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 bla(CTX-M) (25 isolates, 20 ECL) and included bla(CTX-M-15) (19 isolates) and six other variants. ESBL bla(SHV) (six variants) was noted among 39 isolates and bla(SHV-12) (23 positive results) was the most frequent variant. Other ESBL genes (bla(OXA-1/30) [20 isolates] and bla(TEM-10) [3]) were also noted. Transferrable AmpCs were detected among 8 isolates (5 bla(DHA-1), 2 bla(FOX-5), and 1 bla(CMY-2) in ECL). Carbapenemase-encoding genes detected (19 isolates) included five bla(KPC-2), 11 bla(KPC-3), and one each of bla(KPC-4), bla(KPC-6), and bla(NDM-1). Isolates carrying these genes were five C. freundii, one E. aerogenes, and 13 ECL. The bla(KPC-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 bla(SHV-7). CAZ-AVI was active against 99.5% (408/410) of the isolates, and two isolates were resistant to CAZ-AVI: one ECL carrying bla(NDM)-1 (MIC, >32 µg/ml) and one isolate carrying bla(KPC-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 bla(CTX-M) or bla(SHV). 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