In vitro activity of the novel β-lactamase inhibitor taniborbactam (VNRX-5133), in combination with cefepime or meropenem, against MDR Gram-negative bacterial isolates from China

Objectives: To evaluate in vitro activity of the novel beta-lactamase boronate inhibitor taniborbactam (VNRX-5133) combined with cefepime or meropenem against 500 urinary Gram-negative bacilli. Methods: Cefepime/taniborbactam and 14 comparators were tested by broth microdilution or agar dilution methods. A total of 450 Enterobacteriaceae and 50 Pseudomonas aeruginosa were selected from 2017 to 2019 based on different beta-lactamase-producing or resistance phenotypes. For carbapenem-non-susceptible isolates, the modified carbapenem inactivation method (mCIM), EDTA-CIM (eCIM) and amplification of carbapenemase genes were performed. For NDM-producing isolates and those with cefepime/taniborbactam MICs >8mg/L, the MICs of meropenem/taniborbactam and/or mutations in PBP3 were investigated. Results: Taniborbactam improved cefepime activity with the same efficiency as avibactam improved ceftazidime activity against 66 KPC-2 producers, 30 non-carbapenemase-producing carbapenem-non-susceptible Enterobacteriaceae and 28 meropenem-susceptible P. aeruginosa. However, cefepime/taniborbactam exhibited more potent activity than ceftazidime/avibactam against 56 ESBL-producing, 61 AmpC-producing, 32 ESBL and AmpC co-producing, 87 NDM-producing and 21 MBL-producing Enterobacteriaceae predicted by phenotypic mCIM and eCIM, 82 Enterobacteriaceae that were susceptible to all tested beta-lactams and 22 carbapenem-non-susceptible P. aeruginosa. A four-amino acid 'INYR' or 'YRIN' insertion, with or without a one/two-amino acid mutation in PBP3, may have caused cefepime/taniborbactam MICs >8mg/L among 96.6% (28/29) of the NDM-5-producing Escherichia coli, which accounted for the majority of isolates with cefepime/taniborbactam MICs >8mg/L (76.1%, 35/46). Conclusions: Taniborbactam's superior breadth of activity, when paired with cefepime or meropenem, suggests these beta-lactam/beta-lactamase inhibitor combinations could be promising candidates for treating urinary tract infections caused by ESBL and/or AmpC, KPC or NDM-producing Enterobacteriaceae or P. aeruginosa.