β-Lactamase characterization of Gram-negative pathogens recovered from patients enrolled in the phase 2 trials for ceftazidime-avibactam: clinical efficacies analyzed against subsets of molecularly characterized isolates.
Antimicrob Agents Chemother. 2015 Dec 14;
Authors: Mendes RE, Castanheira M, Gasink L, Stone GG, Nichols WW, Flamm RK, Jones RN
Abstract
The correlation of clinical efficacy of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized β-lactam resistance mechanisms from the complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials. Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MICs of ≥2 μg/ml (69 isolates) and non-fermentative-Gram-negative bacilli (NF-GNB; three isolates) with ceftazidime MICs of ≥16 μg/ml were characterized for their narrow and extended-spectrum β-lactamases (ESBL) content. Enterobacteriaceae (one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs ≥2 and ≥16 μg/ml, respectively, were tested for carbapenemases. All cUTI E. coli had the lineage background investigated (ST131-like vs non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test-of-cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen-positive). All screen-positive cUTI pathogens were CTX-M-producing E. coli, except for one E. cloacae with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other β-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBL Enterobacteriaceae was recovered at the baseline visit. When an ESBL Enterobacteriaceae was present the favorable response was 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Equally favorable responses were observed with ceftazidime-avibactam (75.0%) and carbapenems (76.7%) when an ST131-like E. coli was recovered at baseline, whereas higher percentages were noted when a non-ST131-like was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.
PMID: 26666936 [PubMed - as supplied by publisher]