Characterization of β-Lactamase Content of Ceftazidime-Resistant Pathogens Recovered during the Pathogen-Directed Phase 3 REPRISE Trial for Ceftazidime-Avibactam: Correlation of Efficacy against β-Lactamase Producers

• Published in: Antimicrobial agents and chemotherapy 2019-06, Vol.63 (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: Adolescent; Adult; Aged; Aged, 80 and over; beta-Lactamases; beta-Lactamases - metabolism; Ceftazidime; Ceftazidime - pharmacology; Enterobacteriaceae; Enterobacteriaceae - drug effects; Enterobacteriaceae - metabolism; Escherichia coli - drug effects; Escherichia coli - metabolism; Female; Humans; Male; Mechanisms of Resistance; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - metabolism; Young Adult
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02655-18

REPRISE was a pathogen-directed (ceftazidime-resistant) phase 3 prospective, open-label, randomized, multicenter trial that evaluated the efficacy, safety, and tolerability of ceftazidime-avibactam (CAZ-AVI) and best available therapy (BAT) in the treatment of hospitalized adults with complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). This study characterized the β-lactamase content of ceftazidime-resistant and recovered during the baseline visits of patients enrolled in REPRISE. Ceftazidime had MIC results of >64 μg/ml against baseline and variants were the most common β-lactamases found in (detected in 94.3% of all isolates) and (91.2%), whereas often carried plasmid AmpC (pAmpC) (66.7%). (6 isolates), (3), (3), and (2) were detected in 4.9% (14/284) of Overall, clinical cure rates against the were 91.2% and 90.8% for the CAZ-AVI and BAT groups, respectively, or 92.5% and 92.9% in the subset of patients infected with isolates harboring Patients with baseline isolates carrying AmpC genes (pAmpC and/or overexpression of intrinsic AmpC) showed clinical cure rates of 80.0% and 89.5% for CAZ-AVI and BAT arms, respectively. Favorable microbiological responses were generally lower than clinical cure rates in both arms, but CAZ-AVI (80.0 to 85.0%) showed microbiological response rates consistently higher than those for BAT (57.9 to 64.3%) among patients with non-carbapenemase-producing Lower microbiological response rates (50.0%) were found in patients with carbapenemase producers from both arms. This study expands on efficacy data analysis of CAZ-AVI among patients infected with ceftazidime-resistant pathogens, especially -carrying isolates, and although clinical cure rates for CAZ-AVI and BAT were similar, eradication rates for CAZ-AVI were higher than those for BAT. (This study has been registered at ClinicalTrials.gov under identifier NCT01644643.).