Investigation on rifampicin administration from the standpoint of pharmacokinetics/pharmacodynamics in a neutropenic murine thigh infection model.

Abstract

The purpose of this study was to examine the pharmacokinetics/pharmacodynamics of rifampicin against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S.aureus (MRSA), and vancomycin-intermediate S.aureus (VISA) in a neutropenic murine thigh infection model. Three S.aureus isolates (MSSA [ATCC 25923], MRSA and VISA [Mu50]) with rifampicin MIC 0.06 to >256μg/mL were tested. The efficacy was calculated as the change in bacterial density. A maximum effect model was used to determine the PK/PD index that best described the dose-response data. The area under the curve (AUC)/MIC and maximum concentration of drug in serum (Cmax/MIC) were the best correlated with invivo efficacy (AUC/MIC, R(2)=0.96; Cmax/MIC, R(2)=0.97) for S.aureus ATCC 25923 strain, and the dose fractionation-response study did not show significantly different antimicrobial activity (p=0.10). The AUC/MIC values associated with stasis and 1-log kill for the S.aureus ATCC 25923 strain were 386 and 952, respectively. On the other hand, no antimicrobial efficacy was observed against two strains (MRSA and VISA) with MIC of 128μg/mL or more. Rifampicin demonstrated concentration-dependent killing. The AUC/MIC was a predictive PK/PD index.