Activity of Cefepime in Combination with the Novel β-Lactamase Inhibitor Taniborbactam (VNRX-5133) against Extended-Spectrum-β-Lactamase-Producing Isolates in In Vitro Checkerboard Assays

Abstract

Extended-spectrum-β-lactamase (ESBL)-producing strains are increasing worldwide, limiting therapeutic options. Taniborbactam (VNRX-5133) is a newly developed β-lactamase inhibitor with a wide spectrum of activity covering both serine and metallo enzymes. We therefore evaluated cefepime-taniborbactam activity against ESBL-producing isolates and determined the concentrations to be used in MIC determinations in the clinical laboratory. The in vitro activity of cefepime (0.06 to 256 mg liter^-1) combined with taniborbactam (0.03 to 32 mg liter^-1) against 129 clinically and molecularly well-documented ESBL-producing isolates (42 Escherichia coli, 39 Klebsiella pneumoniae, 28 Pseudomonas aeruginosa, 16 Enterobacter cloacae, 2 Citrobacter freundii, and 2 Enterobacter aerogenes) was tested with a broth microdilution checkerboard method based on the ISO standard. The MICs of cefepime alone and in combination, together with percentage resistance at different concentrations of taniborbactam, were calculated for each species and resistance mechanism. The median (range)/MIC₉₀ of cefepime was 32 (0.125 to 256)/256 mg liter^-1 for all Enterobacterales isolates (n = 101), with 72% being resistant, and 32 (8 to 256)/128 mg liter^-1 for the 28 P. aeruginosa isolates, with 86% being resistant. The median (range)/90th percentile concentration of taniborbactam required to restore Enterobacterales susceptibility to cefepime (MIC ≤1 mg liter^-1) was 0.06 (≤0.03 to 32)/4 mg liter^-1 and P. aeruginosa susceptibility to increased exposure to cefepime (MIC ≤8 mg liter^-1) 1 (≤0.032 to 32)/32 mg liter^-1 At a fixed concentration of 4 mg liter^-1 of taniborbactam, cefepime median (range)/MIC₉₀ were reduced to 0.125 (0.06 to 4)/1 mg liter^-1 for Enterobacterales with no resistant isolates found, and to 8 (2 to 64)/16 mg liter^-1 for P. aeruginosa isolates, where 36% remained resistant. The combination cefepime-taniborbactam demonstrated a potent activity against ESBL isolates, restoring susceptibility of all Enterobacterales and two-thirds of P. aeruginosa isolates.

Keywords: ESBL; Klebsiella pneumoniae; Pseudomonas aeruginosa; cefepime; checkerboard; combination; taniborbactam; β-lactamase inhibitor.

FIG 1

Distribution of the maximum effect of cefepime-taniborbactam combinations over the tested concentration range expressed as a 2-fold dilution in the MIC decrease of cefepime. The maximum MIC-lowering effect of the addition of taniborbactam to cefepime, compared to the MIC of cefepime alone, for percentage of isolates of both Enterobacterales and P. aeruginosa is presented on a 2-log transformation x axis. Bars are segmented by the most common groups of resistance genes.