Tackling the unyielding: testing two novel approaches against NDM-producing Enterobacterales and <i>Pseudomonas aeruginosa</i> isolates collected in India

Metallo-β-lactamases are therapeutically challenging due to the limited treatment options. Against such isolates, currently approved newer β-lactam/β-lactamase inhibitor combinations are ineffective. In this study, we tested siderophore cephalosporin, cefiderocol, which utilizes an unconventional iron uptake pathway for efficient cellular penetration, and cefepime/zidebactam that utilizes novel β-lactam enhancer mechanisms for overcoming diverse carbapenemases. Cefiderocol showed limited activity against <i>Escherichia coli</i> isolates co-harboring New Delhi metallo-β-lactamase (NDM) with PBP3 insert, dual carbapenemase (NDM with OXA-48 like)-producing <i>Klebsiella pneumoniae</i>, and NDM-producing <i>Pseudomonas aeruginosa</i> isolates, while cefepime/zidebactam potently inhibited NDM-producing Enterobacterales and <i>P. aeruginosa</i> isolates. NDM being a dominant carbapenemase among Enterobacterales and <i>P. aeruginosa</i> in India, the variable activity of cefiderocol against NDM producers is a concern. Post approval, cefepime/zidebactam could offer a promising treatment option against NDM producers.