title: 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.
abstract: 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.Enterobacteriaceaeisolates displaying ceftriaxone and/or ceftazidime MIC values of ≥2 μg/ml andPseudomonas aeruginosaisolates with ceftazidime MIC values of ≥16 μg/ml were characterized for extended-spectrum-β-lactamase (ESBL) content.EnterobacteriaceaeandP. aeruginosaisolates 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-Mgroup 1 variants (79/90; 87.8%), represented the β-lactamases most frequently observed amongEnterobacteriaceaeisolates. 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-producingEnterobacteriaceaestrains 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.).
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA rodrigo-mendes@jmilabs.com.
authors.forename: Rodrigo E
authors.initials: RE
authors.lastname: Mendes
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Leah N
authors.initials: LN
authors.lastname: Woosley
authors.affiliation: AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Stone
authors.affiliation: AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Patricia A
authors.identifier: 0000-0002-1285-2978
authors.initials: PA
authors.lastname: Bradford
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Flamm
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D053961:Azabicyclo Compounds; D002442:Ceftazidime; D004338:Drug Combinations; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D006088:Gram-Negative Aerobic Bacteria / Q000187:drug effects* / Q000472:pathogenicity*; D006801:Humans; D059413:Intraabdominal Infections / Q000188:drug therapy* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000472:pathogenicity; D008826:Microbial Sensitivity Tests; D001618:beta-Lactamases / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D002442:Ceftazidime; D001618:beta-Lactamases
keywords: CTX-M-15; ESBL; carbapenemase; clinical efficacy