A randomized controlled trial of cefiderocol versus standard therapy for Gram-negative bacterial bloodstream infections: Benefit and risk assessment using DOOR and generalized pairwise comparisons

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• Picked for Microbiology (medical) (top studies of the week, 13 September 2026): High-quality evidence in a top journal

Abstract

BACKGROUND: Gram-negative bacterial bloodstream infections (BSI) cause substantial mortality and morbidity. The GAME CHANGER trial compared cefiderocol with standard of care (SOC) for Gram-negative BSI, with 14-day all-cause mortality (ACM) as the primary endpoint. We evaluated cefiderocol versus SOC integrating efficacy and safety outcomes using desirability of outcome ranking (DOOR) and generalized pairwise comparisons (GPC). METHODS: Composite endpoints were prespecified prior to data review. The DOOR endpoint included treatment failure, infectious complications, serious adverse events (SAEs) and 90-day ACM, with functional improvement as a tiebreaker. The GPC approach included ACM at 30-days, clinical failure, SAEs, functional improvement and hospitalization duration. Analyses were conducted in the main population and carbapenem-resistant subset. RESULTS: The DOOR composite in the main population resulted in a probability of a more desirable outcome with cefiderocol of 50.4% (95% CI 45.6, 55.1). The analysis with GPC resulted in a win ratio and win odds of 1.04 (95% CI: 0.85, 1.28) and net treatment benefit (NTB) of 2.1% (95% CI: -8.0%, 12.2%). In the carbapenem-resistant subset, the DOOR probability with cefiderocol was 46.8% (95% CI 37.4%, 56.1%). The analysis with GPC resulted in a win ratio and win odds of 0.90 (95% CI: 0.60, 1.34) and NTB of -5.4% (95% CI: -25.3%, 14.5%). CONCLUSIONS: In adults with Gram-negative bacterial BSI, cefiderocol was not superior to SOC based on DOOR or GPC analyses in both the main population and carbapenem-resistant subset. Integrating efficacy, safety and functional outcomes using these approaches provides a more comprehensive assessment than mortality alone.

Abstract as published, via PubMed.