Cefiderocol

Cefiderocol is used to treat adults with complicated urinary tract infections, including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.[2][9]

In the United States, cefiderocol is indicated in adults 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.[6]

For the treatment of severe pneumonia (HABP and VABP), it is indicated in patients 18 years of age and older whose pneumonia is not responding to other, more commonly used antibiotics and is confirmed to be caused by one of the following Gram-negative organisms:

• Acinetobacter baumannii complex
• Escherichia coli
• Enterobacter cloacae complex
• Klebsiella pneumoniae
• Pseudomonas aeruginosa
• Serratia marcescens

This indication is supported by the 2018 APEKS-NP study, where cefiderocol was compared in nosocomial pneumonia caused by Gram-Negative bacteria to meropenem, where it was shown not to be inferior to meropenem. The primary endpoint of the study was all-cause mortality at day 14, where both antibiotics were shown to be almost equally effective. [13]

As of 2020, cefiderocol is indicated in the European Union for the treatment of infections due to aerobic Gram-negative bacteria in adults with limited treatment options.[11]

Cefiderocol may cause serious and life-threatening allergic reactions, severe diarrhea caused by C. difficile and seizures.[8]

An increased risk of all-cause mortality was observed in people treated with cefiderocol as compared to other antibiotics in a separate clinical trial in critically ill people with multidrug-resistant Gram-negative bacterial infections.[2][8] The higher all-cause mortality rate was observed in people treated for hospital-acquired/ventilator-associated pneumonia (i.e.nosocomial pneumonia), bloodstream infections, or sepsis. The cause of death has not been established, but some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities.[2] The safety and efficacy of cefiderocol has not been established for the treatment of these types of infections.[2] Hence, cefiderocol label includes a warning regarding the higher all-cause mortality rate.[2]

Already in 2021, the first cases of antibiotic resistance were reported,[14] and as of 2022 alarming proportions of up to 50% of resistance in some cohorts have been reported. In September 2022, the German RKI reported victims of the Ukraine War with cefidercol resistant surgical infections (Klebsiella specie. and Acinetobacter baumannii) who had been treated in Germany.[15]

Its structure is similar to cefepime and ceftazidime, but a chlorocatechol group at the end of the C-3 side chain further enhances its β-lactamase stability and renders it a siderophore.[16]

This means it enters into bacterial cells by binding to iron, which is actively transported into the bacterial cells.[6][17][18][19][20] It was the first siderophore antibiotic to be approved by the U.S. Food and Drug Administration (FDA).[21] It bypasses the bacterial porin channels by using the bacteria's own iron-transport system for being transported in.[22]

Cefiderocol received a Qualified Infectious Disease Product designation from the U.S. Food and Drug Administration (FDA) and was granted priority review.[2] In November 2019, the FDA granted approval of cefiderocol to Shionogi & Co. as an antibacterial drug for treatment of adults 18 years of age or older with complicated urinary tract infections (cUTI), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options.[2][10][6]

The safety and effectiveness of cefiderocol was demonstrated in a study (NCT02321800) of 448 participants with cUTIs.[2][8] Of the participants who were administered cefiderocol, 72.6% had resolution of symptoms and eradication of the bacteria approximately seven days after completing treatment, compared with 54.6% in participants who received an alternative antibiotic.[2] The clinical response rates were similar between the two treatment groups.[2] The trial included participants from Europe, United States and Mexico.[8]

In the clinical trial, participants with cUTI were chosen at random to receive cefiderocol, or another antibacterial drug called imipenem/cilastatin.[8] Both treatments were given intravenously for 7–14 days and neither the participants nor the health care professionals knew which drugs were given until after the trial was complete.[8] Participants could not be switched to an oral antibacterial drug to complete the treatment for cUTI.[8]

The benefit of cefiderocol was measured by the proportion of participants who achieved cure or improvement in their symptoms related to cUTI and a negative urine culture test in comparison to imipenem/cilastatin.[8]

In April 2020, Cefiderocol was approved for medical use in the European Union .[11]

• Committee for Medicinal Products for Human Use (27 February 2020). "Fetcroja : EPAR - Public assessment report" (PDF). European Medicines Agency (EMA). EMA/136096/2020.

• "Cefiderocol". Drug Information Portal. U.S. National Library of Medicine.
• "Cefiderocol sulfate tosylate". Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT02321800 for "A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (APEKS-cUTI)" at ClinicalTrials.gov