CITATION: Witte W. 1998. Antibiotic use in animal husbandry and resistance development in human infections. APUA Newsletter 16(3): 1, 4-6.


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Antibiotic use in animal husbandry and resistance development in human infections
Wolfgang Witte, PhD
Robert Koch Institute, Wernigerode, Germany

Two important factors impact on the emergence and spread of antibiotic resistance: transferable resistance genes and selective pressure by use of antibiotics (1). Besides hospitals with a concentration of patients prone to infections and corresponding antibiotic use, animal husbandry is a second considerable reservoir of heavy antibiotic use and transferable antibiotic resistance. Industrial animal husbandry keeps large numbers of animals in comparably small space and outbreaks of infections can easily spread. For technical reasons there is often mass medication of all the animals of a particular flock. In Europe animals are also under transport stress when shipped from breeding stations to farms for fattening. The consequence is a broad scale antibiotic prophylaxis.

For a number of decades antimicrobials have been used as growth promoters, especially in pig and poultry farming. The use of growth promoters leads to 4 - 5 % more body weight for animals receiving them as compared to controls. Much larger amounts of antibiotics are used in this manner than are used in medical applications: In Denmark in 1994, 24 kg of the glycopeptide vancomycin were used for human therapy, whereas 24,000 kg of a similar glycopeptide avoparcin were used in animal feed. From 1992 to 1996, Australia imported an average of 582 kg of vancomycin per year for medical purposes and 62,642 kg of avoparcin per year for animal husbandry. Vancomycin and avoparcin have the same mode of action; resistance to one can confer resistance to the other.The biological bases of the growth promoting effects are far from being understood; according to data from Sweden, this effect can be mainly demonstrated under suboptimal conditions of animal performance (2).

That antibiotic use in agriculture will result in transfer of antibiotic resistant bacteria and transferable resistance genes to humans was already discussed nearly 30 years ago, especially with regard to growth promoters. In 1969, the Swann Committee of the United Kingdom concluded that there should be no use of antibiotics as growth promoters if they are also used for human chemotherapy and/or if they select for cross resistance against antibiotics used in humans (3). Criteria for legislation in countries of the European Communities responding to this recommendation were published 16 years later (4). However these criteria had been applied only to substances admitted for legislation and not to the "oldies" which are in long time use. Legislation authorities of the US never saw sufficient evidence for prohibiting the use of penicillin or tetracycline as growth promotors. The glycopeptide avoparcin was never registered in the US.

During the past 10 years methods of molecular fingerprinting bacterial pathogens and their resistance genes became a powerful tool for epidemiological tracing and have provided much more conclusive evidence for the spread of antibiotic resistance from animal husbandry to humans.Currently two issues are subject of discussions among the scientific community, agriculture industry, regulatory boards and politicians: antimicrobial growth promoters and veterinary fluoroquinolone use.

Growth promoters
That the comparably low concentrations of growth promoters select for transferable antibiotic resistance has often been doubted. There is however convincing evidence from two sets of studies. Feeding of oxytetracycline to chickens was shown to select for plasmid mediated tetracycline resistance in
E. coli in chickens. Transfer of the tetracycline resistant E. coli from chickens to farm personnel was demonstrated (5, 6).

In the former East Germany in 1983, oxytetracycline was replaced as feed additive by the streptothricin antibiotic nourseothricin. This antibiotic was used country wide only for animal feeding. Resistance was negligible in 1983. Two years later, resistance (mediated by a transposon-encoded streptothricin acetyltransferase gene) was found in
E. coli from the gut of pigs and in meat products. By 1990, resistance to nourseothricin had spread to E. coli from the gut flora of pig farmers, their families, citizens from municipal communities, and patients with urinary tract infections. In 1987, the same resistance determinant was detected in other enteric pathogens, including Shigella which occurs only in humans (7, 8).

With the emergence and spread of glycopeptide resistance, enterococci became a subject of great interest (9). Enterococci colonize the guts of humans and other animals, and easily acquire antibiotic resistance genes and transfer them. During the last 5 years enterococci have been recorded among the top five of bacterial nosocomial pathogens. Although less pathogenic than
E. faecalis, E. faecium has drawn increased attention because of its development of resistance to glycopeptides (9).

In enterococci there are three known genotypes of transferable glycopeptide resistance with the
vanA gene cluster the most widely disseminated one (10). Studies demonstrating selection of transferable, vanA-mediated glycopeptide resistance in E. faecium by use of the glycopeptide avoparcin as a growth promoter in animal husbandry, have again focused attention on the use of antibacterials as growth promoters (11, 12). Glycopeptide resistant E. faecium (GREF) can easily reach humans via meat products (13) and consequently GREF have been isolated from stool specimens from nonhospitalized humans (13). A common structure of the vanA gene cluster has been found in a number of GREF of different ecological origin (human, food, animals; (14), indicating a frequent dissemination of vanA among different strains and also among different conjugative plasmids.

Ergotropic use of avoparcin was stopped Denmark in May 1995, in Germany in January 1996 and in all EU countries in April 1997. When investigated for GREF by end of 1994, thawing liquid from all of the investigated poultry carcasses was found heavily contaminated, by end of 1997 GREF were found in comparably low number in only 25 % of the investigated samples [15]. In parallel a decrease of faecal carriage of GREF by humans in the community was seen: 12 % by end of 1994 and 3.3 % by end of 1997 (15). These findings highlight the potential role of a reservoir of transferable glycopeptide resistance in animal husbandry for spread to humans. With the availability of the streptogramin combination quinupristin/dalfopristin streptogramins became an important alternative for treatment of infections with GREF (not
E. faecalis!)

Until last year, there was no medical use of streptogramins in German hospitals. However streptogramine resistance has been found in GREF from both patients and animals. The resistance is mediated by the
satA gene coding for a streptogramin acetyltransferase. The dissemination of satA was probably driven by use of the streptogramin antibioticvirginiamycin as growth promoter for more than 20 years (16).

Veterinary fluoroquinolone use
A decrease in fluoroquinolone sensitivity in
S. typhimurium has been described which parallels the time of fluoroquinolone use in veterinary medicine. This was especially observed in the United Kingdom for S. typhimurium strain DT 104 (17). Although the MIC's of ciprofloxacin for these isolates (0.25 - 1.0 mg/l) are still below clinical breakpoints for fluoroquinolones (for ciprofloxacin resistance ( 4 mg/l according to NCCLS), the clinical failure of ciprofloxacin for treating infections with S. typhi exhibiting elevated MIC's raises concern with regard to enteric Salmonella spp. In other countries like Germany, France, Australia, and the US S. typhimurium with ciprofloxacin MIC's above 0.25 mg/l are still rare.

Fluoroquinolone resistance in bacteria is mainly due to mutations in the target enzymes (DNA gyrase, topoisomerase IV; 18) and therefore spreads in a clonal way with particular bacterial strains affected.Enterics develop quinolone resistance by stepwise acquisition of mutations at certain positions in the active center of the target enzymes (19). Further accumulation of these mutations by enteric
Salmonella spp. will very probably lead to high level quinolone resistance.

Another intestinal pathogen which has its reservoir in animals is
Campylobacter spp. Fluroquinolone resistant Campylobacter can be isolated from human infections from faecal samples of chickens and from chicken meat (20). Different frequencies of quinolone resistant Campylobacter isolates from human cases of diarrhoe have been reported from several parts of the world. The Campylobacter spp. are obviously polyclonal (several strains harboured in the gut flora of man and animals), comparable to E. coli. Although currently available molecular typing techniques are available to Campylobacter most probably because of polyclonalityquinolone resistant Campylobacter strains have not been traced back to animal flocks.

Global situation for prevention and regulation
Use and licensing of these compounds varies tremendously worldwide. In developing countries, which are responsible for about 25 % of world-meat production, policies regulating veterinary use of antibiotics are poorly developed or absent. In China, raw mycelia are used as animal growth promoters. In Russia, chloramphenicol is still in veterinary use. In Southeast Asia, use of antimicrobials in shrimp farming is unregulated. The problems caused by inappropriate use of antibiotics reach beyond the country of origin. Meat products are traded worldwide, and bacterial populations evolve independent of geographical boundaries.

The agriculture industry is now building large chicken farms in Brazil with the aim to ship the products to arabic countries. The same can be observed for Thailand and shipping to central Europe. As long as global regulations are not feasible, a control of imported meat products for contamination with particular multiresistant bacteria (i.g. GREF) has to be taken into consideration.

The Swann'sCommittee's recommendations have been revived by WHO in 1994 and also concluded again from a workshop in 1997 (21, 22). Nevertheless, when Finland applied for a stop of macrolide use of growth promotors (tylosin, spiramycin) in EU countries, the scientific committee for animal nutrition which is advising the European Commission came now to the conclusion that there is no convincing evidence for selection and spread of resistance. The international dimensions of the spread of antibiotic resistance has been a topic of the last May's top level G8 conference and the need for efficient surveillance has been underlined. Improved surveillance of the incidence and spread of antibiotic resistance is an important prerequisite to regulatory measures. Unfortunately current surveillance projects do not include a monitoring of antibiotic usage in order to see more directly the consequences of selective pressure.

Use of antibacterials as growth promoters includes an uncalculatable hazard. As evident from the emergence of streptogramin resistance in enterococci, a compound or class of compounds that is used now as a growth promoter can, in the future, become important for human chemotherapy. The debate whether animal husbandry can do without antibacterial growth promoters continues. Sweden has demonstrated that procedural modifications can decrease the use of antibiotics, the antibacterials are prohibited as growth promoters since 1986 (23). Learning from the Swedish experience, agricultural science should define conditions for animal fattening without use of antibacterial growth promoters and without sacrificing production.

The often heard argument that giving up these kinds of growth promoters will lead to a substantial increase of the prices for meat products does not hold true. The Bavarian board for animal husbandry has performed a large field trial on the economic impact of antibiotic use for growth promotion which included ~ 400,000 pigs fed
with and ~ 400,000 pigs fed without growth promoters. One kilogram of pork produced without these growth promoters is about 0.10 Deutsche Mark more expensive [unpublished results].

It is further argued that a stop to the use of antibacterial growth promoters will endanger this world's nutrition. It is well known that the total amount of grain currently produced is sufficient to feed the world's human population. Hunger in parts of the world has mainly to do with social conditions and distribution of food. Furthermore, supporters of antimicrobial growth promoters claim that their use protects animals from various kind of infections (24). Isn't it also an ethical aspect to keep animals in such a way that they don't need this permanent prophylaxis? In the long run investments into alternatives to antimicrobials for animal growth promotion and improvement of the conditions of animal performance should pay off in more efficient production.

References

  1. Levy, S.B. Trends Microb. 1994. 2: 341.
  2. Thomke, S., Elwinger, K. Report to the Commission on Antimicrobial Feed Additived Swedish University of Agriculture, Uppsala, 1997.
  3. Reports of Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine (Swann Committee, Her Majesty's Stationary Office, London, September, 1969.
  4. Hellmuth, R., Bulling, E. (eds.). Criteria and methods for the microbiological evalution of growth promoters in animal feeds. Bundesgesundheitsamt Berlin, 1995.
  5. Levy, S.B., Fitzgerald, G.B., Macone, A.B. 1976. Nature 260: 40
  6. Levy, S.B., Fitzgerald, G.B., Macone, A.B. 1976. New Engl. J. Med. 295: 583-586.
  7. Hummel, R., Tschäpe, H., Witte. W. 1986. J. Basic Microbiol. 26: 461-466
  8. Tschäpe, H. 1994. FEMS Microbiol. Lett. 15: 23-32.
  9. Moellering, R.C. Jr. 1993. Clin. Infect. Dis. 14: 1173-1178.
  10. Arthur, M. Reynolds, P., Courvalin, P. 1996. Trends Microbiol. 4: 401.
  11. Aarestrup, J.M. 1995. Microb. Drug Res. 1: 255-257.
  12. Klare, I., Heier, H., Claus, H., Reissbrodt, R., Witte, W. 1995. FEMS Microbiol. Lett. 125: 165-172.
  13. Klare, I., Heier, H., Claus, H. et al. 1995. Microb. Drug Res. 1: 265-272.
  14. Werner, G., Klare, I., Witte, W. 1997. FEMS Microbiol. Lett. 155: 55-61.
  15. Klare, I., Badstübner, D., Konstabel, C. et al. submitted for publication
  16. Werner, G., Klare, I., Witte, W. 1998. Eur. J. Clin. Microbio. Infect. Dis. in press
  17. Threlfall, J. 1996. Lancet 347: 1053.
  18. Everett, M.J., Jiu, Y.F., Ricci, V., Piddock, L. 1996. Antimicrob. Agents Chemother. 40: 2380-2386.
  19. Heisig, P. 1996. Antimicrob. Agents Chemother. 40: 879-885.
  20. Gaunt, P.N, Piddock, L.J. 1996. J. Antimicrob. Chemother. 37: 747
  21. WHO Scientific working group on monitoring and management of bacterial resistance to antimicrobial agents. WHO/CDS/BVI/97.7, Geneva, Switzerland, 1994.
  22. The Medical Impact of the Use of Antimicrobials in Food Animals. Report of a WHO Meeting. Berlin, Germany, 13-17 October 1997.
  23. Weirup M. 1998. Preventive methods replace antibiotic growth promotors: ten years experience from Sweden. APUA Newsletter 16(2):1-4.
  24. Taylor, D. 1997. The uses and abuses of antibacterials in animal husbandry. In: Abstracts of the Conference Antibiotic Resistance: the Threat to International Health, Broadway.
 

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