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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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.