Assessment of human exposures of cefepime-taniborbactam against cefepime-resistant Enterobacterales and Pseudomonas aeruginosa in a 7-day hollow fiber infection model.

Abstract

Taniborbactam is a novel cyclic boronate β-lactamase inhibitor that potentiates the in vitro activity of cefepime against Enterobacterales and Pseudomonas aeruginosa strains harboring serine and metallo-β-lactamases. Taniborbactam lacks intrinsic antibacterial activity. An in vitro hollow fiber infection model (HFIM) was used to evaluate bacterial kill and the potential for treatment-emergent resistance associated with the clinical cefepime-taniborbactam dose of 2-0.5 g every 8 h, administered as a 2 h infusion, for 7 days. Nine cefepime-resistant bacterial strains were studied among one Escherichia coli, five Klebsiella pneumoniae, and three P. aeruginosa that harbored a variety of cephalosporinases, extended-spectrum β-lactamases, and carbapenemases with cefepime-taniborbactam MIC values that ranged from 0.25 to 8 µg/mL. All nine strains grew rapidly when treated with cefepime alone, consistent with phenotypic resistance. Human plasma concentration-time profiles for cefepime and taniborbactam were simulated in the HFIM systems and resulted in bactericidal activity (≥3 log₁₀ CFU/mL reduction) against eight of nine strains when assessed 8 h after initiation of the first dose, and against all nine strains by day 7. Treatment-emergent resistance, defined as bacterial subpopulations with ≥4 times the baseline MIC, was not detected in any cefepime-taniborbactam model from days 1 to 7. Therefore, human cefepime-taniborbactam exposures demonstrated sustained bactericidal activity and suppressed the emergence of resistance in a 7-day HFIM among serine and metallo-β-lactamase-positive Enterobacterales and P. aeruginosa strains. These observations support the clinical development of cefepime-taniborbactam and inform understanding of its potential role in treating serine and/or metallo-β-lactamase-positive Gram-negative bacterial infections.