Characterization of Enterobacter cloacae and Citrobacter freundii species complex isolates with decreased susceptibility to cephalosporins from United States hospitals and activity of ceftazidime/avibactam and comparator agents

Objectives To evaluate the antimicrobial susceptibility and resistance mechanisms to β-lactams among Enterobacter cloacae and Citrobacter freundii from United States medical centres. Methods 2571 E. cloacae and 1008 C. freundii species complex isolates were consecutively collected from 77 medical centres and susceptibility tested by broth microdilution method. Isolates displaying MIC values ≥16 mg/L for ceftazidime or ≥2 mg/L for cefepime (n = 914) were tested for β-lactamase-encoding genes using whole genome sequencing. Results Overall susceptibility to ceftazidime and cefepime were 73.9% and 91.2% among E. cloacae and 74.2% and 93.5% among C. freundii, respectively. Sixty-three isolates harboured a carbapenemase gene, including 56 blaKPC, 2 blaNMC-A, and 5 metallo-β-lactamase genes. Among non-carbapenemase producers, 121 isolates had at least one ESBL-encoding gene, mainly blaSHV (81) or blaCTX-M (61), and 15 had a transferable AmpC gene, mainly blaDHA-1 (8) or blaFOX-5 (6). Carbapenemase, ESBL, or transferable AmpC-encoding genes were not identified among 718 of 914 (78.6%) isolates sequenced. The most active agents against isolates with a decreased susceptibility to ceftazidime and/or cefepime were ceftazidime/avibactam (MIC50/90, 0.5/1 mg/L; 99.3% susceptible), amikacin (MIC50/90, 1/4 mg/L; 99.5% susceptible), and meropenem (MIC50/90, 0.06/0.5 mg/L; 92.9% susceptible). The isolates resistant to ceftazidime/avibactam were the five MBL producers and one E. cloacae isolate with a reduced expression of OmpF and overexpression of AcrAB-TolC. Conclusions Hyperproduction of chromosomal AmpC appears to be the most common mechanism of resistance to ceftazidime and/or cefepime in E. cloacae and C. freundii. Ceftazidime/avibactam remained highly active against most isolates showing decreased susceptibility to ceftazidime and/or cefepime.