Evaluating duration of tylosin phosphate treatment in feedlot cattle for liver abscess prevention to ensure efficacy while addressing concerns about antimicrobial resistance
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Project Summary The problem statement for RFA-FD-20-025 calls for research proposals addressing specific antimicrobial drugs (AMDs) used in food-producing animals by providing substantive evidence that aids in developing a defined duration of use that minimizes AMD exposures and is also efficacious for the target indication. Our overall hypothesis is that tylosin phosphate can be supplemented in beef cattle diets early in the feeding period to achieve important reductions in liver abscess incidence, but removed substantially before slaughter to reduce risks for promoting antimicrobial resistance. This proposal includes: 1) A randomized controlled trial to provide efficacy data for defined duration treatment regimens that will substantially reduce the amount of tylosin phosphate used for preventing liver abscesses (LAs) in cattle, and 2) A systematic review to identify all relevant randomized controlled trials (RCTs) evaluating the efficacy of tylosin supplementation and other LA prevention strategies, and 3) A network meta-analysis that will provide a Bayesian unbiased estimation of the comparative efficacy for limited tylosin supplementation regimens that are evaluated in our RCT, as well as comparisons to other prevention strategies identified in our systematic review. LAs are one of the most common health problems affecting beef production. Supplementing diets with tylosin phosphate is currently the most efficacious prevention method, but currently, approved labeling requires continuous supplementation once it is introduced. Legally, dietary inclusion must be continued until the cattle are slaughtered, which hampers our ability to fulfill ethical obligations to promote antimicrobial stewardship by reducing AMD exposures when possible. Limited research data suggest that tylosin can be removed from diets 30-40d before slaughter while still achieving acceptable efficacy, but that much longer removal periods (e.g., 120d) have lower efficacy. This research will directly evaluate the efficacy of regimens that remove supplementation at 56d and 84d before slaughter in an RCT. In a 160d feeding period, these limits for duration of use would decrease tylosin use by 35% and 53% compared to continuous supplementation. Balancing the need to adequately power non-inferiority statistical comparisons with the costs of conducting our RCT using large pen groups at a commercial feedlot is important. As such, final estimates of comparative efficacy will be obtained from a Bayesian network meta-analysis that leverages the prior knowledge available from all available prior RCTs addressing LA preventive interventions, which we will identify by systematic review of the literature. Network meta-analysis will also allow valid indirect comparisons of efficacy for other interventions that are not directly studied in the RCT. This innovative study methodology will have a much broader application than just for this study. This approach will become a model for other research that assesses the efficacy of interventions related to agriculture, as well as animal and human health outcomes. The research outcomes from this proposal will be immediately applicable throughout the U.S. beef industry, and in other countries that allow tylosin supplementation for reducing the incidence of LAs in beef cattle.
