial-type feedlots. 2. The Relationship of Antibiotic Feeding to Human Health-- Although these studies are very complex and time-consuming, it is important that some effort be started in this direction. The incidence of disease-resistant organisms could be determined in humans in industries in which the workers have close contact with animals and animal products and with people who work in industries that have no contact with animals or animal products. Also the incidence of disease and the effectiveness of therapy should be studied. Some information might be obtained by surveys of exist- ing information. 3. Mechanisms of Action of Antibiotics in Growth Promotion-- Current evidence strongly suggests that the growth-promoting effect from low-level feeding of antibacterial compounds is not solely related to disease prevention. Knowledge of the mechanisms involved is a vital missing link. If known, the study of other means of eliciting a similar response would become feasible. Thus such new knowledge would offer the potential for eliminating some or all of the current reasons for using feeding levels of antibac- terial drugs. ,

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CHAPTER 1 INTRODUCTION The use of subtherapeutic levels of penicillin and the tetra- cyclines in animal feeds has raised the question of the effects of such practices on human health. The Food and Drug Administration (FDA) has proposed a ban on certain antibiotics at subtherapeutic levels in feed because of the potential for compromising the health of humans. A large segment of the regulated industry, including fanners and ranchers, has contended that in nearly 30 years of use, antibiotics at subtherapeutic levels in animals have not compro mised human or animal health or influenced the therapy of human disease. The FDA has contracted with the Assembly of Life Sciences, National Academy of Sciences, for a review and evaluation of human health effects of antibiotics in animal feeds. The Committee to Study Human Health Effects of Subtherapeutic Antibiotic Use in Animal Feeds has been appointed to: 1. study the human health effects of subtherapeutic use of penicillin and tetracyclines (chlortetracycline and oxytetracy- cline) in animal feeds; 2. review and analyze published and unpublished epidemiolog- ical and other data as necessary to assess the human health conse- quences of the subtherapeutic use of penicillin and tetracyclines in animal feeds; and 3. assess the scientific feasibility of additional epidemio- logical studies, and, if needed, to make recommendations about the kind of research necessary, its estimated cost and time requirements, and possible mechanisms to be used to conduct such studies. Under the teems of the contract, subtherapeutic levels are defined as use of the agent at levels of 200 g/ton or less, and/or use of the agent for 2 weeks or longer. Animal feeds include milk replacers, medicated blocks, and liquid feeds. The Committee has requested the Board on Agriculture and Renewable Resources (BARR) to prepare a critical review/position paper on certain aspects of the problem. The following list of questions to be answered was submitted to the BARR (the Chapter 325

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326 numbers after each question refer to the chapter in this report that discusses the question): 1. How effective are antibiotics--especially penicillin and tetracycline--in animal feeds? (Chapter 3) 2. Would animal husbandry methods change if antibiotics were eliminated, or if penicillin and tetracyclines were removed? (Chapter 2) 3. Does animal disease decrease as a result of use of antibiotics and would there be an increase in therapeutic use of antibiotics if subtherapeutic use was discontinued? (Chapter 2) 4. What do the data from European countries show with re- spect to animal health and nutrition where antibiotics have been restricted? Has the restriction of subtherapeutic use led to increased therapeutic use, thus cancelling the benefits of restriction? (Chapter 4) ter 2 5. Is it likely that there would be a black market? (Chap- 2) 6. How much therapeutic use is there and has it caused resistance problems? What is the evidence that therapeutic use of penicillin and tetracyclines contributes to resistance and possible health effects? (Chapter 6) 7. What epidemiological studies exist that would be valuable for the committee to consider? Are there epidemiological studies that should be carried out? (Chapter 6) 8. What amounts of penicillin and tetracyclines are used subtherapeutically? (Chapter 2) 9. What amounts of penicillin and tetracyclines are used therapeutically? (Chapter 6) 10. How are animal feeds prepared and how are the antibiotics used in animal feeds mixed and used by farmers or feedlot operators? (Chapter 2) 11. How are antibiotics for therapeutic use in animals regu- lated? Do veterinarians have guidelines or antibiotic audits? (Chapter 6)

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327 12. Has therapeutic efficacy been compromised by the use of subtherapeutic levels of antibiotics in animal feeds? Are resistant infections more prevalent in animals? (Chapters 5, 6) 13. Critically review the documentation for increase in resistance, pathogenicity, and increase in numbers-of pathogens after use of subtherapeutic antibiotics. (Chapters 5, 6) BARR asked its Committees on Animal Nutrition and Animal Health to set up a panel of their members and outside consul- tants to address these questions. The Panel met on June 11 and July 2 to 3, 1979, and prepared the statement that follows that addresses the 13 questions. The panel is indebted to Enriqueta C. Bond and Roy Widdus, of the Division of Medical Sciences, for providing published research documents on the subject, and to Philip Ross and Selma P. Baron for their advice and guidance in the preparation of the report.

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366 the relative importance of the human as a source of resistant orga- nisms in animals or of animals as a source of resistant organisms in man. Furthermore, it would be impossible at the present time to say whether the resistant organisms arose as a result of subthera- peutic antibiotic feeding, prophylactic use, or therapeutic use for the treatment of a specific disease outbreak. CONTROL AND REGULAT ION Control and regulation of the therapeutic use of antibiotic drugs is under the purview of the FDA, particularly the Bureau of Veterinary Medicine and the Bureau of Foods. Control is exercised through the mechanism of the New Animal Drug Application (NADA). Once approval is granted and the drug is marketed, therapeutic use by veterinarians and in some cases by livestock producers follows. Such usage is based on the indications of the drug; the experience of the practitioner; and the inherent constraints of the dosage, route of administration, and the residue or withdrawal times. In the overwhelming majority of cases care is taken to observe the requirements of proper withdrawal times for either milk or meat. Frog time to time, the question of auditing antibiotic drug usage arises, primarily within the setting of human hospitals. Other than in an institutional setting, the auditing of drug usage would be very time consuming, costly, and difficult to control. EPIDEMIOLOGICAL CONSIDERATIONS There is general agreement that the use of antibiotics in both animals and humans leads to increased frequency of antibiotic resistance. Furthermore, there is little doubt that resistance can be transferred through plasmids from certain resistant micro- organisms to others that were originally sensitive. These in turn have been shown to be transmissible to other animals and, in iso- lated cases, to humans (Levy et al. 1976 a,b; Hirsh 1977~. This resistance transfer or infectious drug resistance has led on the part of some individuals, to the fear that resistant strains could be transferred to other animals and humans, thereby creating a reservoir of pathogens, which when involved in clinical infections, would be unresponsive to antibiotic treatment. While such fears may seem to be a logical extension of current knowledge regarding resistance, there is practically no information on the extent to which this is happening, nor is it clear in the case of the few such instances known whether they were due to low-level antibiotic

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367 feeding, therapeutic use of antibiotics in domestic animals (in- cluding companion and pet animals), or therapeutic or prophylactic use of antibiotic drugs in human beings. These vexing questions are not easily resolved, particularly in view of the fact that both humans and animals often share the same pathogens.

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CHAPTER 7 VOIDS IN KNOWLEDGE AND SUGGESTED RESEARCH Although voluminous research has been conducted regarding the effects of feeding antibiotics on performance, research has been very limited in certain other areas. Research results have shown that resistance of microorganisms exists in animals fed antibiotics and that this resistance can be transferred (Lipton 1977 a,b; Smith 1977a). However, there is inconclusive evidence that the use of antibiotics as growth promotants compromises therapy of humans and -animals. Few well-designed experiments have been reported, and clearly there is a need for well-designed intensive investigations of this important issue. The main objectives of the proposed research to fill in the primary voids concerning antibiotics are to determine: (a) if the feeding of tetracyclines and penicillin compromise animal therapy, (b) the relation of antibiotic feeding to human health, and (c) the mechanism of action of antibiotics in growth promotion. It is suggested that the research described in the following pages be undertaken. EFFECT OF TETRACYCL INK FEEDING ON ANIMAL THERAPY Poultry and Swine The possibility that administration of subtherapeutic levels of antibiotics may compromise therapy has not been adequately in- vestigated. Most previous studies have given negative results with respect to this question, but according to the FDA (U.S. DHEW/FDA 1978) experiments generally were poorly designed. Carefully planned and controlled experiments conducted with poultry and swine should be conducted to attempt to answer this question with organisms such as Salmonella typhimurium. This organism should be used in these animals to determine whether development of resistant organisms will compromise treatment of a severe infection in the species. Chicks and swine should be inoculated with S. typhimurium to induce a low- level, nonlethal infection, and be fed diets with and without tetra- cycline. After a few weeks the animals will be challenged with an inoculum calculated to cause a severe infection resulting in con- siderable mortality. This inoculum should be isolated from animals 368

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369 fed antibiotic and should be documented to contain antibiotic- resistant organisms. The effectiveness of therapeutic levels of tetracyclines and other antibiotics against this infection should be determined. To avoid the problem of possible develop- ment of immunity, animals unexposed to the organism should also be inoculated with the dose to cause a severe infection, and the effectiveness of antibiotic therapy in these animals should also be investigated. Careful laboratory work to monitor development of antibiotic-resistant organisms in the animals and immunity development would be needed. Cattle Cattle in commercial feedlots should be studied that (a) have not received antibiotics; (b) have received a high level of anti- biotic during the first 3 to 4 weeks, followed by a low level during the remainder of the period on feed; and (c) have received a high level of antibiotic during the first 3 to 4 weeks, followed by withdrawal of the drug. Comparisons should be made of tetracycline therapy on sick animals from the lots on the various treatments. Response to therapy should also be monitored by the number of ani- mals treated, the length of stay in the sick pens, and mortality. Measurements should also include antibiotic susceptibility of orga- nisms in treated animals and samples of healthy animals from all lots at periodic intervals. This type of experiment will need to be performed in coopera- tion with university or USDA scientists and feedlots. It would be ideal for most of the feedlots to be in the California and Arizona area where antibiotics are not normally used. However, it would be important that some feedlots, at least those that are treated, be located in the Colorado or Kansas area, where a continuous level of feeding of tetracyclines is routinely practiced. It will be essen- tial that the cooperating feedlots use only tetracycline as the subtherapeutic and therapeutic drug. It will be essential to reim- burse the feedlots for death losses above the normal mortality rate caused by the experimental treatments. Also, some compensation will have to be made for the extra labor involved in handling the cattle, such as monitoring the normal animals for antibiotic-resistant orga- nisms. The organisms used to monitor resistance will likely be a common species of Salmonella and E. colt.

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370 RELATION OF ANTIBIOTIC FEEDING TO HUMAN HEALTH The information which would be required to answer the con- troversial question will necessitate investigations of staggering complexity and cost. It is likely that broad-based studies will involve monitoring of health-related problems among human popula- tions involved in and isolated from low-level antibiotic feed programs. Of course, when studying people involved with animals and animal products, animal health should also be monitored. Baselines must also be established by determining the history of the subjects with regard to antibiotic exposure and the suscepti- bility of the microflora species to antibiotics. Recent experiments with animals have shown that randomly selected individuals already carry some resistant enteric micro- organisms. It may be necessary to study respiratory bacterial flora instead of, or in addition to, the changes or lack of changes in susceptibility by species over a period of time and the nature of any disease episode particularly if suggestive of microbial etiology. The susceptibility of any agent thought to be involved would have to be established and the success of anti- microbial therapy determined clinically and microbiologically. The logistics and mechanics of this type of study will be extremely demanding in time and labor. Some aspects, especially those in- volving humans, would require several years, a large population, or both, for the collection of adequate data. If the microflora present at the onset is already predominantly resistant to the antimicrobials of interest, this study would be pointless. MECHANISMS OF ACTION OF ANTIBIOTICS IN GROWTH PROMOTION Growth promotion from the low-level feeding of antibiotics refers to an improvement in both rate of gain and efficiency of feed conversion. Improvement normally occurs in both measures of performance but not necessarily to the same degree. In view of known factors that influence rate and efficiency of gain, anti- biotic action affecting each measure of performance should prove to be, at least in some respects, different. The different chemical nature, adsorbability, and bacterial spectrum of growth promoting antibiotics suggest that the mode of action in growth promotion cannot be the same for all of the anti- biotics that have proven efficacious. There is also good evidence that antibiotic action affecting growth in the different species is not entirely from the same mode of action. Factors involved are

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371 the complex mechanisms related to disease, feed intake, digestion, absorption, and metabolism of nutrients, as well as antibiotic effects on enteric flora and the systemic bacterial population. In swine, frequent measurement of rate and efficiency of gain in control and antibiotic-fed animals reveals that a response to the antibiotic is not consistent but occurs only occasionally, and for what is usually a short period of time. Such an effect over an extended period promotes average performance above controls. In view of this important temporary effect, studies are sug- gested in which short-term performance measurements (feed intake and rate of gain) are correlated with similar short-term measure- ments related to the microbiology and biochemistry of the different physiological systems in control versus responding animals. In- testinal cannulation to permit sampling of ingesta at different points in the tract, together with simultaneous blood measurements, are needed for such an approach. Experiments designed to uncover mechanisms related to the growth-promo/ant effect might provide a means of exploiting these mechanisms other than by the use of feeding levels of antibacter- ial compounds.

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372 REFERENCES Anderson, E. S. (1968) The ecology of transferable drug resistance in the enterobacteria. Annual Review of Microbiology 22:131 Anonymous (1978) Feed marketing and distribution. Reference issue. Feedstuffs 50~30~:6. Anonymous (1979a) Animal production and public health: TV programme looks at risks. Veterinary Record 104:443. Anonymous ~1979b) Salmonellosis : An unhappy turn of events. Lancet 1:1009. Anonymous ( 1979c) Feed Additive Compendium. Minneapolis, Minn.: Miller Publishing Co. Beeson, W. M. (1978) Use of drugs and chemicals as feed additives to increase the productivity of sheep. Paper prepared for the Office of Technology Assessment, U.S. Congress. Washington, D.C.: U.S. Government Printing Office. Braude, R. (1978) Antibiotics in animal feeds in Great Britain. Journal of Animal Science 46:1425. Braude, R., H. D. Wallace, and T. J. Cunha (1953) The value of antibiotics in the nutrition of swine: A review. Antibiotics and Chemotherapy 3:271. Burroughs, W., C. E. Summers, W. Woods, and W. Zmolek (1959) Feed additives in beef cattle rations. Animal Science Leaflet, AH 805. Ames, Iowa: Iowa State University. Davis, G. K. (1978) Drugs and chemicals in livestock feeding. Paper prepared for the Of f ice of Technology Assessment, U.S. Congress. Washington, D.C.: U.S. Government Printing Office. Fagerberg, D. J. and C. L. Quarles (1979) Antibiotic Feeding, Antibiotic Resistance and Alternatives. Somerville, N.J.: American Hoechst Corporation.

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373 Foster, L. and W. Woods ( 1970) Liver losses in finishing cattle. EC 70-218: 1, University of Nebraska Beef Cattle Report. Lincoln, Nebr.: University of Nebraska. Gilliam, H. C., Jr. and J. R. Martin (1975) Economic importance of antibiotics in feeds to producers and consumers of pork, beef and veal. Journal of Animal Science 40: 1241. Hays, V. W. ( 1978) Effectiveness of feed additive usage of antibacterial agents in swine and poultry production. Paper prepared for Office of Technology Assessment, U. Congress. Washington, D.C.: U.S. Government Printing Office. ,9. Headley, J. C. (1978) Economic aspects of drug and chemical feed additives. Paper prepared for the Office of Tech- nology Assessment, U.S. Congress. Washington, D.C.: U.S. Government Printing Office. Hepp, R. E. (1977) Swine Farrowing Cooperatives. Cooperative Extension Service Bullet E-1056. East Lansing, Mich.: Michigan State University. Hirsh, D. and N. Wiger (1977) Effect of tetracycline upon transfer of an R-plasmid from calves to human beings. American Journal of Veterinary Research 38:1137-1138. Hjerpe, C. A. (1976) Treatment of bacterial pneumonia in feedlot cattle. Page 33, Proceedings of the 8th Annual Convention of the Association of Bovine Practitioners, Atlanta, Georgia. Levy, S. B., G. B. Fitzgerald, and A. B. Mac one (1976a) Changes in intestinal flora of farm personnel after introduction of a tetracycline-supplemented feed on a farm. New England Journal of Medicine 295:583-588. Levy, S. B., G. B. Fitzgerald, and A. B. Macone (1976b) Spread of antibiotic-resistant plasmids from chicken to chicken and from chicken to man. Nature 260:40-42. Linton, A. H. (1977a) Antibiotic resistance: The present situation reviewed. Veterinary Record 100:354 .

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374 Linton, A. H. (1977b) Antibiotics, animals and man: An appraisal of a contentious subject. Pages 315-343, Antibiotics and Antibiosis in Agriculture with Special Reference to Synergism, edited by M. Woodbine. Boston, Mass.: Butterworths. McCauley, E. H. (1974a) The contribution of veterinary service to the dairy enterprise income of Minnesota farmers: Farm production equation analysis. Journal of the American Veterinary Medical Association 165:1094. McCauley, E. H. (1974b) Economics and diseases of farm livestock. Canadian Veterinary Journal 15:213. McDonald, M. C. (1973) A Study of Pasteurella haemolytica isolated from feedlot cattle. M.S. Thesis, University of California, Davis. Melliere, A. L. and W. P. Waitt (1971) Evaluation of weight gain and feed efficiency promoting efficacy of tylosin and tylosin-sulfamethazine in swine during the years 1959-1970. Feedstuffs 43~35~:23. Paulsen, A. and M. Rahm (1979) Development of subsidiary sow- farrowing firms in Iowa. Iowa Agricultural and Home Economics Experiment Station Special Report 83. Ames, Iowa: Iowa State University. Richmond, M. H. and K. B. Linton ( 1980) The use of tetracycline in the community and its possible relation to the excretion of tetracycline-resistant bacteria. Journal of Antimicrobial Chemotherapy 6:33. Scientific Committee for Animal Nutrition (1978) Report's Final Series. Commission of the European Communities. Smith, H. W. (1967) The effect of use of antibacterial drugs, particularly as food additives, on the emergence of drug- resistant strains of bacteria in animals. New Zealand Veterinary Journal 15~9~:153.

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375 Smith, H. W. (1977a) Antibiotic resistance in bacteria and associated problems in farm animals before and after the 1969 Swann Report. Pages 344-357, Antibiotics and Antibiosis in Agriculture with Special Reference to Synergism, edited by M. Woodbine. Boston, Mass.: Butterworths. Smith, M. G. (1977b) Transfer of R factors from Escherichia cold to salmonellas in the ragmen of sheep. Journal of Medical Microbiology 19:29. Stemme, C., V. J. Rhodes, and G. Grimes (1978) Defining the status of large hog farms. Hog Farm Management 15~13~:52. Stemme, C., V. J. Rhodes, and G. Grimes (1979) Defining the shape of the hog industry. Hog Farm Management 16~3~:44. Stowe, C. M. (1975) Antibiotic therapy in veterinary medicine: Uses and misuses. In Pharmacology in the Animal Health Sector, edited by L. E. Davis and L. C. Faulkner, Fort Collins, Colorado. Swann, M. M. et al. (1968) Report of the Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine. London: Her Majesty's Stationery Office. Teague, H. S. (1971) Antibiotics in swine feeds. In Proceedings of the American Pork Congress, March 2, 3, and 4, 1971. Des Moines, Iowa: National Pork Producers' Council. Threlfall, E. J., G. R. Ward, and B. Stowe (1978) Epidemic spread of a Chloramphenicol-resistant strain of Salmonella typhimurium phase type 204, in bovine animals in Britain. Veterinary Record 130:438-444. U.S. Bureau of the Census (1978) Census of Agriculture. Vol. II, Statistics by Subject: Livestock, Poultry, Livestock and Poultry Products, Fish. Washington, D.C. U.S. Department of Commerce. U.S. Department of Agriculture (1978) Economic effects of a prohibition on the use of selected animal drugs. Agr. Econ. Report No. 414. Economics, Statistics and Cooperatives Service. Washington, D.C.: U.S. Department of Agriculture.

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376 U.S. Department of Agriculture (1979a) Cattle on Feed Reports. Economics, Statistics, and Cooperatives Service. Washington, D.C.: U.S. Department of Agriculture. U.S. Department of Agriculture (1979b) Livestock and Meat Statistics. Economic Research Service. Washington, D.C.: U.S. Department of Agriculture. U.S. Department of Health, Education, and Welfare/Food and Drug Administration (1972) The Use of Antibiotics in Animal Feeds. FDA Task Force Report, Bureau of Veterinary Medicine. Rockville, Md.: Food and Drug Administration. U.S. Department of Health, Education, and Welfare/Food and Drug Administration (1978) Draft environmental impact statement: Subtherapeutic agents in animal feeds. Washington, D.C.: Food and Drug Administration, Bureau of Veterinary Medicine. Van Arsdall, R. N. (1978) Structural characteristics of the U.S. hog production industry. Agr. Econ. Report No. 415, Economics, Statistics, and Cooperatives Service. Washington, D.C.: U.S. Department of Agriculture. Warner, R. G. (1972) Antibiotics in veal calf and dairy replacement calf nutrition and disease control. Presentation before the FDA Task Force, Denver, Colorado, September 16-17, 1970. Woods, W. (1970) Antibiotics in beef cattle nutrition disease control. Presentation before the FDA Task Force, Denver, Colorado, September 16-17, 1970. Zimmerman, D. R. (1968) Antimicrobial feed additives for swine. A paper presented at the Annual Meeting of the Iowa Pork Producers, Des Moines, Iowa.