In Vitro Activity of Ceftazidime-Avibactam against Isolates from Patients in a Phase 3 Clinical Trial for Treatment of Complicated Intra-abdominal Infections

Abstract

The increasing prevalence of multidrug-resistant Gram-negative pathogens has generated a requirement for new treatment options. Avibactam, a novel non-β-lactam-β-lactamase inhibitor, restores the activity of ceftazidime against Ambler class A, C, and some class D β-lactamase-producing strains of Enterobacteriaceae and Pseudomonas aeruginosa The in vitro activities of ceftazidime-avibactam versus comparators were evaluated against 1,440 clinical isolates obtained in a phase 3 clinical trial in patients with complicated intra-abdominal infections (cIAI; ClinicalTrials.gov identifier NCT01499290). Overall, in vitro activities were determined for 803 Enterobacteriaceae, 70 P. aeruginosa, 304 Gram-positive aerobic, and 255 anaerobic isolates obtained from 1,066 randomized patients at baseline. Susceptibility was determined by broth microdilution. The most commonly isolated Gram-negative, Gram-positive, and anaerobic pathogens were Escherichia coli (n = 549), Streptococcus anginosus (n = 130), and Bacteroides fragilis (n = 96), respectively. Ceftazidime-avibactam was highly active against isolates of Enterobacteriaceae, with an overall MIC90 of 0.25 mg/liter. In contrast, the MIC90 for ceftazidime alone was 32 mg/liter. The MIC90 value for ceftazidime-avibactam (4 mg/liter) was one dilution lower than that of ceftazidime alone (8 mg/liter) against isolates of Pseudomonas aeruginosa The ceftazidime-avibactam MIC90 for 109 ceftazidime-nonsusceptible Enterobacteriaceae isolates was 2 mg/liter, and the MIC range for 6 ceftazidime-nonsusceptible P. aeruginosa isolates was 8 to 32 mg/liter. The MIC90 values were within the range of susceptibility for the study drugs permitted per the protocol in the phase 3 study to provide coverage for aerobic Gram-positive and anaerobic pathogens. These findings demonstrate the in vitro activity of ceftazidime-avibactam against bacterial pathogens commonly observed in cIAI patients, including ceftazidime-nonsusceptible Enterobacteriaceae (This study has been registered at ClinicalTrials.gov under identifier NCT01499290.).

Keywords: ceftazidime-avibactam; ceftazidime-nonsusceptible; complicated intra-abdominal infection; in vitro activity.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Activities of ceftazidime-avibactam (black bars) and ceftazidime (white bars) against 108 ceftazidime-nonsusceptible Enterobacteriaceae (determined for the microbiologically modified intent-to-treat [mMITT] patient analysis set). For Enterobacteriaceae, ceftazidime-nonsusceptible isolates were defined as those having a ceftazidime MIC of ≥8 mg/liter. mMITT includes 108 of the 109 ceftazidime-nonsusceptible Enterobacteriaceae isolates obtained from all randomized patients.