Mode of action of cefiderocol, a novel siderophore cephalosporin, active against highly resistant Gram-negative bacteria including carbapenem-resistant strains of Enterobacteriaceae and non-fermenting bacteria
Yoshinori Yamano, Masakatsu Tsuji, Meredith Hackel, Daniel Sahm, Roger Echols
1 Disclosures
Shionogi & Co., Ltd IHMA Medical Consultant
Yoshinori Yamano Meredith Hackel Roger Echols Masakatsu Tsuji Daniel Sahm
2 Features of Cefiderocol
• A first-in-class siderophore cephalosporin • Broad coverage against Gram-negative bacteria including CRE and MDR non-fermenters. No activity for Gram-positive or anaerobes. • Best correlation between in vivo efficacy and MIC determined in iron- depleted medium • Cefiderocol demonstrated non-inferiority over treatment with imipenem/cilastatin in cUTI study. Results consistent with superiority (Oral late breaker session) • Good safety and tolerability in clinical studies
3 Potent activity of Cefiderocol against Carbapenem-Resistant Isolates
MIC Distribution of 1,873 Carbapenem-resistant Gram-Negative Poster #1316 Clinical Isolates From Global Surveillance Study
Enterobacteriaceae (1022) Acinetobacter baumannii (368) Pseudomonas aeruginosa (262)
Stenotrophomonas maltophilia (217) Percentage (%) Percentage
MIC (mg/L) 96.2% of all isolates susceptible to cefiderocol at 4 mg/L 4 Activity of Cefiderocol against Carbapenem-Resistant Enterobacteriaceae
Comparison of MIC Distribution with other comparators Poster #1316 Percentage (%) Percentage
MIC (mg/L)
5 Activity of Cefiderocol against MDR P. aeruginosa
Comparison of MIC Distribution with other comparators Poster #1316 Percentage (%) Percentage
MIC (mg/L)
6 Activity of Cefiderocol against MDR A. baumannii
Comparison of MIC Distribution with other comparators Poster #1316 Percentage (%) Percentage
MIC (mg/L)
7 Activity of Cefiderocol against S. maltophilia
Comparison of MIC Distribution with other comparators Poster #1316 Percentage (%) Percentage
MIC (mg/L)
8 Two Important Mode of Action of Cefiderocol
• High stability to carbapenemases • Stable to both serine-type (KPC, OXA etc) and metallo- type carbapenemases (VIM, IMP, NDM, L1 etc) • Efficient penetration through the outer membrane via active iron transporters • Strong chelating ability to Fe3+ as well as siderophores • Utilization of multiple iron transporters of multiple bacterial species of Gram-negative bacteria
9 Stability of Cefiderocol to Carbapenemases
Cefiderocol
Cefepime
Ceftazidime
Meropenem
10 Chelating ability of Cefiderocol with Ferric Iron
Cefiderocol Catechol 3-methoxy cefiderocol
0.035mM Fe3+ OD OD 0mM Fe3+
Wavelength (nm) Wavelength (nm)
• Only cefiderocol showed the different absorption spectrum by the addition of iron, indicating the formation of chelating complex with iron • Log K (stability constant) of cefiderocol-iron chelating complex was calculated to be 4.1 at pH 7 • Pyoverdine, a siderophore produced by P. aeruginosa, has logK of 3.9 to form chelating complex with iron at pH 7 11 Calcein Assay to Evaluate Iron Concentration in Bacterial Cells
: Siderophore Calcein-AM (nonfluorescent)
Fe Fe Fe Fe : Siderophore-iron
Fe
Fe Fe Fe Esterase Fe Fe Fe Add Siderophore
IROMP IROMP Fluorescence of calcein is (Iron regulated OMP) Iron is transported quenched by the iron : Calcein (fluorescent) by sideropohore
12 Uptake of Cefiderocol into Bacterial Cells with Iron
Enhancement of iron uptake into P. aeruginosa cells by cefiderocol
Cefiderocol
Pyoverdine
Catechol 3-methoxy cefiderocol Ceftazidime
Control
Iron in the bacterial cells significantly increased by the addition of cefiderocol or pyoverdine, suggesting that iron uptake into bacterial cells was enhanced in the presence of cefiderocol and pyoverdine
13 Uptake of Cefiderocol into Bacterial Cells under Iron-Depleted Conditions
Enhancement of cefiderocol uptake into P. aeruginosa cells under iron-depleted conditions
iron-depleted conditions
iron-sufficient conditions
Cefiderocol uptake into bacterial cells was enhanced when grown under iron-depleted conditions
14 Conclusion • Cefiderocol was shown to penetrate efficiently through the outer membrane via active iron transporters • Formation of chelating complex with iron as well as pyoverdine • Increase of iron uptake into the bacterial cells in the presence of cefiderocol as well as pyoverdine • Enhancement of cefiderocol uptake into bacterial cells under the iron-deficient conditions, which induce the production of iron transporters
• Cefiderocol exhibited highly potent in vitro antibacterial activity against carbapenem resistant Gram-negative bacteria due to the following reasons • Utilization of active iron transporters • High stability to both serine- and metallo-type carbapenemases
• Cefiderocol is a promising candidate for the treatment of serious infections caused by Gram-negative bacteria including CR strains • Broad Gram-negative activity including non-fermenters P. aeruginosa, A. baumannii and Stenotrophomonas maltophilia
15 End of File