Identifying spectra of activity and therapeutic niches for ceftazidime-avibactam and imipenem-relebactam against carbapenem-resistant Enterobacteriaceae [PublishAheadOfPrint]

We determined imipenem, imipenem-relebactam, ceftazidime and ceftazidime-avibactam minimum inhibitory concentrations (MICs) against 100 CRE isolates that underwent whole genome sequencing. KPCs were the most common carbapenemases. Forty-six isolates carried ESBLs. With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against MBL-producers. Ceftazidime-avibactam (but not imipenem-relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (p<0.0001), and showed a trend to independent association with higher ceftazidime-avibactam MICs (p=0.07). Presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (p<0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity, and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance.

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