In vitro activity of aztreonam–nacubactam and cefepime–nacubactam against a global collection of clinically important Gram-negative Bacilli collected in 2021–2023

Objectives We assessed the in vitro activity of aztreonam–nacubactam and cefepime–nacubactam against a 2021–2023 global collection of clinical isolates of Gram-negative bacilli (12 613 Enterobacterales, 3748 Pseudomonas aeruginosa and 601 Acinetobacter baumannii). Nacubactam is a novel diazabicyclooctane β-lactamase inhibitor that also possesses intrinsic antimicrobial (PBP2 inhibition) and β-lactam enhancer (for β-lactams that bind PBP3 and other non-PBP2 PBPs) activities against Enterobacterales. Aztreonam–nacubactam and cefepime–nacubactam are in clinical development for the treatment of complicated urinary tract infections, acute uncomplicated pyelonephritis and various infections caused by carbapenem-resistant Enterobacterales (CRE). Methods MICs were determined for aztreonam–nacubactam (1:1 ratio), cefepime–nacubactam (1:1 ratio) and 13 comparators using the CLSI broth microdilution method. Results For all Enterobacterales isolates, the MIC90s of aztreonam–nacubactam and cefepime–nacubactam were 1 and 0.5 mg/L, respectively; 99.8% of all Enterobacterales isolates and 99.8% of CRE isolates (n = 917) were inhibited by aztreonam–nacubactam at 4 mg/L and by cefepime–nacubactam at 8 mg/L. Both aztreonam-resistant and cefepime-resistant isolate MICs demonstrated a modal decrease of 64-fold by the addition of nacubactam at a 1:1 ratio. Aztreonam–nacubactam and cefepime–nacubactam were active against the majority of Enterobacterales isolates that were resistant to aztreonam–avibactam, ceftazidime–avibactam, imipenem–relebactam, meropenem–vaborbactam and cefiderocol. The MIC90s for aztreonam–nacubactam and cefepime–nacubactam were 16 and 8 mg/L for P. aeruginosa and >64 and 64 mg/L for A. baumannii. Discussion The results of this study support the continued development of aztreonam–nacubactam and cefepime–nacubactam as potential therapies for infections caused by CRE where resistance or potential toxicity to marketed antimicrobial agents excludes their use.