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Development of antimicrobial resistance (AMR) in the intestinal microbial flora of cattle remains one of the most significant issues of public concern faced by the beef industry, and has led the FDA to drastically restrict the use of fluoroquinolones. Yet, the role of therapeutic use of these drugs in selecting for resistant fecal bacteria is unclear, which led us to develop a novel method to measure active antimicrobial concentrations in multiple areas of the gastrointestinal tract of steers. There remains significant unanswered questions concerning the impact of dosing regimens on the GI tract concentration of antimicrobials, the subsequent selection for AMR, and the persistence of these resistant bacteria. The work outlined in this project will fill this immediate need by directly comparing two FDA-approved dosing regimens for enrofloxacin in cattle and their impact on AMR, and the persistence of these changes in the feces. Our hypothesis is that administration of a single, high dose of enrofloxacin will produce higher drug concentrations in the GI tract and induce less AMR than repeated, lower doses.
Prudent use of antimicrobials by veterinarians is widely considered critical to mitigate the development of AMR in cattle,1-2 and is a key component of the recently announced National Action Plan for Combating Antibiotic-Resistant Bacteria. Nowhere is this more important than the treatment of respiratory disease on feedlots as these animals are close to harvest and the predominant antimicrobials used are prescription drugs similar to those critical for human use (including enrofloxacin).3-4 Epidemiological associations between parenteral antibiotic administration in these animals and resistance in enteric organisms often only evaluate a single bacterial species or isolate.5-6 While useful in describing broad associations, these studies are inherently limited by the inability to correlate the development of AMR with antibiotic concentrations in the GI tract. The lack of a clear method of evaluating antimicrobials' risk of promoting resistance is an inherent problem in adequately mitigating the food safety risk of AMR in cattle.7Upon initial approval of enrofloxacin for treatment in cattle, the Food and Drug Administration prohibited of extra-label use of this drug in food animals to preserve the effectiveness of fluoroquinolones for treating disease in humans, yet made no distinction between the two approved dosing regimens of enrofloxacin and how that may be a factor in producing resistance. Yet, evidence suggests that it is not necessarily a specific drug that causes resistance, but the method and duration of exposure as potentially determined by the dose and dosing schedule.8-9 The approval of administration of enrofloxacin as a single, high dose or repeated lower doses provides us with a perfect opportunity to test these assumptions in cattle using novel techniques that are not possible in humans. From our studies, we expect determine the impact of dosing regimen on distribution of enrofloxacin into the GI tract. We believe that many factors, including pharmacokinetics of antibiotics, the physiochemical properties, formulations, and dosing scheme, determine the flux from systemic administration to the intestinal lumen. As enrofloxacin is partially metabolized into ciprofloxacin,10 which has a different lipophilicity and protein binding, its use in this study provides an ideal opportunity to additionally investigate the impact of these chemical differences on drug movement into the gut. Further, we believe that our methods will provide a framework to evaluate new and existing antibiotics for their potential to produce resistance in intestinal bacteria, allowing regulatory authorities and drug manufacturers to screen future antimicrobial medications for food animals. The research proposed in this application is significant because the findings are expected form the basis for rational prudent antimicrobial use guidelines for cattle, a key mechanism to reduce the food safety risk of AMR in cattle.