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

• Published in: Antimicrobial agents and chemotherapy 2017-06, Vol.61 (6)
• Main Authors: Mendes, Rodrigo E, Castanheira, Mariana, Woosley, Leah N, Stone, Gregory G, Bradford, Patricia A, Flamm, Robert K
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Azabicyclo Compounds; beta-Lactamases; beta-Lactamases - pharmacology; beta-Lactamases - therapeutic use; Ceftazidime; Enterobacteriaceae; Escherichia coli - drug effects; Escherichia coli - pathogenicity; Gram-Negative Aerobic Bacteria; Gram-Negative Aerobic Bacteria - drug effects; Gram-Negative Aerobic Bacteria - pathogenicity; Humans; Intraabdominal Infections; Intraabdominal Infections - drug therapy; Intraabdominal Infections - microbiology; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - pathogenicity; Mechanisms of Resistance; Microbial Sensitivity Tests; Pseudomonas aeruginosa
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02447-16

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. isolates displaying ceftriaxone and/or ceftazidime MIC values of ≥2 μg/ml and isolates with ceftazidime MIC values of ≥16 μg/ml were characterized for extended-spectrum-β-lactamase (ESBL) content. and 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, group 1 variants (79/90; 87.8%), represented the β-lactamases most frequently observed among 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 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 ClinicalTrials.gov under registration no. NCT01499290 and NCT01500239.).