Antibiotics in Meat ProductionThomas H. Jukes, PhD, DSc

THE USE of antibiotics in feedinganimals is connected in a remarkableway to clinical medicine, for this usecame as a by-product of the discoveryof a new antibiotic, aureomycin (nowknown as chlortetracycline), in 1948.Aureomycin was the first of the tet-racyclines, and it was immediatelyput to use for its "broad-spectrum"effectiveness against many patho-genic microorganisms. The fermenta-tion that made aureomycin also pro-duced vitamin B12, which is neededfor growing chickens and pigs onfeeds based on vegetable proteins,such as soybean meal, feeds deficientin vitamin B12. The crude fermenta-tion residues contained, in addition tovitamin B12, small amounts of au-

reomycin that made the animals growmore rapidly than when fed a "com-plete" diet.1 A few grams of anti-biotics such as a tetracycline, penicil-lin, or streptomycin in a ton of feedwill increase growth, apparently be-cause farm animals normally harborsusceptible intestinal microorganismsthat are mildly deleterious withoutbeing frankly pathogenic. Further¬more, antibiotics, especially the tet-racyclines, were effective in arrestingsevere diarrhea that was quite com¬mon on farms and had a debilitatingeffect on the animals. The addition ofantibiotics to animal feeds spreadrapidly throughout many countries ofthe world, starting in 1951.

Such an innovation needed carefulscrutiny for its potential effects on

public health, particularly develop¬ment of resistant strains of patho¬gens. Also, the possible presence ofresidues of antibiotics in meat reach¬ing the meal table needed evaluation.The use of the same antibiotics in

animal feed and in clinical medicinehad disadvantages and advantages. Itwas argued that such a dual usage, byfostering resistance, could impair theusefulness of valuable drugs for hu¬man patients. On the other hand, ex¬tensive experience with administer¬ing an antibiotic to human patientsprovides information on its toxicol¬ogy, and it is of value in assessing theeffect of residues in meat on consum¬

ers.

Toxicological FindingsToxicological findings with both hu¬

man beings and rats showed that tet-racyclines were well tolerated forprolonged periods. Indeed, the ratstudies provided information in geri¬atric changes, because with high lev¬els of chlortetracycline, oxytetracy-cline, and tylosin, longevity wasincreased. With chlortetracycline atlevels of 500 ppm or higher, stainingof bones and teeth occurred in rats.-

Results from feeding farm animals,such as calves and young pigs, in the1950s stimulated pediatricians inmany countries to try prolonged dailyadministration of low levels of anti¬biotics, particularly chlortetracycline,to infants and children. No dele¬terious effects were reported, and a

number of beneficial results were de¬scribed1 (which limitations of spaceprevent reviewing). These includedreductions in morbidity and mortal¬ity, especially in premature infantsand undernourished children,' ' to¬gether with slight increases ingrowth rate. There were no adversereports.Surprisingly, the growth-promot¬

ing effects of feeds containing anti¬biotics did not usually disappear infarm animals in spite of year-after-year usage at the same location, eventhough the intestinal flora promptlybecame largely resistant or toleranttowards these drugs." Also, the clini¬cal usefulness of the tetracyclines,

penicillin, and tylosin still continuesin farm animals, and is of major im¬portance in reducing morbidity.

Resistance Transfer Factor

In about 1959, it was found in Ja¬pan7 that resistance to antibiotics andsulfonamides could pass from one en-terococcal cell to another in a frag¬ment of DNA called a plasmid or epi-some. Genes for resistance readilybecome integrated with the episome.Multiple drug resistance was found tobe transferred in vitro from Esche-richia coli to Shigella. Evidently, theepisome could carry the resistancetransfer factor from nonpathogenicto pathogenic, previously nonresis-tant enterobacteria. The discoveryraised far-reaching possibilities.Large numbers of nonvirulent, resist¬ant coliform bacteria were present inthe intestines of animals receivingantibiotics in their feeds. The infer¬ences from this led to scrutiny and re¬

view of the use of antibiotics in ani¬mal feeds, for there were clinicalproblems, especially in hospitals, re¬

sulting from the spread of resistanceto antibiotics. How much of this re¬sistance comes from the farm? Thequestion was first officially aired inGreat Britain by the "Swann Com¬mittee," which placed emphasis on anoutbreak of tetracycline-resistantsalmonellosis traced back to youngcalves that had been clinically treated

The Author: Thomas H. Jukes holds aBS degree in agriculture and a PhD de¬gree in medical biochemistry. His workhas included studies on riboflavin, nico-tinic acid, vitamin B», pantothenic acid,choline in nutrition, vitamins, cancerchemotherapy, and antibiotics. Since1963, he has been with the University ofCalifornia, Berkeley, as Professor InResidence, Medical Physics, to work onthe genetic code and molecular evolu¬tion, in the Space Sciences Laboratory.He was elected Fellow of the AmericanInstitute of Nutrition In 1973.

If you wish to suggest a topic or write an an-swer for this feature, write to William H. Crosby,Scripps Clinic and Research Foundation, LaJolla, CA 92037.

Reprint requests to Division of Medical Phys-ics, University of California, Berkeley, CA 94720(Dr. Jukes).

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with tetracycline and had not re¬

ceived colostrum.No such outbreaks have occurred in

the United States, despite the exten¬sive use of antibiotics in veterinarymedicine for 25 years. The report bythis committee led to the principalantibiotics for farm animals beingplaced on veterinary prescription inGreat Britain, but this was not fol¬lowed by a marked decrease of theirusage in animal feeds in that country.The "Swann Report"8 was followedby extensive deliberations, lastingtwo years, on the part of a US taskforce on antibiotics in animal feeds,appointed by the Food and Drug Ad¬ministration (FDA).9 The task forceconcluded that both antibiotic-sensi¬tive and antibiotic-resistant bacteriaof animal origin could be pathogenicto humans, and that evidence sug¬gested that the use of certain anti¬biotics for animals promoted an in¬crease in the animal reservoir ofSalmonella.

This matter is under reinvestiga¬tion. The task force also drew atten¬tion to the R factor (resistance trans¬fer factor) question as leading to "thelogical conclusion, though not fullydocumented" of "a human health haz¬ard. " There were differences of opin¬ion within the task force on a numberof points regarding safety. Followingthe report, the FDA is reviewing theeffectiveness of antibiotics in animalfeeds, has required new demonstra¬tions of the safety and efficacy of suchantibiotics, and is undertaking re¬search on this. The FDA has excludedchloramphenicol, semisynthetic peni¬cillins, gentamicin, and kanamycinfrom use in animal feeds, as these an¬tibiotics are most critically needed fortreatment of disease in man.

Economic Impact ofAntibiotics in Feed

The task force report estimated theeconomic value of low levels of anti¬biotics in feed to the producers ofpoultry, swine, beef, and veal, in 1970,at $414 million annually.9 The US De¬partment of Agriculture was quotedin 1975 as saying that a ban on anti¬biotics in feeds would raise consumermeat bills $2.1 billion annually (WallStreet Journal, Jan 6, 1975, p 14). Inlight of the world food crisis, we maythink of this in terms of saving offood—millions of tons of corn—rather

than dollars, because the effect repre¬sents yields of meat per ton of feed.What of infectious resistance? It is

a baffling task to track down thesource of episomes. Surely, if theepisomal transfer of resistance wasproduced extensively by feeding anti¬biotics to farm animals, there wouldbe a higher-than-average occurrenceof resistant infections among farmworkers, and simultaneously the effi¬cacy of antibiotic feeds for animalswould have disappeared. Neither hasbeen recorded, despite the well-known fact that antibiotic-tolerantenteric bacteria always overgrow sen¬

sitive strains when antibiotics are fedto farm animals. The resistant en¬

teric bacteria do not appear to bepathogenic.1 Strains of E coli ofanimal origin were poor and nonper¬sistent colonizers of the human ali¬mentary tract, and the amount oftransfer of R factors was small.10

The part that episomal transferplays in the build-up of resistance isnot yet clear. Transfer appears totake place more readily in test-tubeexperiments than in the gut." Salmo-nellosis is a vexing public health prob¬lem that calls for vigiliance in sani¬tation. Experiments have beenreported recently with calves, pigs,and chickens that contradict the ear¬lier statement that the use of anti¬biotics increases the shedding of Sal¬monella by farm animals.'2 The FDA,in March 1974, stated that no proofhad been produced that the use of an¬tibiotics in food-producing animals ishazardous to human health."

Residues in MeatThere is also concern with residues

in meat in regard to allergenic possi¬bilities and antibacterial effects. Sev¬eral "feed" antibiotics, including bac-itracin, penicillin, and tylosin, havenot been detected in meat. Tetracy-clines were reported at levels inmuscle meat corresponding to 0.02%to 0.1% of the level in the feed, dis¬appearing after a five-day with¬drawal period, and, in the case ofchlortetracycline, being destroyed bycooking.' The Swann Report8 stated:"When the recommendations of doseand withdrawal time are compliedwith, we see no reason to supposethat residues present any danger."The FDA task force9 said that "theexistence in foodstuffs of quantities

of antibacterial agents capable of in¬ducing allergy or hypersensitivityrepresents a human health hazard."Also, when drug withdrawal timesare not adhered to, antibiotic residuesmay be present in meat and meatproducts. The task force added thecomment that this matter was underreview within and outside the FDA.The main concern appeared to bewith allergy rather than possible an¬tibacterial effects of very smallamounts of residues, especially inview of loss of the antibacterial effectfollowing cooking. There have been afew reports of allergic reactions topenicillin in milk," resulting fromtreatment of mastitis with penicillin,but not to antibiotics in meat.

The important points at issue seemto be tracking down the origin of re¬sistance that constitutes a publichealth problem and evaluating theetiology of salmonellosis. The use ofantibiotics in animal feeds helps toincrease the supply of animal proteinin human diets by enabling greaterproduction of meat per unit of feed.

References1. Stokstad ELR, Jukes TH, Pierce J, et al:

The multiple nature of the animal protein factor.J Biol Chem 180:647-653, 1949.

2. Dessau RI, Sullivan WJ: A two-year studyof the toxicity of chlortetracycline hydrochloridein rats. Toxicol Appl Pharmacol 3:654-677, 1961.

3. Jukes TH: Public health significance offeeding low levels of antibiotics to animals. AdvAppl Microbiol 16:1-30, 1973.

4. Robinson P: Control trial of aureomycin inpremature twins and triplets. Lancet 1:52, 1952.

5. Snelling CE, Johnson R: Value of aureomy-cin in prevention of cross infection in hospitalfor sick children. Can Med Assoc J 66:6, 1952.

6. Hays VW: Biological basis for the use of an-tibiotics in livestock production, in The Use ofDrugs in Animal Feeds, Publication 1679. Na-tional Academy of Sciences, 1969, pp 11-30.

7. Watanabe T: Infective heredity of multipledrug resistance in bacteria. Bacteriol Rev 27:87\x=req-\115, 1963.

8. Swann MD: Report of Joint Committee onthe Use ofAntibiotics in Animal Husbandry andVeterinary Medicine. London, Her Majesty'sStationery Office, 1969.

9. Report to the Commissioner of the Food andDrug Administration on the Use of Antibioticsin Animal Feeds, publication FDA 72-6008.Rockville, Md, Food and Drug Administration,1972.

10. Smith HW: Transfer of antibiotic resist-ance from animal and human strains of Esche-richia coli to resident E coli in the alimentarytract of man. Lancet 1:1174, 1969.

11. Jarolmen H, Kemp G: R factor trans-mission in vivo. J Bacteriol 99:487-490, 1969.

12. Kiser JS: Relation of transferable anti-biotic resistance to public health, in Proceedingsof the Pacific Northwest Nutrition Conference,Victoria, British Columbia, Nov 7-8, 1974.

13. Antibiotics and the Foods You Eat, FDAconsumer memo 74-6011. Dept of Health, Educa-tion, and Welfare, 1974.

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