TOPLINE:

Cefiderocol, a siderophore cephalosporin antibiotic, was noninferior, but not superior, to standard-of-care antibiotics in preventing 14-day all-cause mortality in patients with hospital-acquired or healthcare-associated gram-negative bloodstream infections. In the subgroup with carbapenem-resistant infections, cefiderocol likewise did not demonstrate superiority over standard care.

METHODOLOGY:

• Researchers conducted a randomized clinical trial across 17 tertiary hospitals, primarily in Asia, to assess whether cefiderocol was noninferior or superior to standard-of-care antibiotics for preventing mortality in patients with healthcare-associated or hospital-acquired gram‑negative bloodstream infections.
• A total of 504 hospitalized patients were randomly assigned to receive either 2 g of cefiderocol intravenously every 8 hours as a 3‑hour infusion (n = 250; mean age, 62 years; 43% women) or standard-of-care antibiotics (n = 254; mean age, 61 years; 40% women).
• The median treatment duration was 10 days in the cefiderocol group and 13 days in the standard‑of‑care group.
• The primary outcome was all-cause mortality 14 days after randomization; noninferiority was established if the upper bound of the 95% CI for the absolute risk difference in the primary outcome was less than 10%.
• Superiority was established if the upper bound of the 95% CI for the absolute risk difference in the primary outcome was below zero.

TAKEAWAY:

• At 14 days, mortality was 8% in the cefiderocol group vs 7% in the standard-of-care group (absolute risk difference, 1%; 95% CI, -3 to 6), meeting the prespecified noninferiority criterion.
• In the subset of 127 patients with carbapenem‑resistant infections, 14‑day mortality was 14% with cefiderocol compared with 10% with standard‑of‑care antibiotics (absolute risk difference, 5%; 95% CI, -7 to 16).
• Superiority of cefiderocol was not demonstrated in the overall analysis or in the carbapenem-resistant subset.
• Five treatment-emergent serious adverse events — rash, abnormal liver chemistry, delirium, stupor, and rigors — assessed as probably or possibly related to the study drug, occurred in the cefiderocol group.

IN PRACTICE:

“Superiority of cefiderocol was not observed in the total study population or in the subset of patients with carbapenem-resistant organism infection. Clinicians must evaluate whether existing options for these organisms remain viable, especially considering the cost of newer antibiotics,” the authors of the study wrote.

SOURCE:

The study was led by David L. Paterson, MBBS, PhD, Saw Swee Hock School of Public Health, National University of Singapore, Singapore. It was published online on October 7, 2025, in The Lancet Infectious Diseases.

LIMITATIONS:

The 10% noninferiority margin may be excessive given the anticipated 10% all-cause mortality rate in the control group. The study predominantly enrolled patients in Asia, which may limit the generalizability of the results. The sample size was insufficient to draw definitive conclusions about efficacy in the carbapenem-resistant subset. Additionally, patients could have received up to 48 hours of nonstudy antibiotics before randomization, which may have affected outcome measures. 

DISCLOSURES:

The study was supported by Shionogi, the University of Queensland, the Henderson Foundation, and Singapore’s National Medical Research Council. One author was supported by a National Health and Medical Research Council Early Career Fellowship and Emerging Leadership Fellowship. Some authors disclosed receiving research grants, honoraria, or travel support from; serving on advisory boards of; or acting as consultants for multiple pharmaceutical companies. One author disclosed receiving honoraria from Medscape.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.