What is Cefiderocol (Cefiderocol), a cephalosporin antibiotic?

From the Guidelines

Cefiderocol is a novel siderophore cephalosporin antibiotic that should be considered for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa, due to its unique mechanism of action and activity against these resistant organisms 1.

Key Characteristics of Cefiderocol

• Cefiderocol works through a unique "Trojan horse" mechanism, binding to iron and using bacterial iron transport systems to penetrate the outer membrane of Gram-negative bacteria, allowing it to overcome many resistance mechanisms.
• It maintains activity against carbapenem-resistant organisms, including Pseudomonas aeruginosa, Acinetobacter baumannii, and various Enterobacterales.
• The typical adult dosage is 2 grams administered intravenously every 8 hours, with each infusion given over 3 hours, and dosage adjustments are required for patients with renal impairment.

Clinical Use and Efficacy

• Cefiderocol may be considered as an alternative for the treatment of infections involving KPC-producing CRE, although clinical studies of its efficacy in these patients are limited 1.
• The use of cefiderocol is supported by its unique mechanism of action and in vitro activity against resistant organisms, but more evidence is needed to guide its use in different patient categories and infection types.
• Common side effects include diarrhea, nausea, vomiting, and elevated liver enzymes, and hypersensitivity reactions are possible in patients with beta-lactam allergies.

Recommendations for Use

• Cefiderocol should generally be reserved for infections with limited treatment options to preserve its effectiveness against highly resistant pathogens.
• The choice of cefiderocol versus other antibiotics, such as ceftazidime/avibactam or meropenem/vaborbactam, should be based on local epidemiology, the site of infection, and the emergence of resistance in KPC-producing isolates 1.

From the FDA Drug Label

FETROJA is a cephalosporin antibacterial drug product consisting of cefiderocol sulfate tosylate for intravenous infusion. Cefiderocol functions as a siderophore FETROJA for injection is a white to off-white, sterile, lyophilized powder formulated with 1 gram of cefiderocol (equivalent to 1. 6 grams of cefiderocol sulfate tosylate)

Cefiderocol is a cephalosporin antibacterial drug that functions as a siderophore. It is administered via intravenous infusion. The key characteristics of Cefiderocol include:

• Chemical name: Tris[(6R,7R)-7-[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetamido]-3-({1-[2-(2-chloro-3,4-dihydroxybenzamido)ethyl]pyrrolidin-1-ium-1-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate] tetrakis(4-methylbenzenesulfonate) monosulfate hydrate
• Molecular weight: 3043.50 (anhydrous)
• Molecular formula: 3C30H34ClN7O10S2∙4C7H8O3S∙H2SO4∙xH2O
• Formulation: 1 gram of cefiderocol (equivalent to 1.6 grams of cefiderocol sulfate tosylate), sucrose, sodium chloride, and sodium hydroxide to adjust pH [2] [3]

From the Research

Overview of Cefiderocol

• Cefiderocol is a novel siderophore cephalosporin antibiotic with potent activity against multidrug-resistant, carbapenem-resistant, difficult-to-treat or extensively drug-resistant Gram-negative pathogens 4, 5, 6, 7, 8.
• It is the first approved siderophore beta-lactam antibiotic with a unique mechanism of action that involves forming a complex with extracellular free ferric iron, leading to transportation across the outer cell membrane to exert its bactericidal activity through cell wall synthesis inhibition 5, 7.

Spectrum of Activity

• The spectrum of activity of cefiderocol includes drug-resistant strains of Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp., and Burkholderia spp. and CRE that produce serine- and/or metallo-carbapenemases 4, 6.
• Cefiderocol has been shown to be active against carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia 6.

Clinical Efficacy

• Cefiderocol has been evaluated in several clinical trials, including the APEKS-cUTI, APEKS-NP, and CREDIBLE-CR trials, which demonstrated its non-inferiority to imipenem/cilastatin and meropenem for the treatment of complicated urinary tract infections and nosocomial pneumonia, respectively 4, 5, 8.
• However, a numerically greater all-cause mortality rate was observed with cefiderocol compared to best available therapy in the CREDIBLE-CR trial, particularly in patients with Acinetobacter spp. infections 4, 5.

Pharmacokinetics and Pharmacodynamics

• Cefiderocol achieves adequate concentration in the epithelial lining fluid in the lung and requires dosing adjustment for renal function, including patients with augmented renal clearance and continuous renal-replacement therapy (CRRT) 4, 7.
• The pharmacokinetics of cefiderocol have been evaluated in various patient populations, and its pharmacodynamics have been shown to be effective against Gram-negative pathogens 7.