In Vivo Efficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates

Ceftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of the in vivo efficacy of the combination against these targeted ceftazidime- and carbapenem-resistant Enterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam against Enterobacteriaceae exhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinical Enterobacteriaceae isolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10 CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against the Enterobacteriaceae isolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MIC of 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistant Enterobacteriaceae.