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• At the EUCAST susceptibility breakpoint of ≤ 2 mg/L, cefiderocol inhibited 97.2% of 213 randomly selected isolates from intensive care patients with nosocomial infections (set I) and 52 of 59 (88.1%) selected carbapenemase-producing isolates (set II). • Cefiderocol showed potent in vitro activity against Acinetobacter baumannii (highest MIC, 0.25 mg/L). • Cefiderocol also showed good activity against Enterobacterales and Pseudomonas aeruginosa , with about one third of carbapenemase-producing strains of each group requiring concentrations of > 1 mg/L for inhibition. • Among the Enterobacterales, ESBL-positive isolates were less susceptible to cefiderocol than ESBL-negative isolates. • Overall, cefiderocol inhibited 259/272 (95.2%) Gram-negative bacilli at ≤ 2 mg/L. Objectives: Cefiderocol (CID), also known as S-649266, a novel siderophore cephalosporin, possesses potent activity against multidrug-resistant aerobic Gram-negative bacteria (GNB). This study aimed to determine the in vitro activity of CID against two different sets of GNB: i) a random sample of 213 clinical isolates, including 17 extended-spectrum beta-lactamase (ESBL) producers, obtained from intensive care unit patients with nosocomial infections collected during a multicentre surveillance study (set I); and ii) a group of 59 challenge GNB producing various types of carbapenemases (CP; set II). Methods: Minimum inhibitory concentrations (MICs) were determined using the microdilution method according to the standard ISO 20776-1. Iron-depleted medium was used for testing CID. Results: CID inhibited 97.2% of set I isolates at the EUCAST susceptibility breakpoint of ≤ 2 mg/L. The concentrations of CID inhibiting 50% and 90% (MIC 50/90) of the Enterobacterales isolates (n = 146) were 0.12/1.0 mg/L, with ESBL-positive isolates tending to exhibit higher MICs than ESBL-negative isolates to CID. MIC 50/90 values of CID for isolates of the Acinetobacter baumannii group (n = 13) and Pseudomonas aeruginosa (n = 54) were 0.06/0.12 mg/L and 0.12/0.5 mg/L, respectively. Further, CID inhibited 88.1% of set II CP-producing isolates at ≤ 2 mg/L. All seven class D CP-producing Acinetobacter baumannii were inhibited at ≤ 0.25 mg/L. MIC 50/90 values for CP-producing Enterobacterales (n = 30) and Pseudomonas aeruginosa (n = 22) were 1/4 mg/L and 0.5/2 mg/L, respectively. Conclusion: CID showed potent activity against Acinetobacter baumannii , Enterobacterales and Pseudomonas aeruginosa , including CP-producing isolates. Overall, CID inhibited 259 of 272 (95.2%) GNB at ≤ 2 mg/L. [ABSTRACT FROM AUTHOR]