Cefepime-taniborbactam: Ushering in the era of metallo-β-lactamase inhibition.

Abstract

Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CR-PA) continue to pose a significant threat to human health. Furthermore, the prevalence of metallo-β-lactamase (MBL)-producing CRE and CR-PA is increasing, which are capable of hydrolyzing nearly all β-lactam antibiotics. Cefepime-taniborbactam (FTB) is a novel bicyclic boronate β-lactam-β-lactamase inhibitor combination with direct inhibitory activity against MBLs (Ambler Class B), in addition to Ambler Class A, C, and D serine-β-lactamases. FTB has demonstrated high in vitro activity against CRE and CR-PA, including isolates producing NDM, VIM, KPC, AmpC, OXA-48, and extended-spectrum β-lactamases (ESBLs). Furthermore, FTB has demonstrated in vitro activity against Stenotrophomonas maltophilia and Burkholderia cepacia complex. Resistance to FTB is observed in isolates producing IMP, as well as MBL variants NDM-9, NDM-30, and VIM-83. FTB remains susceptible to non-β-lactamase resistance mechanisms, including penicillin-binding protein 3 (PBP3) target mutations. The pharmacodynamic driver of taniborbactam efficacy is the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC), and the study dose of FTB 2 g/0.5 g every 8 h infused over 2 h achieves sufficient serum and tissue exposures to maintain therapeutic efficacy. Both components are primarily renally eliminated as unchanged drug; therefore, dose adjustments for renal impairment are required. The clinical efficacy of FTB was demonstrated in the phase III Cefepime Rescue with Taniborbactam in Complicated Urinary Tract Infection (CERTAIN-1) trial, where it demonstrated both non-inferiority and superiority (prespecified analysis) to meropenem in the composite of clinical and microbiologic success at the test of cure for the treatment of complicated urinary tract infection. The safety of FTB was demonstrated throughout its clinical development. Thirteen percent of patients experienced a treatment-related adverse drug event in the phase III clinical trial, with 3% of patients requiring discontinuation of the study agent. Cefepime-taniborbactam appears to be a promising addition to the antibiotic arsenal, particularly as the prevalence of infections caused by MBL-producing organisms continues to rise.