Cefepime-taniborbactam demonstrates potent in vitro activity vs Enterobacterales with blaOXA-48

Abstract

ABSTRACT Taniborbactam (formerly VNRX-5133) is a novel, investigational boronic acid β-lactamase inhibitor. The combination of cefepime (FEP) with taniborbactam is active against Enterobacterales carrying class A, B, C, and/or D enzymes. We assessed the activity of FEP-taniborbactam against Enterobacterales clinical strains carrying blaOXA-48 (N = 50, 100%), of which 78% harbored at least one extended-spectrum β-lactamase (ESBL). CLSI-based agar dilution susceptibility testing was conducted using FEP-taniborbactam and comparators FEP, meropenem-vaborbactam (MVB), and ceftazidime-avibactam (CZA). The addition of taniborbactam lowered FEP MICs to the provisionally susceptible range of ≤16 µg/mL; the MIC90 value decreased from ≥64 µg/mL for FEP to 4 µg/mL for FEP-taniborbactam. Notably, FEP-taniborbactam MIC50/MIC90 values (0.5/4 µg/mL) were lower than those for MVB (1/16 µg/mL) and comparable to those for CZA (0.5/1 µg/mL). Time-kill assays with E. coli clinical strains DOV (blaOXA-48, blaCTX-M-15, blaTEM-1, and blaOXA-1) and MLI (blaOXA-48, blaVEB, blaTEM-1, and blaCMY-2) revealed that FEP-taniborbactam at concentrations 1×, 2×, and 4× MIC displayed time-dependent reductions in the number of CFU/mL from 0 to 6 h, and at 4× MIC demonstrated bactericidal activity (3 log10 reduction in CFU/mL at 24 h). Therefore, taniborbactam in combination with FEP was highly active against this diverse panel of Enterobacterales with blaOXA-48 and represents a potential addition to our antibiotic arsenal.IMPORTANCEOXA-48-like β-lactamases are class D carbapenemases widespread in Klebsiella pneumoniae and other Enterobacterales and are associated with carbapenem treatment failures. As up to 80% of OXA-48-like positive isolates coproduce extended-spectrum β-lactamases, a combination of β-lactams with broad-spectrum β-lactamase inhibitors is required to counteract all OXA-48-producing strains effectively. Herein, we evaluated the activity of cefepime-taniborbactam against 50 clinical strains producing OXA-48. We report that adding taniborbactam shifted the minimum inhibitory concentration (MIC) toward cefepime’s susceptible range, restoring its antimicrobial activity. Notably, cefepime-taniborbactam MIC50/MIC90 values (0.5/4 µg/mL) were comparable to ceftazidime-avibactam (0.5/1 µg/mL). Finally, time-kill assays revealed sustained bactericidal activity of cefepime-taniborbactam for up to 24 h. In conclusion, cefepime-taniborbactam will be a welcome addition to the antibiotic arsenal to combat Enterobacterales producing OXA-48.

Keywords

• β-lactamases
• Enterobacterales
• β-lactam
• OXA-48
• carbapenemase
• β-lactamase inhibitor