Efficacy and safety of ceftazidime/avibactam in patients with infections caused by β-lactamase-producing Gram-negative pathogens: A pooled analysis from the Phase 3 clinical trial programme

Objectives: This post hoc pooled analysis evaluated clinical and microbiological outcomes and safety in patients with infections caused by β-lactamase-producing Gram-negative pathogens across five Phase 3, randomized, controlled, multicentre trials of ceftazidime/avibactam in adults with complicated intra-Abdominal infection (cIAI), complicated urinary tract infection (cUTI)/pyelonephritis and nosocomial pneumonia (NP), including ventilator-Associated pneumonia (VAP). Methods: In each trial, RECLAIM/RECLAIM 3 (cIAI), REPRISE (cIAI/cUTI), RECAPTURE (cUTI) and REPROVE (NP, including VAP) patients were randomized 1:1 to IV ceftazidime/avibactam (plus metronidazole for patients with cIAI) or comparators (carbapenems in >97% patients) for 5-21 days. Clinical and microbiological responses at the test-of-cure visit were assessed for patients with ESBLs, and/or plasmidic and/or overexpression of chromosomal AmpC, and/or serine carbapenemases without MBLs identified in baseline Gram-negative isolates by phenotypic screening and molecular characterization in the pooled microbiological modified ITT (mMITT) population. Results: In total, 813 patients (ceftazidime/avibactam, n=389; comparator, n=424) had ≥1 β-lactamase-producing baseline pathogen identified, amongst whom 792 patients (ceftazidime/avibactam, n=379; comparator, n=413) had no MBLs. The most frequent β-lactamase-producing pathogens across treatment groups were Escherichia coli (n=381), Klebsiella pneumoniae (n=261) and Pseudomonas aeruginosa (n=53). Clinical cure rates in the pooled non-MBL β-lactamase-producing mMITT population were 88.1% (334/379) for ceftazidime/avibactam and 88.1% (364/413) for comparators; favourable microbiological response rates were 76.5% (290/379) and 68.8% (284/413), respectively. The safety profile of ceftazidime/avibactam was consistent with previous observations. Conclusions: This analysis provides supportive evidence of the efficacy and safety of ceftazidime/avibactam in patients with infections caused by ESBLs, AmpC and serine carbapenemase-producing Gram-negative pathogens. Trial registration: NCT01499290; NCT01726023; NCT01644643; NCT01595438/NCT01599806; NCT01808092.