Pharmacokinetics and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle

Authors: DEDONDER, KD - Kansas State University; APLEY, MD - Kansas State University; LI, M - Kansas State University; GEHRING, R - Kansas State University; Harhay, Dayna; LUBBERS, BV - Kansas State University; WHITE, BJ - Kansas State University; CAPIK, SF - Kansas State University; KUKANICH, B - Kansas State University; RIVIERE, JE - Kansas State University; TESSMAN, RK - Merial, Ltd

Submitted to: Journal of Veterinary Pharmacology and Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/3/2015
Publication Date: 10/1/2015
Publication URL: https://handle.nal.usda.gov/10113/62361
Citation: Dedonder, K.D, Apley, M.D., Li, M., Gehring, R., Harhay, D.M., Lubbers, B.V., White, B.J., Capik, S.F., Kukanich, B., Riviere, J.E., Tessman, R.K. 2015. Pharmacokinetics and pharmacodynamics of gamithromycin in pulmonary epithelial lining fluid in naturally occurring bovine respiratory disease in multisource commingled feedlot cattle. Journal of Veterinary Pharmacology and Therapeutics. doi:10.1111/jvp.12267.

Interpretive Summary: Bovine respiratory disease is estimated to be responsible for 75% of morbidity and 50% of mortality in beef cattle feeding operations. As a result, this disease is the primary cause of antibiotic use in cattle production systems. Treatment for the control of bovine respiratory disease upon arrival at a feeding facility, also known as mass medication, has been a common practice in feedlots and cattle backgrounding facilities even before the first approval of an antibiotic for this purpose in 1992. The objectives of this study were to examine differences in the concentration and movement of the macrolide antibiotic, gamithromycin, in the plasma and lungs of treated cattle, and to determine the relationship between those factors and treatment outcome for bovine respiratory disease. The results suggest that a greater exposure, in terms of drug concentration and time of exposure, favored a successful case outcome. However, variability in the susceptibility of the bovine respiratory disease pathogens present also impacts treatment outcome.

Technical Abstract: The overall objectives of this study were to determine if a correlation exists between individual pharmacokinetic parameters and treatment outcome when feeder cattle were diagnosed with bovine respiratory disease (BRD) and treated with gamithromycin (Zactran®) at the label dose, and if there was a stronger correlation between treatment outcome and gamithromycin concentration in plasma or in the effect compartment. The study design was a prospective, blinded, randomized clinical trial with masked subjective evaluators. Three groups of 60 (450-500 lb) steers/bulls were purchased from auctions in Missouri, Kentucky, and Tennessee, USA. Upon feedlot arrival cattle were randomly allocated within origin to sham injection or gamithromycin metaphylaxis. Cattle were scored daily for signs of BRD by a veterinarian blinded to treatment. Animals meeting the BRD case definition were enrolled and allocated to a sample collection scheme consisting of 1) nasopharyngeal swabs, 2) PELF, and 3) plasma samples for bacterial isolation (1 and 2) and gamithromycin analysis by HPLC-MS/MS (2 and 3). Treatment for BRD with gamithromycin was administered after collection of time 0 samples. Gamithromycin susceptibility of M. haemolytica (n=300) and P. multocida (n=238) were determined using broth microdilution and custom frozen panels containing gamithromycin at concentrations from 0.03 to 16 µg/ml. A two compartment pharmacokinetic model with a PELF compartment for gamithromycin in plasma and PELF was developed using rich datasets from unpublished studies. The sparse data from our study were then fit to this model using nonlinear mixed effects modeling to estimate individual parameter values which were used to simulate full time-concentration profiles for each animal in the study, which were analyzed using non-compartmental methods so that PK/PD indices (AUC24/MIC, AUC8/MIC, CMAX/MIC) could be calculated for plasma and PELF (also T>MIC). A marginally significant correlation was found between treatment outcome and both plasma (P = 0.06) and PELF (P = 0.08) AUC’s. We found a statistical difference in mean residence time MRT (P = 0.03), with a longer MRT of gamithromycin in the PELF favorable to a successful case outcome. Additionally, we have included the calculation of each of the PK/PD indices, and although no statistical differences were observed, our findings indicate that for both M haemolytica and P multocida a larger drug exposure in terms of concentration, and time of exposure, was favorable to a successful case outcome. That there was a statistically significant difference in MRT in PELF between treatment successes and failures, seems also suggestive of the possibility that a larger exposure of drug is favorable to case outcome. Ultimately, the findings of this study indicate that treatment outcome appears to be related more closely to variability in pharmacokinetics and not to pathogen MIC.