In Vitro Activity of Imipenem-Funobactam Against Clinical Isolates of Gram-Negative Bacilli

Objectives: The intent of this study was to report reference in vitro antimicrobial susceptibility testing results for funobactam (formerly XNW4107) in combination with imipenem against recent, worldwide clinical isolates of Gram-negative bacilli. Methods: MICs for imipenem in combination with a fixed concentration of funobactam (8 mg/L), and seven comparator agents, were determined using the reference CLSI M07 broth microdilution method for 4003 clinical isolates of Gram-negative bacilli (2008 Enterobacterales, 999 Acinetobacter baumannii, and 996 Pseudomonas aeruginosa) collected from 211 unique clinical laboratory sites in 54 countries as part of industry-sponsored antimicrobial surveillance studies in 2021 and 2022. MICs were interpreted by 2026 CLSI M100 breakpoints. Most isolates with imipenem-funobactam MICs of ≥4 mg/L (95.4%) underwent whole genome sequencing to identify acquired β-lactamase gene carriage. Results: MIC₉₀ values for imipenem-funobactam were 2 mg/L for all 2008 isolates of Enterobacterales, and 1, 0.5, and 0.5 mg/L, respectively, for metallo-β-lactamase (MBL)-negative Enterobacterales (n = 1969), non-Morganellaceae Enterobacterales (NME) (n = 1752), and MBL-negative NME (n = 1718) isolate subsets. MIC₉₀ values for imipenem-funobactam and imipenem alone were identical or within one doubling dilution for all 14 species of Enterobacterales tested except Klebsiella pneumoniae, Citrobacter freundii, and Enterobacter bugandensis which showed differences of 32-fold (imipenem-funobactam MIC₉₀, 0.5 mg/L; imipenem MIC₉₀, 16 mg/L), 8-fold (0.25 mg/L; 2 mg/L), and 4-fold (0.25 mg/L; 1 mg/L), respectively. Both for all A. baumannii isolates (n = 999) and for MBL-negative isolates (n = 962), the imipenem-funobactam MIC₉₀ value (4 mg/L) was 32-fold lower than for imipenem alone (128 mg/L). Both for all P. aeruginosa (n = 996) isolates and MBL-negative isolates (n = 962), we observed a 4-fold difference in potency between imipenem-funobactam (MIC₉₀, 4 mg/L) and imipenem alone (MIC₉₀, 16 mg/L). Isolates carrying MBL demonstrated the highest MICs for imipenem-funobactam. Conclusions: Imipenem-funobactam demonstrated potent in vitro activity against most carbapenem-resistant isolates of A. baumannii, K. pneumoniae, NME and many isolates of carbapenem-resistant P. aeruginosa. Continued development of imipenem-funobactam is warranted.