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

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 32mg liter21) 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)/MIC 90 of cefepime was 32 (0.125 to 256)/256mg liter -1 for all Enterobacterales isolates (n = 101), with 72% being resistant, and 32 (8 to 256)/128mg 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 ≤1mg liter -1 ) was 0.06 (≤0.03 to 32)/4mg liter -1 and P. aeruginosa susceptibility to increased exposure to cefepime (MIC ≤8mg liter -1 ) 1 (≤0.032 to 32)/32mg liter -1 . At a fixed concentration of 4mg liter21 of taniborbactam, cefepime median (range)/MIC 90 were reduced to 0.125 (0.06 to 4)/1mg liter -1 for Enterobacterales with no resistant isolates found, and to 8 (2 to 64)/16mg 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. ...