Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime. A deficiency of the iron transporter PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across the outer membrane. The deficiency of OmpK35/36 in Klebsiella pneumoniae and the overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.

Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the third-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole-14C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa.

Cefiderocol (formerly S-649266) is an investigational siderophore cephalosporin. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) was prepared according to the Clinical and Laboratory Standards Institute (CLSI) protocol and used to perform broth microdilution testing of cefiderocol against a 2014-2015 collection of clinical isolates of Gram-negative bacilli from North America (n = 4,239) and Europe (n = 4,966). The concentrations of cefiderocol inhibiting 90% of isolates tested (MIC90s) were 0.5 μg/ml (North America; n = 3,007) and 1 μg/ml (Europe; n = 3,080) for all isolates of Enterobacteriaceae; 1 μg/ml (North America; n = 30) and 4 μg/ml (Europe; n = 139) for meropenem-nonsusceptible (MIC ≥ 2 μg/ml) isolates of Enterobacteriaceae; 0.5 μg/ml for both North American (n = 765) and European (n = 765) isolates of Pseudomonas aeruginosa; 0.5 μg/ml (North America; n = 151) and 1 μg/ml (Europe; n = 202) for meropenem-nonsusceptible (MIC ≥ 4 μg/ml) isolates of P. aeruginosa; 1 μg/ml for both North American (n = 309) and European (n = 839) isolates of all Acinetobacter baumannii strains as well as for both North American (n = 173) and European (n = 595) isolates of meropenem-nonsusceptible A. baumannii; and 0.5μg/ml (North America; n = 152) and 0.25 μg/ml (Europe; n = 276) for isolates of Stenotrophomonas maltophilia. MICs of cefiderocol were ≤4 μg/ml for 99.9% (6,078/6,087) of all Enterobacteriaceae, 97.0% (164/169) of meropenem-nonsusceptible Enterobacteriaceae, 99.9% (1,529/1,530) of all P. aeruginosa isolates, 100% (353/353) of meropenem-nonsusceptible P. aeruginosa isolates, 97.6% (1,120/1,148) of all A. baumannii isolates, 96.9% (744/768) of meropenem-nonsusceptible A. baumannii isolates, 100% of isolates of S. maltophilia (428/428) and 93.8% of isolates of Burkholderia cepecia (11/12). We conclude that cefiderocol demonstrated potent in vitro activity against a recent collection of clinical isolates of commonly encountered Gram-negative bacilli, including carbapenem-nonsusceptible isolates.