Molecular β-Lactamase Characterization of Aerobic Gram-Negative Pathogens Recovered from Patients Enrolled in the Ceftazidime-Avibactam Phase 3 Trials for Complicated Intra-abdominal Infections, with Efficacies Analyzed against Susceptible and Resistant Subsets

Antimicrob Agents Chemother. 2017 May 24;61(6):e02447-16. doi: 10.1128/AAC.02447-16. Print 2017 Jun.


The correlation of the clinical efficacy of ceftazidime-avibactam (plus metronidazole) with that of meropenem was evaluated in subjects infected with Gram-negative isolates having characterized β-lactam resistance mechanisms from the complicated intra-abdominal infection (cIAI) phase 3 clinical trials. Enterobacteriaceae isolates displaying ceftriaxone and/or ceftazidime MIC values of ≥2 μg/ml and Pseudomonas aeruginosa isolates with ceftazidime MIC values of ≥16 μg/ml were characterized for extended-spectrum-β-lactamase (ESBL) content. Enterobacteriaceae and P. aeruginosa isolates with imipenem and meropenem MIC values of ≥2 and ≥8 μg/ml, respectively, were tested for carbapenemase genes. The primary efficacy endpoint was clinical cure at test of cure (TOC) among the members of the microbiologically modified intention-to-treat (mMITT) population. A total of 14.5% (56/387) and 18.8% (74/394) of patients in the ceftazidime-avibactam and meropenem arms had isolates that met the MIC screening criteria at the baseline visit, respectively. CTX-M variants alone (29.7%; 41/138) or in combination with OXA-1/30 (35.5%; 49/138), most commonly, blaCTX-M group 1 variants (79/90; 87.8%), represented the β-lactamases most frequently observed among Enterobacteriaceae isolates. Among the patients infected with pathogens that did not meet the screening criteria, 82.2% showed clinical cure in the ceftazidime-avibactam group versus 85.9% in the meropenem group. Among patients infected with any pathogens that met the MIC screening criteria, clinical cure rates at TOC were 87.5% and 86.5% for the ceftazidime-avibactam and meropenem groups, respectively. Ceftazidime-avibactam had clinical cure rates of 92.5% to 90.5% among patients infected with ESBL- and/or carbapenemase-producing Enterobacteriaceae strains at the baseline visit, while meropenem showed rates of 84.9% to 85.4%. The ceftazidime-avibactam and meropenem groups had cure rates of 75.0% and 86.7%, respectively, among patients having any pathogens producing AmpC enzymes. The efficacy of ceftazidime-avibactam was similar to that of meropenem for treatment of cIAI caused by ESBL-producing organisms. (This study has been registered at under registration no. NCT01499290 and NCT01500239.).

Keywords: CTX-M-15; ESBL; carbapenemase; clinical efficacy.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use*
  • Azabicyclo Compounds
  • Ceftazidime
  • Drug Combinations
  • Escherichia coli / drug effects
  • Escherichia coli / pathogenicity
  • Gram-Negative Aerobic Bacteria / drug effects*
  • Gram-Negative Aerobic Bacteria / pathogenicity*
  • Humans
  • Intraabdominal Infections / drug therapy*
  • Intraabdominal Infections / microbiology
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / pathogenicity
  • Microbial Sensitivity Tests
  • beta-Lactamases / pharmacology*
  • beta-Lactamases / therapeutic use*


  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Drug Combinations
  • avibactam, ceftazidime drug combination
  • Ceftazidime
  • beta-Lactamases

Associated data