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.
Highlights
The correlation of the clinical efficacies of ceftazidime-avibactam and comparators was evaluated against baseline Gram-negative isolates having characterized -lactam resistance mechanisms from complicated urinary tract infection and complicated intra-abdominal infection phase 2 trials
The majority of carbapenem-resistant Enterobacteriaceae (CRE) isolates in the United States harbor a Klebsiella pneumoniae carbapenemase (KPC) serine carbapenemase-encoding gene (6). blaKPC genes are mostly detected in Klebsiella pneumoniae, but they have been observed in numerous Enterobacteriaceae species and have become endemic in several hospitals worldwide (7)
A total of 192 microbiologically evaluable (ME) patients were included in the study, with 26 and 20 ME patients included in the ceftazidimeavibactam and carbapenem arms, respectively, for the complicated urinary tract infection (cUTI) trial, while 60 and 70 patients, respectively, were included in the arms for the complicated intra-abdominal infection (cIAI) trial (11, 12)
Summary
Clinical isolates, study treatment, and endpoints. Male and female patients between the ages of 18 and 90 years were enrolled in the phase 2 clinical trials for ceftazidime-avibactam (clinicaltrials.gov identifiers NCT00752219 and NCT00690378) (11, 12). The ME population was defined as clinically evaluable patients with a confirmed cUTI or cIAI, at least one baseline pathogen susceptible to the study therapy agents, who received treatment, and who had a clinical assessment at the TOC visit (see references 11 and 12 for additional information). Isolates that met the MIC screening criteria described above were subjected to a microarray-based assay, the Check-MDR CT101 kit, according to the manufacturer’s instructions (Check-Points, Wageningen, Netherlands) This kit has the capabilities to detect CTX-M groups 1, 2, 8 ϩ 25, and 9, non-ESBL and ESBL variants of TEM and SHV, plasmid AmpC (ACC, ACT/MIR, CMY, DHA, and FOX), and KPC- and NDM-encoding genes (14). All E. coli strains recovered during the cUTI trial were investigated by pulsed-field gel electrophoresis (PFGE) for the presence of two single nucleotide polymorphisms (SNPs), namely, thymine 144 and adenine 450 in the pabB gene, as previously described by Dhanji et al (20). The presence of these two SNPs is known to be unique to sequence type 131 (ST131) strains, and they were described here as “ST131-like.”
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