Pharmacodynamic evaluation of tigecycline against Acinetobacter baumannii in a murine pneumonia model

Abstract

Tigecycline is an extended-spectrum antibiotic with activity against Acinetobacter spp. (ACB), an increasingly common cause of nosocomial pneumonia. Although this compound is under investigation for this indication, supportive pharmacodynamic data are not yet available at this infection site. The objective of this study was to characterize the exposure-response relationship of tigecycline with ACB in an established murine pneumonia model. The pharmacokinetic profile of tigecycline was evaluated in infected neutropenic mice. Tigecycline 6.25, 12.5, 25, 50, 100, 200, 300 and 400 mg/kg, in single or two to six divided subcutaneous doses, were tested against all ACB isolates. Efficacy, defined as the log(10) change in bacterial cfu/mL, was assessed after a 24 h course of therapy. Tigecycline exposures in serum were corrected for dose-specific protein binding. The relationship between the area under the free concentration-time curve to MIC (fAUC/MIC) and change in bacterial density was determined using the sigmoid E(max) model. Tigecycline displayed linear pharmacokinetics with a mean half-life of 11.3 +/- 1.4 h. Efficacy correlated well with fAUC/MIC (R(2) = 0.96). The mean 80%, 50% effective and stasis exposures (fAUC/MIC) were 17, 8 and 6, respectively. Maximal efficacy for the five Acinetobacter baumannii studied was 3.4 log kill. Tigecycline efficacy in this murine ACB pneumonia model was well predicted by fAUC/MIC. Requisite tigecycline exposures for efficacy appear to be higher for ACB pneumonia than for other pathogens reported of non-respiratory infections.