The Food and Drug Administration approved cefiderocol as an alternative treatment for carbapenem-resistant urinary tract infections (UTI), including pyelonephritis, in patients who had no or few therapeutic options. In a viewpoint published in Clinical Infectious Diseases, study authors discuss the uncertainties and challenges in the interpretation of CREDIBLE-CR trial and the benefit-risk considerations for the use of cefiderocol in clinical practice.

Results from the APEKS-cUTI trial ( Identifier: NCT02321800) showed statistical superiority of cefiderocol. However, study authors note that this result was primarily driven by the microbiologic endpoint at the test of cure visit. While the clinical response rates were similar in both treatment groups, study authors point out that the correlation between reduction in colony count and clinical benefit is unclear.

Results from the APEKS-NP trial ( Identifier: NCT03032380) estimated that mortality rates were similar in the treatment and best available therapy (BAT) groups. However, the confidence interval could not rule out increased mortality for cefiderocol.

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Results from the CREDIBLE-CR trial ( Identifier: NCT02714595) indicated that the cefiderocol group had a higher rate of all-cause mortality compared to the BAT group. Deaths due to treatment failure in the cefiderocol group normally occurred early in the course of treatment. Patients receiving cefiderocol had a 10% higher mortality in certain subgroups compared with patients receiving BAT, including:

  • Patients with a clinical diagnosis of hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, healthcare-associated bacterial pneumonia, bloodstream infection, or sepsis
  • Men or women
  • Patients aged 65 years or younger
  • Patients aged 75 years or older
  • Asian and “other” race
  • Patients with A baumannii or P aeruginosa baseline pathogens
  • Acute Physiology and Chronic Health Evaluation II score of 16 or greater
  • Asia-Pacific or American region

Patients on cefiderocol generally saw increased mortality and higher rates of treatment failure progressing to sepsis and death. The study authors noted that the CREDIBLE-CR trial was not an “adequate and well-controlled trial,” due to several limitations: small sample size, a descriptive analysis without statistical testing, and inclusion of cUTI with other serious infection types.

The FDA voted that there was substantial evidence of the safety and efficacy of cefiderocol, including pyelonephritis, in patients with limited or no alternative treatment options, while also noting concern about increased mortality. A warning for use in indications other than cUTI was also recommended.

Overall, study authors state that the FDA’s approval of cefiderocol was based on “an adequate and well-controlled trial demonstrating safety and effectiveness of cefiderocol compared to imipenem.” When taking all the trials into consideration, the “benefit-risk profile of cefiderocol was considered favorable for a limited use indication.”

To date, the safety and efficacy of cefiderocol has not been established for the treatment of nosocomial pneumonia, bloodstream infection, or sepsis.


Naseer S, Weinstein EA, Rubin DB, et al. U.S. Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetrojaâ). Clin Infect Dis. 2020;ciaa1799. doi:10.1093/cid/ciaa1799.

This article originally appeared on Infectious Disease Advisor