Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents Tested against Contemporary (2016) Clinical Enterobacteriaceae Isolates

Abstract

Background. Avibactam (AVI) is a non-β-lactam β-lactamase (BL) inhibitor that inhibits Ambler class A, C, and some class D enzymes (eg, ESBL, KPC, and AmpC), and aztreonam (ATM) is a monobactam stable to hydrolysis by metallo-β-lactamases (MBL). Methods. A total of 10,451 Enterobacteriaceae(ENT) consecutively collected from 84 United States (US) medical centers and 250 carbapenem-resistant ENT (CRE) collected from 38 centers in 25 other countries (ex-US) were tested for susceptibility (S) by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories). CRE strains were screened for the presence of carbapenemase (CBP)- encoding genes using whole genome sequencing analysis. Results. All ENT isolates from US (MIC50/90, ≤0.03/0.12 μg/mL), except for 1 Escherichia coli strain with an ATM-AVI MIC of 8 μg/mL, and all ex-US CRE isolates (MIC50/90, 0.25/0.5 μg/mL) were inhibited at ATM-AVI MIC of ≤4 μg/mL (CLSI S breakpoint for ATM). Among US isolates, ATM-AVI was also very active against CRE (n = 120; MIC50/90, 0.12/0.5 μg/mL; highest MIC, 4 μg/mL), multidrug-resistant (MDR; n = 876; MIC50/90, 0.06/0.25 μg/mL), extensively drug-resistant (XDR; n = 111; MIC50/90, 0.12/0.5 μg/mL), pan-drug resistant (n = 2; MICs ≤0.03 and 0.12 μg/mL), and ceftazidime- non-S Enterobacter cloacae (MIC50/90, 0.25/1 μg/mL) isolates. Meropenem was very active against US ENT overall (MIC50/90, 0.03/0.06 μg/mL; 98.8%S per CLSI), but showed limited activity against MDR (86.2%S) and XDR (30.6%S) isolates. Amikacin and colistin were active against 74.2% and 81.7% of US CRE, 93.4% and 58.3% US MDR, 65.8% and 57.7% of US XDR, and 58.0% and 79.2% of ex-US CRE isolates, respectively. A total of 106 CBPs were detected in 106 US CRE isolates, including 102 KPC-like, 2 SME-4, 1 NDM-1, and 1 IMP-27. Also, 248 CBPs were identified on 241 ex-US CRE isolates, including 124 KPC-like, 64 OXA-like, 50 NDM-like, 7 VIM-1, 2 IMP-4, and 1 SME-4. All CRE isolates, including all CBP-producing ENT (US and ex-US), were inhibited at ATM-AVI MIC of ≤4 μg/mL. Conclusion. ATM-AVI demonstrated potent in vitro activity against a large collection of contemporary (2016) ENT isolated from patients in US hospitals and CRE isolates collected worldwide, including NDM, KPC, OXA, VIM, and SME producers.