Cefiderocol Approved by FDA for cUTI

The US Food and Drug Administration (FDA) has approved cefiderocol (Fetroja) for the treatment of complicated urinary tract infections (cUTI), including kidney infections caused by susceptible gram-negative microorganisms in adults, who have limited or no alternative treatment options. The approval was granted to Shionogi Inc.

Cefiderocol is a siderophore cephalosporin. It is active against all classes of β-lactamases, which enables it to overcome the primary mechanisms of gram-negative bacterial resistance to β-lactam antibiotics.

The safety and effectiveness of cefiderocol was demonstrated in a study of 448 patients with cUTIs. In the study, 72.6% of patients who received cefiderocol had resolution of symptoms and eradication of the bacteria approximately 7 days after completing treatment, compared to 54.6% of patients who received an alternative antibiotic. The clinical response rates were similar between the treatment groups.

Labeling for cefiderocol includes a warning regarding the higher all-cause mortality rate observed in cefiderocol-treated patients compared to those treated with other antibiotics in the CREDIBLE-CR study in critically ill patients with multidrug-resistant gram-negative bacterial infections.

On October 16, an FDA advisory committee backed cefiderocol efficacy for cUTI 14-2. However, concern was expressed over increased mortality observed in the CREDIBLE-CR study, but complicating factors related to different condition states were suggested as the higher mortality rates were only observed in the hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) subgroup, as well as the bloodstream infection/sepsis subgroup, rather than the cUTI group.

According to the FDA's statement, the cause of the increase in mortality has not been established. Some of the deaths were a result of worsening or complications of infection, or underlying co-morbidities. The agency also notes that safety and efficacy of cefiderocol has not been established for the treatment of HABP/VABP, bloodstream infections, or sepsis.

In clinicial studies, the most common adverse reactions related to cefiderocol included diarrhea, constipation, nausea, vomiting, elevations in liver tests, rash, infusion site reactions, candidiasis,cough, headache and hypokalemia (low potassium). Cefiderocol should not be used in individuals with a known history of severe hypersensitivity to beta-lactam antibacterial drugs.

"The FDA approval of cefiderocol for complicated UTIs is in keeping with the recommendations made by the advisory committee who recognize the continued unmet medical need for new therapeutic options against multidrug resistant gram-negative bacteria, but cannot explain the higher mortality rates in the CREDIBLE-CR study," Ryan K. Shields, PharmD, MS, Contagion®’s Multidrug-Resistant Infections Section Editor, said on the approval. "The warning of higher all-cause mortality in the label will ideally serve as a reminder to clinicians that additional data are needed to evaluate the efficacy of this agent against MDR pathogens."