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The Effect of Antimicrobial Treatment and Withdrawal on the Population Dynamics of Enteric Bacteria Expressing Resistance in the Pig


To evaluate the effect of treatment with, and subsequent withdrawal of, antimicrobial agents on the acquisition, dissemination and persistence of genes imparting resistance within the bacterial flora of the pig intestine.<P>
The study is investigating the effect of four in-feed antimicrobial agents, each with a different resistance mechanism and pharmacokinetic properties, on gastrointestinal tract during and following treatment.

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There is widespread concern that the use of antibiotics in livestock production is directly contributing to the alarming increase in antibiotic resistance found in bacteria of medical importance. Antibiotics are used extensively in livestock production, both for the treatment and control of disease and to promote growth. The vast majority of the antibiotics used are administered in the animals’ food or water, thus directly exposing the bacteria in the gastrointestinal tract to the antibiotic. Consequently this practice is likely to induce and perpetuate antibiotic resistance in enteric bacteria, many of which can pass up the food chain and colonise the gastrointestinal tracts of humans. Resistance in the enteric bacteria of livestock pose a threat to public health both directly and indirectly. The direct threat comes from enteric bacteria, which are recognised zoonotic pathogens. The indirect threat comes from bacteria carrying resistance genes on mobile genetic elements, such as plasmids, some of which also impart multiple antibiotic resistance. Nevertheless, it remains unclear to what extent the use of antibiotics in livestock production contributes to the increasing incidence of antimicrobial resistance found in bacteria of medical importance.
<P>The purpose of the research conducted under OD2003 was to determine the effect of antibiotic treatment on the emergence and persistence of antibiotic resistance in the enteric bacteria of pigs. Pigs were specifically chosen for this study because it is in this sector of livestock production that antibiotic treatment is greatest. Three therapeutic antibiotics and one growth promoter were evaluated. The therapeutic antibiotics chosen were the tetracycline chlortetracycline, the fluoroquinolone enrofloxacin, and the macrolide tylosin, all of which are used commonly in pig production and have analogues widely used in human medicine. In addition the growth promoter avilamycin was evaluated; this product is unrelated to any antibiotics currently used in medicine.
<P>The project has run well and all of the agreed milestones have been met. The data generated provides a unique insight into the effects of antibiotic treatment on the emergence and persistence of genes conferring resistance in enteric bacteria. The data generated should also prove valuable for formulating control strategies to reduce the risks posed by antimicrobial usage in livestock production. Thus far six papers have been accepted for publication by peer-reviewed journals, four more are currently in preparation, and two papers have been presented at international conferences.
The studies conducted under OD2003 demonstrate that oral treatment of pigs with any one of the three therapeutic antibiotics investigated, results in a rapid increase in the number of enteric bacteria expressing resistance, including zoonotic pathogens. (objectives 1 and 2). The resistance genes were identified for each antibiotic: those identified for chlortetracycline and tylosin have been previously reported on plasmids, however their location was not confirmed in this study. Following drug withdrawal, the number of bacteria expressing resistance declines only slowly, high numbers persisting well beyond the drug withdrawal periods (objectives 1 and 4). Current drug withdrawal periods, which are intended only to safeguard public health from the adverse effects of drug residues in meat products, are inadequate to safeguard public health from the risk posed by resistant bacteria induced by the use of therapeutic antibiotics in livestock production. The public health risk posed by the three therapeutic antibiotics evaluated could be significantly reduced by extending the current drug withdrawal period by 7 days for both chlortetracycline and enrofloxacin, and by introducing a 3-week withdrawal period for tylosin. <P>
In contrast to the therapeutic antibiotics investigated, our study using the growth promoter avilamycin showed that resistance emerges relatively slowly, only becoming detectable after 82 days of treatment. Furthermore, following drug withdrawal, resistance waned rapidly, becoming undetectable after two weeks. These findings suggests that the use of the growth promoter avilamycin poses little risk to human health and this could be negated by simply introducing a 2-week withdrawal period. <P>
In conclusion, the experiments conducted under OD2003 provide strong evidence that the current use of antibiotics in pig production results in recently-treated animals entering the human food chain shedding high numbers of resistant bacteria. Our findings demonstrate that the risk to public health is much higher for the therapeutic antibiotics evaluated than for the growth promoter avilamycin. The finding of this study indicate that the risk posed by the antibiotics evaluated could be greatly reduced. by increasing the withdrawal period by 7 days for chlortetracycline and enrofloxacin, and introducing a withdrawal period of 3 weeks for tylosin and 2 weeks for avilamycin.

University of Bristol
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