Molecular (cid:2) -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

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 (cid:2) -lactam resistance mechanisms from the complicated intra-abdominal infection (cIAI) phase 3 clinical trials. Enterobacteriaceae isolates displaying ceftriaxone and/or ceftazidime MIC values of (cid:3) 2 (cid:4) g/ml and Pseudomonas aeruginosa isolates with ceftazidime MIC values of (cid:3) 16 (cid:4) g/ml were characterized for extended-spectrum- (cid:2) -lactamase (ESBL) content. Enterobacteriaceae and P. aeruginosa isolates with imipenem and meropenem MIC values of (cid:3) 2 and (cid:3) 8 (cid:4) g/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, bla CTX-M group 1 variants (79/90; 87.8%), represented the (cid:2) -lactamases most frequently observed among Enterobacteriaceae isolates. 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-producing Enterobacteriaceae strains 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.) Molecular results of selected for molecular characterization of -lactamase Enterobacteriaceae and P. aeruginosa isolates exhibiting imipenem/meropenem MIC results of g/ml, respectively, tested carbapenemase-encoding the potential for prior use of other antibiotics that might confound the assessment of the treatment effect. For patients with moderate renal impairment at baseline (estimated Cockcroft-Gault-calculated creatinine clearance [CrCL] of (cid:2) 30 to (cid:5) 50 ml/min, based on local laboratory serum creatinine levels at screening), adjustments were made to the ceftazidime- avibactam dose (1 g of ceftazidime combined with 0.25 g of avibactam as a 2-h intravenous infusion every 12 h) or to the meropenem dose (1 g as a 30-min infusion every 12 h). No adjustment was made for metronidazole. Cultures were obtained for all patients either from blood samples taken at the baseline visit or (intraoperatively) from the intra-abdominal site of infection. Patients with bacteria not expected to respond to either study drug (e.g., Stenotrophomonas spp. and Acinetobacter spp.) were considered to have ineligible baseline pathogens and were excluded from this analysis. Clinical cure was determined by the local investigators at the TOC visit, which occurred 28 to 35 days after randomization. Clinical cure was deﬁned as resolution or as improvement in signs and symptoms of cIAI such that no further treatment was required. Other deﬁned primary endpoints were failure or indeterminate status (see Mazuski et al. for additional information) (16). Susceptibility testing, selection criteria, and screening of (cid:2) -lactamases. All baseline clinical isolates were centrally tested for susceptibility by broth microdilution (Clinical and Laboratory Standards Institute [CLSI]; M07-A10; 2015) (24). Enterobacteriaceae isolates displaying ceftriaxone and/or ceftazidime MIC results of (cid:3) 2 (cid:4) g/ml (25) and P. aeruginosa isolates with ceftazidime MIC results of (cid:3) 16 (cid:4) g/ml were selected for further characterization of (cid:2) -lactamase content, including ESBL genes. Enterobacteriaceae and P. aeruginosa isolates exhibiting imipenem/meropenem MIC results of (cid:3) 2 and (cid:3) 8 (cid:4) g/ml, respectively, were also tested for the presence of carbapenemase-encoding genes, as previously described (17). Isolates that met the MIC screening criteria described above were subjected to testing with a microarray-based assay Check-MDR CT101 kit according to the manufacturer’s instructions (Check-Points, Wageningen, Netherlands). This kit has the capability to detect CTX-M groups 1, 2, 8 (cid:3) 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 (17). Supplemental multiplex PCR assays were utilized to detect additional ESBL-encoding genes ( bla GES , bla VEB , bla PER , and oxacillinase enzyme-encoding genes [the bla OXA-2 , bla OXA-10 , and bla OXA-13 groups, bla OXA-18 , and bla OXA-45 ]) and carbapenemase-encoding genes ( bla IMP , bla VIM , bla NDM-1 , bla OXA-48 , bla GES , bla NMC-A , bla