In vivo pharmacodynamics of new-generation β-lactamase inhibitor taniborbactam (formerly VNRX-5133) in combination with cefepime against serine-β-lactamase-producing Gram-negative bacteria

Abstract

Objectives: Cefepime/taniborbactam is a cephalosporin/cyclic boronate β-lactamase inhibitor combination under development for the treatment of infections due to MDR Enterobacterales and Pseudomonas aeruginosa. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic index, relative to taniborbactam exposure, that correlated most closely with the efficacy of the cefepime/taniborbactam combination and the magnitude of index required for efficacy against serine-β-lactamase-producing strains. Methods: Twenty-six clinical Enterobacterales (expressing ESBLs, plasmid-mediated AmpC and/or carbapenemases of classes A or D; cefepime/taniborbactam combination MICs 0.06-16 mg/L) and 11 clinical P. aeruginosa (AmpC overproducing or KPC expressing; cefepime/taniborbactam combination MICs 1-16 mg/L) were evaluated. A cefepime human-simulated regimen (HSR) equivalent to a clinical dose of 2 g q8h as a 2 h infusion was given in combination with taniborbactam for 24 h. For a subset of P. aeruginosa isolates, a sub-therapeutic cefepime exposure was utilized. Results: Dose-fractionation studies revealed that dosing frequency had no impact on taniborbactam potentiation of cefepime activity. Relative to the initial bacterial burden, the median taniborbactam fAUC0-24/MIC associated with 1 log kill in combination with the cefepime HSR for Enterobacterales and P. aeruginosa isolates was 2.62 and 0.46, respectively. In combination with sub-therapeutic cefepime, the median taniborbactam fAUC0-24/MIC associated with 1 and 2 log kill against AmpC-overproducing P. aeruginosa was 2.00 and 3.30, respectively, relative to the bacterial burden in the cefepime-treated groups. The taniborbactam HSR (equivalent to 0.5 g q8h as a 2 h infusion) was adequate to attain ≥1 log reduction against all test isolates. Conclusions: Our data show that the cefepime/taniborbactam combination (2 g/0.5 g q8h as a 2 h infusion) exerts potent in vivo activity against cefepime-resistant isolates, including serine-carbapenemase producers.