Background: VNRX-5133 is a novel cyclic boronate-based broad-spectrum β-lactamase inhibitor with potent and selective direct inhibitory activity against both serine- and metallo-β-lactamases (Ambler Classes A, B, C and D). In this analysis, we evaluated the activity of cefepime (FEP) in combination with VNRX-5133 and comparators against 1,120 recent Enterobacteriaceae clinical isolates, including carbapenem-resistant strains.
Methods: MICs of FEP with VNRX-5133 fixed at 4 µg/mL (FEP/VNRX-5133) were determined following CLSI M07-A10 guidelines against 1,120 Enterobacteriaceae from community and hospital infections collected globally in 2012-2013. Resistant phenotypes were based on 2017 CLSI breakpoints. As FEP/VNRX-5133 breakpoints have not yet been established, the FEP 2 g q8h susceptible dose dependent (SDD) breakpoint of ≤8 µg/mL was considered for comparative purposes.
Results: FEP/VNRX-5133 showed potent in vitro activity against drug resistant subsets of Enterobacteriaceae, with MIC90 values ranging from 1 µg/mL against ceftazidime-, levofloxacin-, or piperacillin-tazobactam-nonsusceptible isolates, to 8 µg/mL against meropenem-nonsusceptible isolates. FEP/VNRX-5133 inhibited >93% of all resistant subsets at ≤8 µg/mL.
Conclusion: Cefepime in combination with VNRX-5133 demonstrated potent in vitro activity against Enterobacteriaceae, including cephalosporin-, fluoroquinolone- and carbapenem-resistant (CRE) isolates. Because this drug combination exhibited substantial potential for the treatment of infections caused by isolates often resistant to first line therapy, further development is warranted.