Pharmacokinetic–pharmacodynamic integration and modelling of florfenicol in calves

Abstract

Florfenicol was administered subcutaneously to 10 calves at a dose of 40mg/kg. Pharmacokinetic-pharmacodynamic (PK-PD) integration and modelling of the data were undertaken using a tissue cage model, which allowed comparison of microbial growth inhibition profiles in three fluids, serum, exudate and transudate. Terminal half-lives were relatively long, so that florfenicol concentrations were well maintained in all three fluids. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration were determined in vitro for six strains each of the calf pneumonia pathogens, Mannhemia haemolytica and Pasteurella multocida. An PK-PD integration for three serum indices provided mean values for P.multocida and M.haemolytica, respectively, of 12.6 and 10.4 for Cmax /MIC, 183 and 152h for AUC0-24h /MIC and 78 and 76h for T>MIC. Average florfenicol concentrations in serum exceeded 4×MIC and 1.5×MIC for the periods 0-24 and 48-72h, respectively. Ex vivo growth inhibition curves for M.haemolytica and P.multocida demonstrated a rapid (with 8h of exposure) and marked (6 log10 reduction in bacterial count or greater) killing response, suggesting a concentration-dependent killing action. During 24-h incubation periods, inhibition of growth to a bacteriostatic level or greater was maintained in serum samples collected up to 96h and in transudate and exudate samples harvested up to 120h. Based on the sigmoidal Emax relationship, PK-PD modelling of the ex vivo time-kill data provided AUC0-24h /MIC serum values for three levels of growth inhibition, bacteriostatic, bactericidal and 4 log10 decrease in bacterial count; mean values were, respectively, 8.2, 26.6 and 39.0h for M.haemolytica and 7.6, 18.1 and 25.0h for P.multocida. Similar values were obtained for transudate and exudate. Based on pharmacokinetic and PK-PD modelled data obtained in this study and scientific literature values for MIC distributions, Monte Carlo simulations over 100000 trials were undertaken to predict once daily dosages of florfenicol required to provide 50% and 90% target attainment rates for three levels of growth inhibition, namely, bacteriostasis, bactericidal action and 4 log10 reduction in bacterial count.