Administration of chlortetracycline to beef cattle: evaluation of antimicrobial activity, resistance selection, duration of detection, and efficacy

Abstract

Chlortetracycline (CTC) is one of the most widely used antimicrobials in food-animal production. Approved routes of administration for CTC in cattle are through the feed or water. This dissertation evaluates the antimicrobial activity, resistance selection, duration of detection, and efficacy of chlortetracycline administered to beef cattle. A systematic review was conducted to determine the effect of in-feed tetracyclines on the antimicrobial resistance of enteric bacteria in cattle. Results of the review demonstrated that regardless of antimicrobial exposure, tetracycline resistant E. coli were prevalent in bovine feces. Additionally, environmental factors play a major role in harboring and disseminating antimicrobial-resistance genes. In the second study, the susceptibly profile of E. coli isolates was investigated in anaplasmosis-endemic pastured cattle herds provided four different free-choice formulations (700, 5000, 6000, 8000 g/ton) of CTC-medicated mineral for five consecutive months to control anaplasmosis. Most animals, pre- and post- CTC exposure, harbored E. coli isolates with CTC MIC values > 4 µg/ml, falling in the CSLI categories of intermediate or resistant. No pattern or clear development of resistance was observed in E. coli isolated from CTC-treated cattle. The third study explored the antimicrobial activity of CTC and its transformation products (ECTC and ICTC) against enteric and environmental bacteria via microbroth dilution. Resistance associated with CTC has been extensively researched, but little has been reported on resistance associated with its transformation products 4-epi-CTC (ECTC) and iso-CTC (ICTC). Upon examination our study reported antimicrobial activity of chlortetracycline in Bacillus subtilis, Campylobacter jejuni, Pseudomonas aeruginosa, Clostridium perfringens, and Staphylococcus aureus. In contrast, 4-epi-CTC, displayed antimicrobial activity against B. subtilis and C. jejuni. No activity was displayed for iso-CTC in any of the bacteria tested. The fourth study investigated plasma and urine elimination characteristics of three regimens (Group A: 22 mg/kg of bodyweight daily, Group B: 350 mg/head per day, and Group C: 70 mg/head per day) of chlortetracycline administered through the feed to beef cattle. Mean ± standard deviation values for plasma T ½ (for the period up to 6 days following the last day of administration) for groups A, B, and C were 1.1 ± 1.5, 1.3 ± 1.4, and 1.3 ± 1.3 days, respectively. Terminal urine T ½ values (from 23 to 79 days post administration) were 35.4 ± 1.5, 51.7 ± 1.9, and 64.7 ± 1.9 days for groups A, B, and C, respectively. The persistence of CTC in the urine and the long-reported urine half-lives suggest chlortetracycline remains in the animal for a prolonged period of time. Finally, a pharmacokinetic approach was utilized to investigate two in-feed CTC regimens (Group A: 22 mg/kg of bodyweight daily and Group B: 350 mg/head per day). The dose-adjusted total drug 24-hr mean (± SD) AUC values were 4.181 ± 1.724 µg·hr/ml and 0.302 ± 0.064 µg·hr/ml for treatment groups A and B, respectively. Treatment group A achieved >90% target (AUC₂₄/MIC of 25) attainment at an MIC of 0.06 µg/ml, whereas treatment group B displayed only 12.6% target attainment at the lowest MIC evaluated (0.015 µg/ml). These results suggest a very low potential for efficacy against common bovine pathogens. Taken together, these studies help define resistance selection pressure from administration of CTC in the mineral of pasture cattle, compare antimicrobial effects of CTC and two common degradation products, characterize the duration of detection of CTC after administration in both plasma and urine, and determine the potential for efficacy from two commonly used in-feed CTC regimens.