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APPENDIX E ANTIMICROBIAL RESIDUES AND RESISTANT ORGANISMS: THEIR OCCURRENCE, SIGNIFICANCE, AND STABILITY Stanley E. Katz1 The occurrence of antibiotic residues in animal tissue and animal products resulting from the subtherapeutic, prophylactic, or therapeutic use of antibiotics is a function of the antibio- tic, the method of application, the level of treatment, and, most importantly, adherence to withdrawal periods. Because of the extreme variability in both the use of drugs and adherence to withdrawal periods, it is inevitable that residues would occur in a small but significant percent of animal products found in the marketplace. RESIDUE LEVELS FROM SUBTHERAPEUTIC ANTIBIOTIC USE Huber (1971) reported the results of a 1969 survey of ani- mals slaughtered in Illinois, Wisconsin, Iowa, and Indiana. In 27% of the swine slaughtered, there was evidence of recent treat- ment with antibacterial substances, of which 10% were penicillin. Because of the lack of visible evidence of injection, these resi- dues most likely were the result of improper withdrawal times or levels of usage. There was a 9% rate of positive findings in beef cattle, 2% of which were attributed to penicillin. In veal, 7% of 17% of the samples in which antibiotics were found resulted from penicillin. Some 21% of market lambs were positive for antibacter- ial residues. Of these, 4X were positive for penicillin. The presence of antimicrobial residues was found in 26% of the chickens, 6% of which were positive for penicillin activity. The incidence of antibiotic residues in milk during the early 1950's was approxi- mately 11%, dropping to 0.5% at the time of Huber's report. Mussman (1975) reviewed the inspection and sampling proce- dures used in the U.S. Department of Agriculture (USDA) program to monitor levels of residues in conformance with Food and Drug Administration (FDA) regulations and analyzed the data contained in the USDA Biological Residue Report for 1973 (USDA, 1974~. The USDA figures indicated that 5.3% of 529 carcass samples examined for residues of streptomycin, tetracycline, erythromycin, neomycin, oxytetracycline, and chlortetracycline were positive; only 17 of Department of Biochemistry and Microbiology, Cook College - New Jersey Agricultural Experiment Station, Rutgers University, The State University of New Jersey, New Brunswick, N.J. 158

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159 5,301 samples, or 0.32%, were positive for penicillin; and 12 samples of 728, or 1.6%, were positive for sulfonamides. Non- specific antimicrobial activity was found in 154 (2.9%) of 5,301 samples. Table 1 summarizes the U.S. Department of Agriculture sampling program for 1976-1978. Violations exist when residue levels exceed established tolerances or when residues are found when no residue is permitted. If the results of the USDA sampling program are at all repre- sentative, there is no doubt that violative residues occur in almost all animals used for food and that residues that are not in viola- tion occur in even higher percentages. The rates of antibiotic and sulfonamide residue violations are lowest among poultry and cattle, and the highest rates occur in swine and in veal calves. The levels of residues that can be expected from feeding subtherapeutic quantities of antibiotics vary with the degree of absorption from the intestinal tract. Because of very poor ab- sorption from the intestine, residues resulting from the consump- tion of such antibiotics as streptomycin, neomycin, bacitracin, and the bambermycins rarely, if ever, occur. Residues from the subtherapeutic feeding of chlortetracycline (CTC) and oxytetracy- cline (OTC) occur regularly and have been also reported for peni- cillin. In chickens, the continuous feeding of 50 to 200 g of CTC per ton of feed resulted in residue levels ranging from 0.036 to 0.11 fig CTC/g muscle tissue and from 0.058 to 0.199 fig CTC/g liver tissue (Katz et al., 1972~. These residues disappeared after 1 day of withdrawal from the medicated feed. Messersmith et al. (1967) reported residue levels of 0.08 fig CTC/g muscle and 0.46 fig CTC/g liver resulting from feeding 100 g CTC/ton to swine. After a 5-day withdrawal, no detectable levels could be measured in muscle and fat, but trace levels were de- tected in the liver and kidney. Gale et al. (1967) reported from 0.04 to 0.08 fig CTC/g muscle and from 0.24 to 0.46 fig CTC/g liver from the continuous feeding of lOO g/ton. After a 5-day withdrawal period, there were no measurable levels in muscle, and only trace levels could be found in the liver. OTC residues occurring in poultry muscle from the continuous feeding of 25 to 200 g/ton were approximately 1/1,000 of the feeding level. This is similar to levels resulting from the feeding of CTC. Measurable tissue resi- dues of CTC disappeared after a 1-day withdrawal period (Katz _ al., 1972~. Cooking destroyed all residues of both OTC and CTC in the muscle (Katz et al., 1972, 1973; Meredith et al., 1965~. The only CTC residues surviving cooking were found in the liver.

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160 TABLE l Violative Actions for Antibiotics and Sulfonamides Ant ibiot icViola- SulfonamideViola Species SamplesLions ~SamplesLions 1976: Cattle 54571.347640.9 Calves 1, 37 81 188. 63 27123. 7 Sheep and goats7057.110011.0 Swine 2 4741. 61, 4 931419. 4 Chickens 15510.633110.3 Turkeys 2 5800. 06 48162. 5 Geese and ducks16010. 626500. 0 1977: Cattle 1,739221.317542.3 Calves 1,120464.116653.0 Sheep and goats17 621.11200. 0 Swine 44961.39,4611,24213.1 Chickens 36600.0100. 0 Turkeys 45030~744540~9 Geese and ducks16110. 620610. 5 1978: Cattle 1,769462.624320. Calves 1,409946.721462.8 Sheep and goats21052. 440615.0 Swine 1, 399765.46, 6876489.7 Chickens 470 ~1.711910.8 Turkeys 447153.3443194.4 Geese and ducks17521.114800. 0 aFrom U. S. Department of Agriculture, 1977-1979. 1

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161 Residues of OTC and CTC in eggs were not completely destroyed by cooking. The lower temperatures and shorter times of cooking were responsible for the survival of the residues. Filson _ al. (1965) found CTC levels ranging from 0.072 ~g/ml in the serum of old birds to 0.330 ~g/~1 in the serum of young birds that had received 200 g of the antibiotic per ton of feed. They reported no muscle deposition levels, but it is gen- erally assumed that muscle residue levels usually correspond to serum levels. Another potential source of tetracycline residues, especially if the kidneys are used as the indicator organ, would be tetracy- clines released from deposition in the bones. Bruggemann et al. (1966) noted that the bones of all domestic animals fed tetracy- cline contain measureable amounts of the antibiotic. After the feeding of the tetracycline ceases, levels in the bones decrease, indicating mobilization and excretion. After feeding pigs lOO fig procaine penicillin per gram of feed, Loftsgaard et al. (1968) found residues of 2 ~g/ml urine and levels in muscle no higher than 0.005 ~g/g. Kidney levels ranged from 0.003 to 0.24 Egg, and liver levels were 0.012 agog. After feeding the unmedicated basal ration for 24 hours, the investigators found no measurable antibiotic activity. However, residues from intramus- cular injections of procaine penicillin disappeared by day 6. After injections of benzathine penicillin G. activity was detected in the urine and kidney for as long as 14 days. The feeding of procaine penicillin to broilers and laying hens did not result in any penicillin activity in the blood, muscle, liver, and kidney tissue of broilers or in the eggs of hens fed 100 g/ton. Approximately 98% of the penicillin activity was destroyed in the upper portion of the intestinal tract, and little or no activity reached the small intestine (Katz et al., 1974; Messersmith et al., 1967~. One of the major degradation products was penicilloic acid. McCracken (1977) reported that intramuscular injections of 3 mg penicillin and OTC per kilogram of body weight yielded muscle residue levels less than 0.04 ~g/g and 0.20 agog, respectively. Surprisingly, no residues in muscle were found after an intramus- cular injection of neomycin at 100 mg/kg. These few reports indicate that OTC and CTC residues can and do appear as a result of subtherapeutic and therapeutic oral feeding. Residues attributed to the feeding of penicillin were variable, but

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162 tended to be very low or at the level of detectability of the methodology used. Most of the analytical methods used for peni- cillin were capable of detecting levels of 0.0125 Agog or less. FATE OF ANTIBIOTIC RESIDUES Residues of the tetracyclines in the muscle tissue of ani- mals will not survive normal food preparation procedures. No residues will enter the diet of humans unless the muscle tissue is eaten raw or very rare. Cooking degrades CTC to isochlorte- tracycline (Shirk _ al., 1957), and OTC is thought to be con- verted to a- and O-apooxytetracyclines (Katz et al., 1973). The literature contains no data to indicate that either of these compounds has any biological significance. Tetracycline residues remain only in products that are sub- jected to a minimum amount of cooking. Even in chickens soaked in CTC solutions to increase shelf life, which resulted in tissue levels of 3 Agog or greater (Broquist et al., 1956), no residues could be measured after cooking (Kohler et al., 1955~. However, if residues do survive cooking, the potential for biological action remains. After feeding raw chicken meat containing an average of 2.6 Agog CTC to dogs, Rollins et al. (1975) found an increase in the number of resistant colifonms shed by the dogs. The metabolic fate of tetracycline has been studied by sev- eral investigators. Kelly and Buyske (1960) found that tetracy- cline was metabolically unaltered in the rat and, for the most part, in the dog. Eisner and Wulf (1963) reported that epichlor- tetracycline and demethylchlortetracycline were metabolic products of CTC. The formation of isochlortetracycline in the intestinal tract of poultry was observed by Shirk et al. (1957~. Katz and Fassbender (1967) reported that epichlortetracycline and an unknown highly fluorescent compound was formed in feeds, but that isochlor- tetracycline was not. These authors suggested that an equilibrium was established between CTC and its epimer followed by a breakdown of either the CTC or its epimer into unidentified products. There is no apparent significance to the presence of tetra- cycline residues if the product is adequately cooked, unless some unknown compound forms in the animals fed the antibiotics or the breakdown products of tetracyclines stimulate the development of resistance in enteric organisms or the transfer of resistance determinants between R+ Escherichia cold and recipient E. cold or salmonellae. In Great Britain, the data indicate that the destruction of CTC and OTC residues during cooking renders the meat adequately safe for consumption by humans (Brander, 1970~.

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163 ALLERGIC RESPONSE The situation is somewhat different with penic it tin resi- dues. Huber (1971) reported that 10% of the general population is sensitive to penicillin. McGovern et al. (1970) stated that from 1% to 10% of the population of North America and Western Europe may be allergic to it. Parker (1963) and Levine and Ovary (1961) suggested that degradation products from acid and alkaline breakdowns could be responsible for hypersensitivity reactions. Altman and Tompkins (1978) reported that penicillin degrades, forming benzyl penicilloic acid, a major determinant of hypersensitivity, and some minor determinants. These degradation products are haptens that can become antigens when they conjugate to endogenous protein In viva. Katz et al. (1974) found that penicilloic acid formed in the intestinal tract of chickens that had been fed growth promotional and prophylactic levels of peni- cillin. Weinstein (1975) estimated that 66% of a dose of penicillin passed into the intestine of humans where it was inactivated. Such inactivation would undoubtedly lead to the formation of peni- cilloic acid and the possible adsorption and deposition of this compound into muscle tissue. The use of injectables and the residues resulting from them can always be a source of unwanted and potentially dangerous residues. Perhaps the only truly documented death resulting from residues of penicillin occurred when a butcher consumed fresh pork that contained 0.31 Agog penicillin (Tscheyschner, 1972~. As early as 1956 it was known that penicillin residues could survive pasteurization at 60C and 71C, but not at 121C (Shahani _ al., 1956~. Katz et al. (1978) reported that penicillin resi- dues in meat could survive all but the most rigorous cooking. These investigators measured only penicillin activity and provided no information concerning the degradation products. Breakdown Products The literature does not provide much information regarding the significance of breakdown products in relation to potential hypersensitivity reactions from eating products containing resi- dues and breakdown products of penicillin. Warrington et al. (1978) found that both the major and minor degradation products

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164 of benzyl penicillin were useful reagents in determining hyper- sensitivity. Hypersensitivity of one-fifth of the patients that they tested would have been missed if only the major product had been tested. Borrie and Barrett (1961) reported the case history of a woman who had relapses of allergy when she consumed dairy products. The problem disappeared when the patient received no commercial dairy products or milk known to be free from penicillin. Batchelor _ al. (1967) reported that a penicilloylated poly- mer with a high molecular weight produced immunological responses in the guinea pig. Ferrando (1975) reported that 40 units of benzyl penicillin was sufficient to trigger allergic responses in very sensitive individuals. He noted that some investigators have suggested that from 2 to 3 units of penicillin would trigger anaphylactic reac- tions in sensitive people. From his own calculations and from the opinions expressed by allergists in France and elsewhere in Europe, he believes that the risk is "more theoretical than real." The significance to human health of the residues of peni- cillin and its breakdown products cannot be determined by review- ing the literature. However, it is known that the breakdown products of penicillin do have biological significance ranging from their ability to sensitize individuals to their action as selecting agents for the development of antibiotic resistance in _ colt. Since up to 10% of the population is potentially sensi- tive to penicillin and its breakdown products, the risk is too great to be ignored. Oral feeding of subtherapeutic doses of penicillin should be avoided, and injections should be carefully controlled. ROUTES OF ADMINISTRATION - Residues of other antibiotics resulting from injections can be a more serious problem than residues attributed to feeding because of the higher concentrations that can be deposited and/or sequestered in the tissue. As was noted previously, the only documented fatality from hypersensitivity to penicillin was caused by a penicillin residue that resulted from an injection of the antibiotic. Gaines _ al. (1978) pointed out that dihydrostrep- tomycin residues of 2 and 10 Agog, which were observed in bovine kidneys after intramuscular injection or intramammary infusion, caused a significant increase in resistance in the enteric bacteria

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165 of animals. Residues of dihydrostreptomycin, unlike those of tetracycline, are known to be refractory to thermal decomposi- tion (Inglis and Katz, 1978) and are strong selectors of resistant organisms (Huber, 1971~. Wilson (1958) reported that streptomy- cin readily sensitized from 2% to 3% of the nurses who handled it. Residues of neomycin have been found in serum and urine up to 144 hours after administration of an intramuscular injection. Residues of this antibiotic have been reported to be relatively stable in cooked eggs (Katz and Levine , 1978) and in cooked muscle tissue of animals (Katz and Levine, 1980, unpublished data). Residues arising from injectables are a more serious problem because of the high levels in which they accumulate. Therefore, every effort must be made to minimize the use of in jectables in animals going to market. THE ROLE OF RESIDUES IN THE DEVELOPMENT OF RESISTANCE It is doubtful that antibiotic residues or their degradation products will provide any selective pressure on enteric bacteria contaminating the carcasses of animals. Residue levels are usually low, contact tome in relation to the number of generations rela- tively short, the nutritional requirements too variable and usually insufficient for sustained growth, and the temperature of storage too low for growth. The selection process requires the inhibition of susceptible strains, thereby allowing the more resistant strains to grow. The transfer of resistant determinants between strains of E. cold would be of low frequency, or nonexistent, for all the aforementioned reasons. The resistant organisms contaminating the carcasses come from the environment of the slaughterhouse itself--not from the residues that may be present. THE EFFECT OF REGULATION ON RES IDUES Enforcement of FDA regulations controlling tolerances for antibiotic residues is a function of the perceived seriousness of the problem and the amount of money that regulatory agencies budget for this purpose. It is both impossible and impractical to design a program to insure that every animal going to slaughter and every gallon of milk is free of residues. The USDA sampling program, which results in the Biological Residue Reports (e.g., USDA, 1977- 1979) is the first line of information allowing regulatory officials to define a problem and marshal! efforts to solve it. Practices

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166 that can result in residues, such as ignoring withdrawal times, the use of antibiotics beyond the period of effective growth pro- motion, the subtle sales approach used by the drug companies suggesting that continuous usage could be an insurance policy protecting against carcass condemnations, should be modified. There is no doubt that strict adherence to proper usage and adherence to withdrawal periods, which are both stimulated by increased regulatory activity, will minimize the residue problem. This regulatory approach was successful in lowering the incidence of residues in milk from 11% to 0.5% (Huber, 1971) and appears to be having similar success with the sulfonamide residues in swine. Only through monitoring and changes in agricultural prac- tice can the problem be minimized. State Agricultural Experiment Stations, through their research and extension arms, should pro- vide the farmer with the knowledge to develop proper agricultural practices. The pharmaceutical industry should sell farmers only effective drugs and stipulate adamantly the requirements for their use. Considering the size and complexity of the enforcement pro- blem and the limits of the laboratory and inspection staffs, regu- latory efforts are reasonable. EXCRETION OF ANTIBIOTICS Antibiotics that are not absorbed, not metabolized or are free or bound in a conjugated form are excreted in the feces and urine. Antibiotics such as streptomycin, which are not readily absorbed, are excreted in their active form (Huber, 1971~. Neo- mycin, like streptomycin, is poorly absorbed in the gut and is excreted unchanged in the feces (Weinstein, 1975~. Bacitracin is poorly absorbed from the intestinal tract, but a large percentage of the dose is destroyed in the intestinal tract (Scud) et al., 1947). Many different antimicrobials are absorbed in varying amounts from the intestinal tract. Those that are most easily absorbed, such as the tetracyclines, are excreted in both urine and feces. Huber (1977) estimated that from 10% to 25% of an oral dose of the tetracyclines is excreted in the feces. Elmund et al. (1971) ob- served that 75% of the CTC ingested by yearling steers was excreted. Alderson et al. (1975) reported that 217 of the OTC fed to sheep was recovered from the feces. In the accumulated feces of feedlots, the level of tetracyclines extracted was 75% of that fed (Elmund et _ ., 1971~. Webb and Fontenot (1975) reported that the litter of broilers contained levels of OTC ranging from 5.5 to 29.1 Agog

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167 (average, 10.9 ~g/g); CTC ranging from 0.8 to 26.3 ~g/g (average, 12.5 Agog); penicillin ranging from O to 25 ~g/g (average 12.5 Agog); bacitracin levels ranging frog 0.16 to 36.0 Agog (average, 12.3 ~g/g); and arsenic residues ranging from 1.1 to 59.7 Agog (average 40.4 Agog). They found no residues of neomycin. Arsenicals are excreted unchanged and can be recovered from feces at a level of 0.1 Agog after 12 days of ingesting the com- pound in doses of 90 g/ton (Overby and Frost, 1960~. Morrison (1969) reported a rather constant level of arsenic in soil after 20 years of fertilization with poultry litter. This finding may be related to metabolism and microbial conversions. Arsenicals, such as 3-nitro-4-hydroxyphenylarsonic acid, are partially reduced to the 3-amino product. Moreover, arsanilic acid residues can be metabolized to arsenate in soils (Woolson, 1977~. PERSISTENCE OF ANTIMICROBIALS IN SOILS . In agricultural areas, residues of antimicrobials can be leached from soils and pastures into streams. Van Dijck and Van de Voorde (1976) reported that 12 of 41 water samples showed in- hibitory activity against Staphylococcus aureus, but believed that the low activity in the water samples posed no hazard. Unfortu- nately, they made no attempt to correlate this inhibition with the types of antimicrobials used in the area. There is a paucity of definitive information on the degrada- tion of antibiotics and antimicrobials in the environment. Although Jefferys (1952) observed that penicillin is readily inactivated in garden soils, the FDA (1978) reported that no information was availa- ble on the time required for the inactivation in soils or in wastes from animals. Streptomycin forms such strong complexes with clays that it can be irreversibly inactivated at low levels (Pinck et al., 1961~. Soulides et al. (1961) observed that bioactive streptomycin can be desorbed, and Pramer and Starkey (1951, 1972) reported that it could be microbiologically decomposed in soil. The FDA (1978) summarized the information on the stability of tetracyclines in the environment. In soils, where as much as 5 tons of waste from cattle feedlots was applied per acre as a fer- tilizer, no measurable CTC activity could be detected. Rums ey et al. (1975) reported that measurable levels of CTC were not found In most run-off water from pastures on which wastes containing that antibiotic had been spread. Little pertinent information has been reported for OTC. Metcalf (1976) reported that sulfamethazine was

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168 biodegradable in a 33-day terrestrial-aquatic model ecosystem, but he provided no data on the stability of the compound in soils and in mixtures of feces and soil. From the data available it is difficult to make an accurate assessment of the persistence of antibiotics in the environment. We know that antibiotics degrade in soils, but must learn how quickly they do and what effects they have on the bacterial populations in the soil. Antibiotics are added to the soil in a mixture of feces, urine, and bedding that probably does not ex- ceed 50 tons per acre. Therefore, this mixture accounts for no more than 5% of the top 15-cm layer of soil. Based on the aver- age amount of antibiotics in broiler litter ~ ~ 12.5 ~g/g) (Webb and Fontenot, 1975), the level of antibiotic in the soil would be approximately 0.6 Agog. Because of the absorptive reactions, the low concentrations of antibiotics, and the variety of organisms available to act upon the antibiotic molecules, it is doubtful that the antibiotics will persist for any great length of time in the soil. Will low levels of antibiotics added to the soil cause the development of antibiotic-resistant populations? There is no general answer. It is doubtful that penicillin will survive sufficiently long in soil to act as a selective agent (Jefferys, 1952~. Jefferys also reported that streptomycin was absorbed irreversibly into soil at relatively low concentrations and became inactivated. Hence, streptomycin would be an unlikely selective agent. The tetracyclines can survive microbial degradation in the gut of animals and be present in fresh ma- nure at a concentration of 14 ~g/g and at 0.34 Agog in aged manure (Elmund et al., 1971~. The degradation of CTC in soil fertilized with cattle feedlot manure was indicated by a find- ing of no measurable CTC (Rumsey et al., 1975~. Although soluble, weakly absorbed, and potentially mobile in the soil, it is doubtful that the tetracyclines will be a strong selec- tive agent. SHEDDING OF RES ISTANT ORGANISMS Animals fed antibiotics shed antibiotic-resistant organisms (Smith, 1969; Smith and Crabb, 1957~. The longer they are fed antibiotics, the greater the percentage of antibiotic-resistant organisms that will be shed. For the most part, the ubiquitous _ cold has been used as an indicator organism because it is

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171 Anderson (1974) found that the number of organisms carrying R factors declined faster in the gut than did sensitive strains and that they may be at an ecological disadvantage in nature in the absence of selection pressure from antibiotics. He suggested that the rapid decline in the resistant organisms resulted from an impaired vitality of the organisms rather than the loss of R factors from the cell. Although there is a difference of opinion regarding whether resistant strains have a selective advantage for survival in the environment over nonresistant strains, the evidence in favor of their not having a selective advantage is more compelling. Anderson's observations of a decline in the number of antib~otic- res~stant organisms in some populations, Grabow's comparison of survival in various waters, and Smith's observations all point to the fact that there are no easily measurable differences in sur- vival rates in the environment between resistant and nonresistant _ cold strains. If anything, there might be a slight advantage to the antibiotic-sensitive E. cold because of the observations - that resistant populations decline and are replaced by nonresist- ant strains over an extended period. However, there is one in- escapable fact: because both antibiotic-resistant and sensitive strains survive for long periods in the environment, changes of populations will be slow. The source of the relatively high incidence of antibiotic- resistant E. cold in sewage, effluents, and streams can never be established. Only where the sources of the organisms are easily discernible can a considered judgment be made. Smith (1970) concluded that human beings rather than animals are the main source of antibiotic-resistant E. colt. He found that the incidence of antibiotic-resistant organisms was generally low in rivers and canals that flowed through rural areas and high in rivers that flowed through urban areas. In waters with the highest incidence of antibiotic-resistant organisms, inadequately treated sewage was the source. No antibiotic-resistant E. cold were found in a river before it entered predominantly urban areas. Feary _ al. (1972) concluded that the high incidence of re- sistance to streptomycin and tetracycline among coliforms isolated from waters near livestock feedlots were probably a direct result of the use of antibiotics in the feed. Hughes and Meynell (1974) indicated that there has been an increase in antibiotic-resistant coliforms in rivers since 1970. Popp (1974) reported that thorough treatment of sewage failed to remove salmonellae and that there

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172 were considerable numbers of the organisms in the water into which the treated sewage flowed. Morse and Duncan (1974) concluded that the aquatic environment was a favorable environment for the sur- vival of salmonellae. The above data seem to indicate that human beings rather than animals are the main source of antibiotic-resistant E. cold in the environment. CONCLUSIONS namely: Several conclusions can be drawn from literature reviewed, (1) The incidence of antibiotic residues in animal products will continue at a relatively modest rate regardless of surveys and enforcement procedures. The current surveillance procedures are extremely effective in identifying problem areas, but no regu- latory system can guarantee a residue-free food supply. (2) Residues of oxytetracycline and chlortetracycline will usually not enter the human diet fin less the foods containing these residues are subjected to minimal cooking times and temperatures. Hence, such residues should not be considered a serious factor in the development of resistance among intestinal microorganisms. The thermal degradation products of the tetracyclines are not known to have any biological effects. ~ 3) Penicillin residues and related breakdown products are not innocuous and have the potential of causing hypersensitivity reactions. Because approximately 10% of the population is potent- ially sensitive to penicillin and its breakdown products, the sub- therapeutic feeding of penicillin should be avoided and the use of injectable forms carefully controlled. (4) Antibiotic residues and/or their degradation products are doubtful agents for the selection of antibiotic-resistant organisms or as promoters of resistance transfer on the carcasses of animals. Resistant organisms result from contamination by in- testinal contents during the handling of the carcasses. (5) Although there is a paucity of definitive information, the available data indicate that antibiotics are not stable in the soil and should not act as a selective agent for the develop- ment of antibiotic resistance among microorganisms in the soil.

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173 (6) Antibiotic-resistant microorganisms shed by animals per- sist for extended periods in the environment but do not appear to have any superior advantage for survival as compared to sensitive strains. (7) Although animal agriculture contributes drug-resistant species to the environment, especially in rural areas, human be- ings rather than animals appear to be the main source of antibio- tic-resistant organisms in the environment.

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174 REFERENCES Ahart, J. G., G. C. Burton, and D. C. Blenden. 1978. The influ- ence of antimicrobial agents on the percentage of tetracycline- resistant bacteria in faeces of humans and animals. J. Appl. Bacteriol. 44:183-190. Alderson, N. E., W. Knight, R. Robinson, J. Colaianne, and P. Bradley. 1975. Ovine absorption and excretion of oxytetracycline. J. Anim. Sci. 41:388-399 (Abstract). Altman, L. C., and L. S. Tompkins. 1978. Toxic and allergic man~- festations of antimicrobials. Postgrad. Med. 64:157-167. Anderson, J. D. 1974. The effect of it-factor carriage on the sur- vival of Escherichia cold in the human intestine. J. Med. Microbial. 7:85-90. Batchelor, F. R., J. M. Dewdney, J. G. Feinberg, and R. D. Weston. 1967. A penicilloyalted protein impurity as a source of allergy to benzyl-penicillin and 6-aminopenicillanic acid. Lancet 2:1175-1177. Berkowitz, J. H., D. J. Kraft, and M. S. Finstein. 1974. Persist- ence of salmonellae in poultry excrete. J. Environ. Qual. 3: 158-160. Borrie, P., and J. Barrett. 1961. Dermatitis caused by penicillin in bulked milk supplies. Br. Med. J. 2:1267. Brander, G. C. 1970. Possible hazards to man from the use of drugs in and on animals. Br. Med. Bull. 26:217-221. Broquist, H. P., A. R. Kohler, and W. H. Miller. 1956. Retardation of poultry spoilage by processing with chlortetracycline.- Agric. Food Chem. 4:1030-1032. Bruggemann, J., U. Losch, M. Merkenschlager, and I. Offterdinger. 1966. [In Genman; English summary.] Ablagerung von Tetracy- clin ~m Knocengewelbe von Tieren bei dem Zusatz von Tetracyclin zum Futter. Zentralbl. Veterinaenmed. 13:59-74. Cooke, M. D. 1976a. Antibiotic resistance among coliform and faecal colifonm bacteria from natural waters and effluents. N. Z. J. Mar. Freshwater Res. 10:391-397.

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