Abstract
Objective
Funobactam (FNB), a novel β-lactamase inhibitor, has shown potential capability to restore the activity of β-lactam antibiotics. However, the antibacterial activity of imipenem-funobactam (IPM-FNB) combined with other antibiotics remains insufficiently studied against carbapenem-resistant gram-negative bacteria (CR-GNB).Methods
A total of 199 clinical CR-GNB isolates, including carbapenem-resistant Escherichia coli (CREC, 32 isolates), carbapenem-resistant Klebsiella pneumoniae (CRKP, 47 isolates), carbapenem-resistant Acinetobacter baumannii (CRAB, 58 isolates), and carbapenem-resistant Pseudomonas aeruginosa (CRPA, 62 isolates), were collected across China from 26 medical centers. Antimicrobial susceptibility of IPM-FNB combined with aztreonam, ceftazidime, sulbactam, amikacin, ciprofloxacin, polymyxin B, or tigecycline was determined by broth microdilution with checkerboard assays, and the fractional inhibitory concentration index (FIC) was calculated. Time-kill assays were performed for partial isolates selected according to the FIC.Results
Against CREC and CRKP, IPM-FNB combined with aztreonam mainly exhibited synergistic effects (75.0% and 70.0%, respectively), with bactericidal activity in representative isolates against New Delhi metallo-β-lactamase (NDM)- and Klebsiella pneumoniae carbapenemase (KPC)-2-producing isolates. Against CRAB, IPM-FNB combined with sulbactam demonstrated the highest synergistic effect (68.8%) and showed rapid, sustained bactericidal activity in time-kill assays. Against CRPA, most combinations showed additive effects, although IPM-FNB plus aztreonam achieved synergistic bactericidal activity in the tested isolate.Conclusions
IPM-FNB combined with sulbactam shows promising activity in vitro against CRAB that may warrant further investigation. In addition, IPM-FNB combined with aztreonam demonstrates promising in vitro synergistic activity against CREC and CRKP, including both KPC-2- and NDM-producing isolates. Additive activity was most common in IPM-FNB combinations against CRPA.