Semi-mechanistic PK/PD modeling of enrofloxacin against sensitive Pasteurella multocida: inter-strain variability and prediction of efficacy in pigs.

Abstract

AIMS: This study aimed to investigate the inter-strain variability of enrofloxacin activity against Pasteurella multocida and to apply a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach to predict the expected efficacy of enrofloxacin in pigs. METHODS AND RESULTS: In vitro and ex vivo time-kill curve (TKC) experiments were performed with enrofloxacin against nine susceptible P. multocida strains, and a semi-mechanistic PK/PD model was developed. Both bacterial net growth rates and enrofloxacin-mediated killing rates varied substantially among isolates; however, an overall strong bactericidal effect was consistently observed. At very high enrofloxacin concentrations, most strains exhibited a reduced killing rate (Eagle effect). A population PK model of enrofloxacin in pigs was also developed using published data. The integrated PK/PD model was then applied to simulate the expected efficacy in pigs of the United States and European dosing regimens (injectable formulations) of enrofloxacin against P. multocida, yielding comparable results across sensitive strains. CONCLUSIONS: Simulations from the PK/PD model suggest that the current CLSI breakpoints may be appropriate for defining enrofloxacin susceptibility in P. multocida, even from pigs treated with the European dosing regimen.