title: 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.
abstract: The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized β-lactam resistance mechanisms from 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 nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥ 16 μg/ml were characterized for their narrow- and extended-spectrum β-lactamase (ESBL) content. Enterobacteriaceae (one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥ 2 and ≥ 16 μg/ml, respectively, were tested for carbapenemases. All cUTI E. coli had the lineage background investigated (ST131-like versus 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 isolate 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 isolate was recovered at the baseline visit. When an ESBL Enterobacteriaceae isolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-like E. coli isolate was recovered at baseline, as when a non-ST131-like isolate 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.
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: AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Leanne
authors.initials: L
authors.lastname: Gasink
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: Wright W
authors.initials: WW
authors.lastname: Nichols
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Flamm
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D002442:Ceftazidime / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D004338:Drug Combinations; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D055815:Young Adult; D001618:beta-Lactamases / Q000235:genetics*
chemical_list: D053961:Azabicyclo Compounds; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D002442:Ceftazidime; D001618:beta-Lactamases