The largest global real-world evidence study of cefiderocol (Fetroja) has revealed that timing of administration significantly impacts treatment outcomes for serious gram-negative bacterial infections, according to new data presented at ESCMID Global 2025.
Analysis from the European cohort of the PROVE (Retrospective Cefiderocol Chart Review) study showed a clear trend toward higher clinical cure rates when cefiderocol was administered earlier in the treatment course rather than as a last resort option.
Clinical Outcomes Based on Treatment Timing
The multinational study examined 567 hospitalized patients across five European countries who received cefiderocol for at least 72 hours. Researchers found that patients who received the antibiotic for documented infections achieved a 67.4% clinical cure rate, while those receiving it as empiric therapy saw a 64.6% cure rate. In contrast, patients who received cefiderocol as salvage therapy—after other antibiotics had failed—experienced a notably lower clinical cure rate of 58.2%.
"These data suggest a trend towards worse clinical outcomes when the use of cefiderocol to treat gram-negative bacterial infections is reserved as a last line treatment option compared with those who received the treatment earlier," explained Dr. Oliver A. Cornely, Director of Translational Research at the University of Cologne. "This trend may offer clinicians new evidence to justify the early and effective use of cefiderocol in patients with suspected resistant infections."
Patient Population and Infection Characteristics
The study population reflected seriously ill patients with difficult-to-treat infections. Over 55.9% were critically ill in intensive care units at the time of cefiderocol initiation, and 41.3% required organ support. The carbapenem resistance rate exceeded 70% among enrolled patients, highlighting the challenges in treating these infections.
Respiratory tract infections were most common, accounting for over 50% of cases (299 patients), followed by urinary tract infections in more than 12% (73 patients). The study also documented bloodstream infections, intra-abdominal infections, and skin structure infections.
Pathogen-Specific Outcomes
The most frequently identified pathogens were Pseudomonas aeruginosa (41.3%), Acinetobacter baumannii (15.0%), and Enterobacterales (14.6%)—all designated as priority pathogens by the World Health Organization.
Notably, patients with Pseudomonas aeruginosa infections achieved a particularly high clinical cure rate of 73.1%, suggesting cefiderocol's strong efficacy against this challenging pathogen. Clinical cure rates varied by infection site:
- Urinary tract infections: 90.4%
- Intra-abdominal infections: 64.7%
- Skin structure infections: 63.9%
- Bloodstream infections: 60.7%
- Respiratory tract infections: 59.2%
The overall clinical cure rate across all infection types and pathogens was 65.3%.
Study Design and Context
The PROVE study is a five-year international, retrospective, observational medical chart review conducted between November 2020 and July 2024. It was designed to evaluate the real-world efficacy and safety of cefiderocol in adult patients with serious gram-negative bacterial infections.
Previous data from the study presented at IDWeek last year showed similar promising results in a larger cohort of 1,075 patients with carbapenem-resistant infections. In that analysis, cefiderocol demonstrated a clinical cure rate of 64% and a response rate of 71.6% by the end of treatment.
Mechanism of Action and Approvals
Cefiderocol employs a novel mechanism for penetrating the outer cell membrane of gram-negative pathogens. It acts as a siderophore, binding to ferric iron and actively transporting into bacterial cells through iron transporters, in addition to entering cells through passive diffusion via porin channels. This dual-entry mechanism allows cefiderocol to achieve high concentrations in the periplasmic space, where it inhibits cell wall synthesis.
The FDA approved cefiderocol in 2019 for treating complicated urinary tract infections, including pyelonephritis, in patients 18 years and older. The approval was later expanded to include hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.
In Europe, cefiderocol is approved for treating infections due to aerobic gram-negative organisms in adults with limited treatment options.
Clinical Implications
Sean Nguyen, PharmD, BCIDP, Medical Director at Shionogi, emphasized the significance of these findings: "These data provide clinicians with new evidence that supports the consideration of using cefiderocol in earlier lines of treatment in seriously ill patients who present with or have suspected risk factors for carbapenem-resistant infections rather than reserving it when other antibiotics are no longer an option."
The study results suggest that delaying cefiderocol use until other treatments have failed may compromise patient outcomes. For clinicians facing difficult-to-treat gram-negative infections, particularly in critically ill patients or those with risk factors for carbapenem resistance, earlier consideration of cefiderocol may lead to improved clinical success rates.
As antimicrobial resistance continues to pose significant challenges in healthcare settings worldwide, these real-world findings provide valuable guidance for optimizing treatment strategies against serious gram-negative infections.
