Efficacies of Ceftazidime-Avibactam and Ceftazidime against Pseudomonas aeruginosa in a Murine Lung Infection Model

Abstract

ABSTRACTThis study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28Pseudomonas aeruginosaisolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. ThefT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28P. aeruginosastrains used, the ceftazidime-avibactam MICs were 4 to 64 μg/ml, and those of ceftazidime were 8 to >128 μg/ml. The change in log10CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log10CFU againstP. aeruginosawith ceftazidime-avibactam MICs of ≤32 μg/ml (ELF upper 95% confidence limit forfT>MIC [ELFfT>MIC] of ≥19%), except for one isolate with a ceftazidime-avibactam MIC of 16 μg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 μg/ml (ELFfT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 μg/ml (ELFfT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 μg/ml (ELFfT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 μg/ml, where the ELFfT>MIC was 0%. ELFfT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective againstP. aeruginosa, with MICs of up to 32 μg/ml with an ELFfT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused byP. aeruginosa.