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CHAPTER 3 CRIT ICAL REVIEW OF THE EPIDEMIOLOG ICAL LITERATURE Ef fects on human health resulting from the use of antimi- crobials in animal feeds have been reviewed by distinguished scientists in the United States and Europe. Reports prepared by the Swann Committee (Swann et al., 1969), the Food and Drug Administration (FDA) Task Force (FDA, 1972), the FDA Environ- mental Impact Statement staff (FDA, 1978), the Office of Technology Assessment (1979), and the World Health Organization (1974, 1976, 1978) provide extensive coverage of the issues and background information. The majority opinion expressed in each report was that an increased prevalence of antimicrobial-resistant organisms presents a threat to human health and that the subther- apeutic use of antimicrobials increases the prevalence of R organisms in animals. In all of the reports authors were not able or did not attempt to quantitate or estimate the relative contri- but~on of the subtherapeutic use of antimicrobials in animals to health problems in humans caused by R+ organisms--one of the objectives of this study. Majorities of the individuals involved in these various studies recommended policies aimed at restricting the subtherapeutic use of ant~microbials in animal feeds, particu- larly for those agents used in the therapy of diseases in humans. The therapeutic use of antimicrobials in both animals and humans has been shown to result in an increased prevalence of resistant bacteria (Anderson, 1968a; Finland, 1979; Mercer et al., 1971~. Similar results have been demonstrated for subtherapeutic use in both animals and humans (Goldberg et al., 1961; Savage, Appendix D; Siegel, 1976; Sprunt, 1977~. There is little evidence to indicate the quantitative contri- butions of these usages to effects on human health attributable to antimicrobial-resistant bacteria. The epidemiological literature on this topic is reviewed below. INVESTIGATIONS OF EPIDEMICS A number of investigations of epidemics have indicated that antimicrobial-resistant bacteria from animals can cause infections in humans (Anderson, 1968a; Anderson and Datta, 1965; Center for Disease Control, 1977; Fish et al., 1967; Lyons et al., 1980; Rowe _ al., 1979; Threlfall et al., 1978a, b). Some of these epidemics, involving Salmonella typhimurium phage type 1 (Anderson and Datta, 1965), phase type 29 (Anderson, 1968a), and phage types 204 and 193 22

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23 (Rowe _ al., 1979; Threlfall, 1978a,b), took place in the United Kingdom. One case in Canada was also caused by S. typhimurium (Fish _ al., 1967~. Another outbreak, which took place in Connecticut, involved S. Heidelberg (Center for Disease Control, 1977; Lyons et al., 1980~. In the earlier outbreaks in the United Kingdom, there was substantial evidence indicating that the resistant bacteria were selected by indiscriminate therapeutic use of antimicrobials in animals (Anderson, 1968a; Anderson and Datta, 196 5~. The value of phase typing, as it is used in the United Kingdom, is its clear demonstration that the entire sequence of events involved in trans- mission of R+ organisms to humans via food is possible. In the Connecticut outbreak, the investigators demonstrated that the reservoir of the multiply resistant Salmonella infection was likely to have been harbored by a group of 1-week-old calves owned by one of the ill persons. Lyons et al. (1980) indicate that these calves had been treated by their owner for the diarrhea that they had when brought to the owner's farm. In the Canadian case, the patient became ill approximately 1 week after illness was observed in a cow with which he had had direct physical contact. The cow had been treated therapeutically with antimicrobials by the owner at the onset of the illness. Organisms identified as S. typhimurium phase type 10 with identical antimicrobial-resistance profiles were iso- lated initially from the cow and later from the patient. Although reports of these epidemics document the transfer of resistant bac- teria from animals to humans, there are no studies to quantitate the frequency of that occurrence. Furthermore, not all observations have reinforced the sugges- tion that a reservoir of resistant bacteria in animals provides the major source of resistant bacteria in humans. In a study conducted in Omaha, Nebraska between 1968 and 1978, Meyer and Lerman (1980) documented the rise and fall in prevalence of resistant strains of Shigella sonnet, which was a predominant pathogen in humans during that period. In 1973, they observed a peak in the prevalence of resistance to ampicillin and a similar pattern of resistance to five other antimicrobials. There was no evidence that the use of ampi- cillin in humans had changed during the course of the study. Cherubin et al. (1980) reported a very similar pattern of rise and fall of resistance to ampicillin for Salmonella typhimurium iso- lated in New York City from 1965 to 1968. He attributed this pattern in humans to an epidemic of a resistant strain but pointed out that isolates from calves and other animals in New York State did not exhibit a similar change. Calves continued to harbor ampicillin- resistant strains at a prevalence that increased annually from 1972

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24 to 1978. Thus, there is evidence for waves of resistant enteric flora in humans and in animals that do not correlate we th each other or with patterns of antimicrobial usage in humans. This suggests a substantial degree of separation of reservoirs in humans and animals. POPULATION SURVEYS By conducting retrospective health surveys of farm families, rural families with no animals, and urban families, all having had a recent hospital admission, Smith et al. (1974) attempted to determine whether association with farm animals was connected with greater risk of disease. Comparing admission diagnoses, they found no significant differences and no preponderance of antimicrobial- resistant bacterial disease. However, since there were insufficient numbers of subjects in the survey and the study design was not sat- isfactory, no general conclusion can be drawn. In other attempts to determine the possible consequences to human health from the subtherapeutic use of antimicrobials in ani- mal feeds, investigators have studied the relative prevalence of antimicrobial-resistant bacteria among various groups or have attempted to demonstrate the possibility of particular steps in the chain connecting the antimicrobials in animal feeds to increased carriage of R+ bacteria in humans. Discussions of many of these studies are contained in the consultant reports to the committee (Appendixes A-J). Those that deal with the epidemiological aspects of the question are reviewed briefly below. Limitations on the inferences that can be drawn from these narrow studies are detailed in Chapter 2. As far as the committee could determine, there ha+e been no adequate attempts to relate an increased carriage of R organisms to putative increased morbidity and mortality or dilemmas caused by resistance in the treatment of infection. Thus, predictions of the magnitude of any possible risk cannot be made from results of studies on particular stages or steps in the transmission chain. The prevalence of resistant enterobacteria in groups with vary- ing exposure to domestic livestock has been investigated by Betinov] (1972), Dorn et al. (1975), Fein et al. (1974), Linton et al. (1972), Siegel (1976), Siegel et al. (1975), Smith and Crabb (1961), Smith _ al. (1974), Wells and James (1973), Wiedemann and Knothe (1971), and Woods et al. (1972~.

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25 Smith resistance ~. . ~ al e (1974) compared the proportion of E. cold with antimicrobials among several groups of Iowa families and their livestock. They compared rural families with and with- out livestock, urban families, and both urban and rural families in which one member had recently been discharged from hospital in- patient status. Results generally indicated that the proportion of _ cold with resistance to four or more antimicrobials was greatest among families with livestock, regardless of their recent association with hospitals, and lowest among both urban and rural groups without a recent hospital association or proximity to livestock. These results include neither quantification of the transfer of resistance between animals and humans nor specifica- tion of resistance patterns. Since all livestock raised by these families had received some antimicrobials, some members of these families had been exposed to both the livestock fed antimicrobials and the feed containing the antimicrobials. However, the study does suavest that persons working with livestock that are receiving antimicrobials do harbor more resistant E. cold than do families not exposed to livestock. independent of recent hospital exposures. Unfortunately, the history of antimicrobial use by these humans was not documented. Comparing rural and urban dwellers in England, Linton et al. (1972) found a much higher proportion of drug-resistant coliform bacilli in the feces of rural adults working with livestock than in rural adults not so employed. Urban adults harbored an inter- mediate proportion of resistant organisms. Both urban and rural children less than 5 years old harbored the highest proportion of all groups tested. Although this finding suggests an association between working with livestock and increased levels of resistant organisms, the authors supplied no information on antimicrobial usage in either animals or humans nor was there a comparison of specific resistance patterns between the flora of the animals and that of the humans exposed to them. Dorn _ al. (1975) conducted a small study comparing the specific resistance patterns between Missouri farm families raising beef and hogs and their and consuming home-raised meat and their animals. They found significant association between resistance patterns in animals and families who consumed home-raised meat but not between patterns in animals and families who did not consume meat they raised. They concluded that the exposure of humans to E. cold from animals through consumption of meat was more plausible than mere contact with animals as an explanation for interspecific crossover of transferable drug resistance. animals and between families both raising

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26 Siegel _ al. (1975) compared the proportion of antimicro- bial-resistant colifonms in five groups of Illinois persons with varying exposure to antimicrobials and animals fed antimicrobials. They found that the proportion of the enteric flora with resist- ance to antimicrobials in these groups ranked in the following decreasing order: (1) people working on farms in contact with farm animals receiving antimicrobials in feed, (2) people residing on the same farms but not in contact with the animals, (3) people treated with antimicrobial drugs, (4) untreated people residing with treated individuals, and (5) untreated people not residing on livestock farms. In general, groups 1, 2, and 3 had similarly high proportions of colifonms with resistance to oxytetracyclines, dihy- drostreptomycin, and ampicillin, group 5 had the lowest proportion, and group 4 was usually intermediate. These results indicate that living on farms, raising livestock fed antimicrobials, or being treated with antimicrobials resulted in approximately equivalent proportions of organisms with resistance to these three antimicro- bials and that persons without direct exposure to antimicrobials or animals fed antimicrobials have fewer resistant organisms. Since Siegel and his colleagues presented few data concerning specific antimicrobials used in humans or animals or specific matching re- sistance patterns, it is not possible to evaluate the role of feed containing subtherapeutic levels of antimicrobials in increasing the prevalence of resistant bacteria in either animals or people. From studies conducted in the Federal Republic of Germany, Wiedemann and Knothe (1971) indicated that both farm workers and city dwellers carried enterobacteria with resistance to antimicro- bials (in some cases plasmid-med~ated), but that the proportion of the total enterobacterial flora with resistance was higher in farm workers. The significance of the results they obtained by comparing the percentages of farm workers, their relatives, feed handlers, city dwellers, slaughterhouse workers, chickens, calves, and pigs carrying resistant Enterobacteriaceae cannot be evaluated since the number of subjects in each category was not reported. Each of the studies noted above suffers from various methodo- logic deficiencies that should be avoided in future efforts. None adequately quantitates the nature and extent of exposure to antimi- crobials. Particularly lacking are data pertaining to those drugs given therapeutically to the study subjects. Moreover, the studies do not specify the type of antimicrobial given to the animals. Most of the investigators do not adequately describe the contact between the animals and the subjects. Since these studies are cross-sectional, they can indicate whether an association exists between an increased prevalence of resistant bacteria in humans and contact with animals, or direct contact with feeds containing antimicrobials, but cannot establish that such contacts cause the increase. In only one study

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27 was there an attempt to match the specific resistance patterns of _ cold from animals to those from exposed humans. None of the studies adequately documents the health status of the study subjects. Despite their limitations, these studies lead to certain conclusions. Animals fed antimicrobial agents for extended periods or treated with antimicrobials develop resistant entero- bacteria. People in close contact with those animals and their antimicrobial-containing feed are more likely to harbor resistant organisms in their gut flora than those without contact with animals. Patients who have received therapeutic drugs have a sim- ilar or even greater likelihood of carrying resistant organisms. Children who have not personally received antimicrobials also seem to have a high prevalence of R+ organisms in their flora for rea- sons that are currently not clear. Future studies can be based on the assumption that these conclusions have been reasonably well established. Two more surveys that deserve attention compared the preva- lence of resistant E. cold in meat-eaters and in those who did not eat meat. Such a comparison would indicate if eating meat from animals that were presumed to have received antimicrobials was asso- ciated with an increased carriage of R+ organisms. In a study by Guinke _ al. (1970) the groups selected as meat-eaters were mili- tary kitchen personnel and office workers; those who did not eat meat were vegetarians and infants less than 6 months of age. Because the groups were relatively small and not strictly comparable, the conclusions drawn from these studies are questionable. But the percentages of the 77 vegetarians and 87 infants yielding resistant _ cold were not significantly lower than those in the meat-eating groups. This study does not provide evidence that eating meat is associated with an increased intestinal carriage of resistant coli- fonms. Lebek (1972) reported the distribution of R factors among E`. cold isolated from feces of healthy and ill human subjects. The percentages of various groups studied having R+ organisms in their fecal flora were: hospital patients, 84% (74 of 88~; healthy nurses, 82% (82 of 100~; healthy soldiers, 51% (26 of 51~; healthy 6-9 year olds, 65% (66 of 101~; and healthy vegetarians, 57% (16 of 28~. The vegetarians were described as belonging to a religious c~mmun- ity that takes no drugs and lives on a vegetarian diet," and the children, according to their parents, had not received antimicrobial drugs during the 2 years preceding the investigation. Although it is difficult to determine if the groups were strictly comparable, the results again do not support the concept that eating meat is asso- ciated with an increased intestinal carriage of resistant colifonms.

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28 EXPERIMENTAL STUD IES In the experimental studies described below, investigators have examined aspects of the transfer of resistant bacterial strains from animals to humans. By themselves these studies do not allow quantitative prediction of risk for the general popula- tion. Hirsh and coworkers (Burton _ al., 1974; Hirsh et al., 1974~_ _ examined the effects of varying doses of oxytetracycline (OTC) on colonization of the gut in humans following ingestion of resistant E. cold of bovine origin. No differences were found in length of time the organisms were excreted by those fed either O or 50 mg OTC/day, but 1,000 mg/day did potentiate the establishment of tetra- cycline-resistant E. colt. In more direct experiments, Smith (1969) fed to a human various doses of resistant E. cold of animal origin containing unique resist- ance markers. The resident strains occasionally acquired resistance from the animal donor strains but the resistance was not maintained. In an experiment that simulated the most likely exposure to be encountered by the general public, Linton (1977) studied five humans who, over a period of 3 months, handled, cooked, and ingested 15 chickens that had been sampled for E. colt. One of the five subjects was clearly colonized after handling but before eating. The coloniza- tion was transient. As in the experiment by Smith, plasmid-mediated resistance from E. cold in chickens was transferred to a strain of _ cold in the original resident flora of the human host. In "feeding" studies, highly artificial conditions are sometimes created, e.g., huge doses are sometimes fed to a subject in a medium such as bicarbonate. Hence, results must be extrapolated with caution. In two more experiments, investigators attempted to determine whether the administration of low doses of tetracycline to animals resulted in the transfer of resistant bacteria to humans. Hirsh and Wiger (1977) studied the fecal flora from 30 calves, 16 of which were fed 350 mg/day of tetracycline, and from their 20 handlers. A low level of transfer was found irrespective of whether the calves were receiving tetracycline. Levy and coworkers (Levy, 1978; Levy et al., 1976a,b) observed an increased prevalence of antimicrobial-resistant intestinal bac- teria in a farm family in contact with chickens fed tetracycline and the tetracycline-containing feed. Later, they detected resistance in organisms isolated from chickens not fed antimicrobials and from farm personnel other than the family. Of particular interest was the reversibility of the apparent selection for resistant organisms

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29 after 9 months of usage. This was indicated by the finding that resistant organisms were not observed 6 months after discontinuance of the supplement. Furthermore, the use of only one antimicrobial (tetracycline) did lead to selection of strains with multiple resistance. There were some problems with the design of this study. More appropriate controls could have been used, and the sampling frequencies could have been more nearly equal. Resistance patterns reported in the earlier paper by Levy et al. (1976a) did not always include resistance to tetracycline, the agent in the chicken feed exerting the selection pressure. When the results of these studies are examined together, they suggest that supplementation of animal feeds with antimicrobials can select for resistance in the enteric organisms of animals. This resistance can be transferred to humans who are in contact with these animals and their feeds or to those who handle the carcasses, e.g., those who prepare food for cooking. The resistance profiles selected may include resistance to agents in addition to those added to the feed since resistance genes are often linked. In some studies the prevalence of resistance has been shown to decline when supple- mentation is discontinued. In other instances herds receiving feed believed to be free of antimicrobials and with no recent history of antimicrobial therapy have a high prevalence of R+ organisms (Smith et al., 1974)e This may be attributable to contamination of the feed (Siegel, 1976~. In January 1980, this topic was discussed at a conference sponsored by the U.S. Department of Agriculture on the contamination of feed by the sulfonamides. However, it cannot be predicted with certainty that the overall prevalence of antimicro- bial-resistant organisms in animals will decrease to low levels if the subtherapeutic use of antimicrobials in feed is ended. A large and complicated study was designed and conducted by Siegel (1976~. He attempted to use bacteriophage typing to identify E. cold strains so that he could follow their transfer from various . animal sources to humans--on the farm, in the slaughterhouse, or in the surrounding community. Despite some methodological problems, the study indicates that swine were the probable source of bacterial phage types that were found in poultry and beef cattle. These phage types were the same as those found most often in humans on farms. Presumably, they also originated from the pigs. Some of the farm strains that were prevalent on the carcasses were also found in slaughterhouse workers and in the slaughterhouse. There was evi- dence that other strains--some of which were carried by the workers or were present in the slaughterhouse--were transferred onto the carcasses at this point. Analysis of the flora of the consumers of the pork products was more difficult. Although pork consumers shared some common phage types with the workers in the slaughterhouse and

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30 on the farm, the route and extent of transfer was impossible to measure. This type of observational study is limited in what it can demonstrate, since it cannot indicate the direction in which organisms transfer. Genetically marked organisms, such as those used by Smith (1969) and Hirsh et al. (1974), might provide a better technique for following transmission. CASE REPORTS Some case reports provide evidence for the transfer of plasmid- mediated resistance under normal conditions. Petrocheilou and coworkers (1977, 1979) described tetracycline-resistant plasmids found in a number of E. cold strains from a woman who had received prolonged tetracycline treatment for acne vulgaris. Her husband, who had received no antimicrobial therapy, also harbored such strains. The two E. cold strains were indistinguishable as were the plasmids they carried. This observation suggests that E. cold carrying R plasmids may spread from individuals under treatment to untreated close contacts. The study by Neu _ al. (1973) suggested that specific resis- tance patterns could be transferred (in the intestines of one patient and in the urinary tract of another) from one organism to another. The transfer was suggested by the similar spectra of antimicrobial resistance. Corroboration of the transfer by plasmid DNA homology studies, such as those reported by Petrocheilou and coworkers (1977, 1979), was not attempted in the study of Neu et al. (1973~. Brumfitt and coworkers (1971) studied urinary tract infections caused by E. cold in patients living at home. Seven (19%) of 37 fe male patients had infections characterized by resistant E. cold and 23 (62%) carried some resistant E. cold in their fecal flora. In eight patients who had predominantly resistant (> 607) E. cold fecal flora, five had urinary tract infections characterized by resistant E. colt. In 15 patients whose fecal flora contained a ~- lower proportion of resistant E. cold (0-507), only one patient had a urinary tract infection characterized by a resistant strain. From these findings, the investigators concluded that resistant strains of E. colt, when carried in the intestine, were neither more nor less likely to infect the urinary tract than were nonresistant strains. SUBTHERAPEUTIC USE IN HUMANS The committee also examined reports pertaining to the conse- quences of long-term administration of subtherapeutic levels of ant~microbials to humans to learn if there were adequate data which,

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31 upon extrapolation, might allow conclusions to be drawn about the effects on Herman health that could result from sub~herapeutic levels of antimicrobials in animal feeds. Goldberg et al. (1961) demonstrated that low dosages (10 mg per day) of OTC increased the prevalence of resistant bacteria in prison volunteers. Some subjects who did not receive OTC shed resistant coliforms. In those individuals whose resistant bacter- ial flora was increased by OTC, the prevalence of resistant coli- forms returned to normal within 2 months after the OTC treatment was stopped. Haight and Pierce (1954) reported a study in which naval recruits were given 250 mg of chlortetracycline or 100,000 units of procaine penicillin per day orally for 7 weeks. Those receiving antimicrobials gained more weight than did the controls. There are a number of categories of infections for which anti- microbials have been used prophylactically in humans (Utz, Appendix A). A major use is the administration of tetracyclines to control acne in adolescents (Schmidt et al., 1973~. Antimicrobials are also used in the prevention of endocarditis subsequent to rheumatic fever (McVay and Sprunt, 1953~. Valtonen et al. (1977) have described the effects on enteric bacterial flora that result from neomycin prophy- laxis in patients with hypercholesterolemia. The committee examined many original research reports and a number of review articles on the subtherapeutic use of antimicro- bials in humans including the following. Many papers on the use of tetracyclines to control acne have been reviewed by the American Academy of Dermatology (1975~. Jukes (1973) described a variety of reports on the long-term administration of antimicrobials to infant and children or to patients with tropical sprue. Reports on the sub- therapeutic and prophylactic use of antimicrobials in humans have been reviewed extensively by the Council for Agricultural Science and Technology (in press) and Pfizer, Inc. (1978~. The subtherapeutic or prophylactic administration of antimi- crobials to humans generally results in an increased prevalence of resistant organisms in the recipient. Sprunt (1977) demonstrated that this increase is lower when intermittent doses are injected intramuscularly than when prophylaxis is administered orally. More- over, she reported that lower doses eliminate only a small portion of the resident flora, thereby permitting fewer resistant organisms to survive and multiply.

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32 In most of these studies no added health risk attributable to resistant organisms was recorded. However, the number of individuals involved in any one study of prophylaxis was small, and the study designs did not have as their primary objective the detection of adverse health effects of antimicrobial use. Thus, it is not possible to quantify the risk of infection from resistant bacteria resulting from such antimicrobial usage. Risks from prophylactic use are indicated in a recent report of two patients who developed endocarditis due to resistant viridans streptococci after undergoing oral penicillin prophylaxis subse- quent to rheumatic fever (Parrillo et al., 1979~. How commonly this happens is not known. Since reports of such occurrences are rare, the committee believes that they probably occur infre- quently. EXPERIENCE WITH REGULATIONS IN OTHER COUNTRIES Surveys of resistance in isolates from animals and humans have been conducted in several countries following the institu- tion of various regulations governing the addition of antimi- crobials to animal feeds. The reports of these surveys should be reviewed although they contain information that is far from conclusive. Moreover, surveys of the prevalence of resistance do not necessarily indicate "qualitative" changes in resistance, e.g., new combinations of resistance, more efficient transfer mechanisms, or a wider potential host range for a new plasmid. In the United Kingdom the regulations recommended by the Swann committee (Swann _ al., 1969) were implemented in 1971 although no baseline data on antimicrobial use or resistance patterns had been collected. The development of the regulations and their effects have been reviewed by Braude (1978), Linton et _ . (1977), and Smith (1977~. The "Swann regulations" restricted primarily feed supplementation with antimicrobials that have value in the therapy of infections in humans. However, the restricted antimicrobials have remained available through veterinary pre- scription for use in animals. Smith (1977) reported that "in the four years since [the 'Swann'] prohibition, the amount of tetracy- cline-resistant _ cold in the pig population might have decreased slightly but the incidence of pigs excreting these organisms (100% in 1975) had not." In the United Kingdom, SoJka et al. (1977) re- ported that from 1971 to 1974 there was no evidence of a consistent decline in total resistance; however, they reported a small increase in resistance to tetracycline in salmonellae isolated from animals.

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33 Since 1974, 30%-35% of the Salmonella isolates from humans in . the United Kingdom have been resistant to antimicrobials. Recently, there has been a rise in multiple resistance due to a particular prevalent phage type. In 1965, also in the United Kingdom, approx- imately 40% of the Salmonella isolates from bovines were resistant. By 1978 this had risen considerably: approximately 70% of the Salmo- nella isolates from bovines were resistant (L. Ward, Central Public Health Laboratory, United Kingdom, personal communication). Linton _ al. (1977) and Braude (1978) point out that there is little indication that the overall sales of antimicrobials for veterinary use have declined as a consequence of the Swann regulations. Farm animals may well be receiving the same amounts of antimicrobials as in the past, ostensibly for different purposes, i.e., prophylaxis or treatment of disease rather than for growth promotion, and possibly by alternative routes of administration (Braude, 1978~. Regulations developed by the European Economic Community to control the use of antimicrobials in animal feeds came into force in 1974. They proscribed the addition of tetracyclines to feed, a practice that had been increasing in the Netherlands since the 1960's. Subsequent to this prohibition, a decrease in the prev- alence of tetracycline-resistant strains of Salmonella in pigs and ~ ~ A _ (1979~. It is difficult to attribute this decrease unequivocally to the ban on tetracyclines as feed additives since an epidemic of one antimicrobial-resistant phase type (505) of Salmonella typhimurium contributed greatly to the prevalence of resistant strains in the early 1970's. It is questionable whether the decrease in resistance to tetracv~line after 1974 was due to the chance in regulations or to humans was resorted by van Leeuwen et al. =_ _ _O~ _ __ the cessation of the epidemic of this particular resistant strain in both humans and pigs. The prevalence of resistant strains before that epidemic was similar to the levels after regulations came into force. A similar decrease in resistance was not observed in isolates from calves for which tetracycline is still used therapeutically. Phage type 505 of S. typhimurium was not prevalent in this species. There are no data to show if the use of tetracycline has in fact decreased during the period studied by van Leeuwen and colleagues (1974-1978~. In the Federal Republic of Germany, Bulling and coworkers (1973) and Stephan et al. (1976a,b, 1977a,b) reported a decline in tetracy- cline-resistant S. typhimurium and S. Panama in calves and pigs since the 1974 ban. There are no comparable data on isolates from humans in Germany nor on antimicrobial use in that country. A specific strain of S. typhimurium (phase type 505) was a major contributor to the resistance pattern in the Netherlands and the Federal Republic of Germany. Since the epidemic caused by that

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34 strain has now dissipated, it remains to be seen whether the trend of reduced prevalence of resistance will continue. Data from Europe do not indicate whether restrictive regulations have actually reduced or averted hazards to human health. CONCLUS IONS DRAWN FROM THE LITERATURE Relatively little research on the subtherapeutic use of antimicrobials in animal feeds and the use of antimicrobials in animals generally is truly epidemiological. Reports are often based on regrettably few subjects observed for brief periods. The findings of such research are fragmented bits of information con- cerning isolated sections of the meat production system. Therefore, they do little to resolve the question: does the subtherapeutic use of antimicrobials in animal feeds relate to excessive morbidity and mortality of humans? However, the data indicate that antimicrobial- resistant organisms transfer from animals to humans who have been in contact with them on farms. Moreover, abattoir workers have been shown to harbor the same phase types as found in farm animals. The extent of subsequent person-to-person exchange has not been adequately determined. Furthermore, there is no evidence to prove that resistant bacteria are more prevalent among people consuming meat and meat products than among other groups. There are no data linking human illness with the subtherapeu- tic use of antimicrobials in any aspect of animal husbandry, but the absence of information is certainly not to be equated with proof that the proposed hazards dd not exist. For many questions pertain- ing to the subtherapeutic use of antimicrobials, the research is inadequate or nonexistent. The committee discussed in detail how this situation might be remedied. Chapter 4. Its suggestions are contained in