Shionogi presented compelling real-world evidence at IDWeek 2025 demonstrating that cefiderocol (Fetroja/Fetcroja) achieves significantly better clinical outcomes when used earlier in the treatment course for serious gram-negative bacterial infections. The data reinforces the antibiotic's role as a critical weapon against increasingly drug-resistant pathogens.
PROVE Study Reveals Timing-Dependent Efficacy
The five-year PROVE (Retrospective Cefiderocol Chart Review) study, conducted between November 2020 and July 2024 across more than 1,000 patients in the U.S. and EU, provided crucial insights into real-world cefiderocol performance. The U.S. cohort analysis included 508 patients with serious infections caused by gram-negative bacteria who received cefiderocol for the first time and for at least 72 hours, with a median treatment duration of 10 days.
The study population represented critically ill patients, with 57.3% requiring intensive care unit admission and 47.6% receiving organ support such as mechanical ventilation or vasopressor medication at cefiderocol initiation. Despite this severity, the overall clinical cure rate across different infection sites reached 70.1%.
Most significantly, clinical cure rates varied dramatically based on timing of administration. Patients who received cefiderocol as empiric treatment—before causative bacteria identification—achieved a 73.7% clinical cure rate. In contrast, when cefiderocol was reserved as salvage therapy, the clinical cure rate dropped to 54.3%.
"Real-world studies like PROVE build on the insights of controlled clinical trials by showing how therapies perform in real-life clinical settings against the difficult-to-treat infections patients currently face in the U.S.," said Cornelius (Neil) Clancy, MD, Professor of Medicine at the University of Pittsburgh. "These results demonstrate that cefiderocol effectively treated seriously ill patients with a range of GN pathogens across multiple infection sites, particularly when used earlier in the treatment course – even before identifying the causative bacteria when appropriate risk factors exist."
Broad Spectrum Activity Against Resistant Pathogens
The analysis revealed cefiderocol's effectiveness across diverse infection types and pathogens. Respiratory tract infections were most common (53.5%), followed by skin and skin structure infections (14.6%) and bloodstream infections (9.3%). The most frequent monomicrobial infections involved Pseudomonas aeruginosa (29.9%), Acinetobacter baumannii (21.7%), Enterobacterales (11.4%), and Stenotrophomonas maltophilia (4.9%). Notably, cefiderocol remained effective against polymicrobial infections, which represented 29.9% of cases.
Bloodstream Infection Outcomes
A separate analysis of 226 patients with bloodstream infections from the global PROVE cohort of 1,075 patients demonstrated cefiderocol's efficacy against these life-threatening conditions. Bloodstream infections are the leading cause of mortality from infection, making effective treatment critical. The analysis showed a 63.7% overall clinical cure rate, with higher success rates observed when cefiderocol was used empirically (72%) versus as salvage therapy.
Activity Against Beta-Lactam Resistant Bacteria
Real-world data from PROVE revealed that cefiderocol maintained effectiveness against bacteria resistant to newer beta-lactam–beta-lactamase inhibitor (BL-BLI) combinations. The antibiotic achieved similar clinical cure rates against both susceptible (70.5%) and non-susceptible (70.2%) bacteria. Critically, BL-BLI non-susceptible infections showed minimal cross-resistance to cefiderocol, with 90.6% remaining susceptible.
SENTRY Surveillance Confirms Sustained Activity
Data from the SENTRY Antimicrobial Surveillance Program, which monitors pathogen prevalence and antimicrobial susceptibility patterns worldwide, provided additional validation of cefiderocol's continued effectiveness. Five years of surveillance data from 2020 to 2024 demonstrated consistent high susceptibility rates for cefiderocol against gram-negative bacteria, including carbapenem non-susceptible strains.
"Bacterial isolates collected from SENTRY were examined to determine their susceptibility to multiple antibiotics, including BL-BLI combinations and cefiderocol," said Marianna Castanheira, PhD, FIDSA, FAAM, Chief Scientific Officer at Element Materials Technology. "This analysis identified isolates that were resistant to BL-BLI combinations, a serious threat to public health, but remained susceptible to cefiderocol."
The surveillance data also highlighted cefiderocol's activity against metallo-beta-lactamase (MBL)-carrying A. baumannii, a class of bacteria with high resistance to multiple antibiotics and limited treatment options. Cefiderocol emerged as one of the few agents tested that demonstrated activity against these particularly challenging pathogens.
Clinical Implications for Antimicrobial Resistance
The findings carry significant implications for addressing the growing threat of antimicrobial resistance. Globally, bacterial AMR caused 1.14 million deaths in 2021, with projections suggesting drug-resistant pathogens could cause more than 39 million deaths over the next 25 years if no action is taken. Infections caused by carbapenem-resistant gram-negative bacteria are often associated with high mortality rates.
Cefiderocol, an innovative siderophore cephalosporin, is indicated in the U.S. for patients 18 years and older with complicated urinary tract infections and hospital-acquired/ventilator-associated bacterial pneumonia caused by certain susceptible gram-negative microorganisms. The drug carries important safety warnings, including an observed increase in 28-day all-cause mortality in certain patient populations compared to best available therapy in clinical studies.
The real-world evidence from PROVE and ongoing surveillance data from SENTRY provide healthcare providers with critical information for optimizing cefiderocol use in clinical practice, particularly emphasizing the importance of early, appropriate administration in patients with risk factors for drug-resistant infections.
