Efficacies of ceftazidime-avibactam and ceftazidime against Pseudomonas aeruginosa in a murine lung infection model

Abstract

This 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 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the ceftazidime-avibactam MICs were 4 to 64 μg/ml, and those of ceftazidime were 8 to >128 μg/ml. The change in log10 CFU 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 log10 CFU against P. aeruginosa with ceftazidime-avibactam MICs of ≤32 μg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>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 (ELF fT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 μg/ml (ELF fT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 μg/ml (ELF fT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 μg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective against P. aeruginosa, with MICs of up to 32 μg/ml with an ELF fT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused by P. aeruginosa.

FIG 1

Serum concentration-time profile after human simulated plasma doses of 2 g ceftazidime–0.5 g avibactam every 8 h as a 2-h infusion in humans compared with that observed in infected female ICR mice.

FIG 2

Epithelial lining fluid concentration-time profile after human simulated plasma doses of 2 g ceftazidime–0.5 g avibactam every 8 h as a 2-h infusion in humans compared with that observed in infected female ICR mice.

FIG 3

Efficacy of human simulated serum doses of 2 g ceftazidime–0.5 g avibactam every 8 h as a 2-h infusion against P. aeruginosa in the neutropenic lung infection model. Error bars represent means ± SD.

FIG 4

Efficacy of ceftazidime as a directed epithelial lining fluid (ELF) fT>MIC regimen against P. aeruginosa in the neutropenic lung infection model. Error bars represent means ± SD.

FIG 5

Epithelial lining fluid (ELF) concentration-time profile after human simulated plasma doses of 2 g ceftazidime–0.5 g avibactam every 8 h as a 2-h infusion observed in infected and uninfected mice monitored during the third and final 8-h period.