Low Frequency of Ceftazidime-Avibactam Resistance among Enterobacteriaceae Isolates Carrying blaKPC Collected in US Hospitals from 2012 to 2015

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456 Enterobacteriaceae isolates carrying bla(KPC) collected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 mu g/ml; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 mu g/ml; 98.9% susceptible at <= 2 mu g/ml) were the most active agents. Only 80.5% and 59.0% of isolates were susceptible to colistin and amikacin, respectively. All three isolates (0.7%) displaying resistance to ceftazidime-avibactam (K. pneumoniae; MICs, >= 16 mu g/ml) were evaluated using whole-genome sequencing analysis and relative quantification of expression levels of porins and efflux pump. Two isolates carried metallo-beta-lactamase genes, bla(NDM-1) or bla(VIM-4), among other beta-lactam resistance mechanisms, and one displayed a premature stop codon in ompK35 and decreased expression of ompK36. Ceftazidime-avibactam was active against 100.0 and 99.3% of isolates carrying bla(KPC-3) (n = 221) and bla(KPC-2) (n = 145), respectively. Isolates carrying bla(KPC) were more commonly recovered from pneumonia (n = 155), urinary tract (n = 93), and skin/soft tissue (n = 74) infections. Ceftazidime-avibactam (97.8 to 100.0% susceptible) was consistently active against isolates from all infection sites. K. pneumoniae (83.3% of the collection) susceptibility rates were 99.2% for ceftazidime-avibactam, 98.9% for tigecycline, and 80.1% for colistin. Ceftazidimeavibactam susceptibility did not vary substantially when comparing isolates from intensive care unit (ICU) patients to those from non-ICU patients. Ceftazidimeavibactam was active against this large collection of isolates carrying bla(KPC) and represents a valuable addition to the armamentarium currently available for the treatment of infections caused by KPC-producing Enterobacteriaceae.