Activity of Cefepime in Combination with the novel ß-Lactamase inhibitor taniborbactam (VNRX-5133) against ESBL-producing isolates in in vitro checkerboard assays
Background. Extended spectrum beta-lactamase (ESBL) producing strains are increasing worldwide limiting therapeutic options. Taniborbactam (VNRX-5133) is a newly developed beta-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. Methods. The in vitro activity of cefepime (0.06-256 mg/l) combined with taniborbactam (0.03-32 mg/l) 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, 2 Enterobacter aerogenes) was tested with a broth microdilution checkerboard method based on ISO standard. The MICs of cefepime alone and in combination together with % of resistance at different concentrations of taniborbactam was calculated for each species and resistance mechanism. Results. The median (range)/MIC90 of cefepime were 32(0.125-256)/256 mg/l for all Enterobacterales isolates (n=101) with 72% being resistant and 32(8-256)/128 mg/l 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/l) was 0.06(≤0.03-32)/4 mg/l and P. aeruginosa susceptibility to increased exposure to cefepime (MIC ≤8 mg/l) 1(≤0.032-32)/32 mg/l. At a fixed concentration of 4 mg/liter of taniborbactam, cefepime median(range)/MIC90 were reduced to 0.125(0.06-4)/1 mg/l for Enterobacterales with no resistance detected and to 8(2-64)/16 mg/liter for P. aeruginosa isolates where 36% remained resistant. Conclusion. The combination cefepime/taniborbactam demonstrated a potent activity against ESBL isolates restoring susceptibility of all Enterobacterales and 2/3 of P. aeruginosa isolates.