Characterization of Enterobacter and Citrobacter spp. Isolates from United States Hospitals by Whole-Genome Sequencing Analysis and Activity of Ceftazidime-Avibactam and Comparator Agents

Background Enterobacter spp. and Citrobacter spp. are common pathogens in a variety of clinical infections. These organisms can overexpress the chromosomal AmpC that encodes resistance to several β-lactams. Additionally, these isolates may carry acquired BL genes. We evaluated the presence of BL and the activity of ceftazidime-avibactam (CAZ-AVI) among 410 isolates collected in US hospitals during 2016. Methods In total, 258 E. cloacae (ECL), 81 E. aerogenes, 70 C. freundii, and 1 C. koseri displaying MIC values ≥16 µg/ml for CAZ and/or ≥2 µg/ml for cefepime were submitted to WGS, de novo assembly and screening for BL genes using an in-house-developed pipeline. Results The most common acquired BL gene was blaCTX-M (25 isolates, 20 ECL) and included blaCTX-M-15 (19 isolates) and six other variants. ESBL blaSHV (six variants) was noted among 39 isolates and blaSHV-12 (23 positive results) was the most frequent variant. Other ESBL genes (blaOXA-1/30 [20 isolates] and blaTEM-10 [3]) were also noted. Transferrable AmpCs were detected among 8 isolates (5 blaDHA-1, 2 blaFOX-5, and 1 blaCMY-2 in ECL). Carbapenemase-encoding genes detected (19 isolates) included five blaKPC-2, 11 blaKPC-3, and one each of blaKPC-4, blaKPC-6, and blaNDM-1. Isolates carrying these genes were five C. freundii, one E. aerogenes, and 13 ECL. The blaKPC-6-carrying ECL exhibited meropenem, doripenem, and imipenem MIC values of 0.06, 0.12, and 0.5 µg/ml, respectively. The majority of the E. aerogenes isolates did not carry acquired BL and the only C. koseri carried blaSHV-7. CAZ-AVI was active against 99.5% (408/410) of the isolates, and two isolates were resistant to CAZ-AVI: one ECL carrying blaNDM-1 (MIC, >32 µg/ml) and one isolate carrying blaKPC-4 and porin alterations (MIC, 16 µg/ml). Susceptibility (S) rates were 1.0, 1.2, and 72.9% for ceftriaxone, ceftazidime, and cefepime, respectively, and 22.0% for piperacillin-tazobactam. Carbapenems were 92.9–93.7% active against these isolates. Conclusion Acquired BL were more frequent among ECL and were mostly blaCTX-M or blaSHV. Carbapenemases were also detected. Cephalosporin resistance is likely due to overexpression of AmpC among E. aerogenes. CAZ-AVI was very active against these isolates, including most (17/19) carbapenemase producers. Disclosures M. Castanheira, Allergan: Research Contractor, Research grant. R. E. Mendes, Allergan: Research Contractor, Research grant. T. P. Doyle, Allergan: Research Contractor, Research grant. A. P. Davis, Allergan: Research Contractor, Research grant. H. S. Sader, Allergan: Research Contractor, Research grant