Application of a novel Desirability of Outcome Ranking endpoint incorporating a Framework for Resistance Assessment and Microbiologic Evaluation in antibiotic trials: a proof-of-concept in a post hoc analysis of the BALANCE trial

Background — Desirability of Outcome Ranking (DOOR) with Response Adjusted for Duration of Antibiotic Risk (RADAR) has been suggested as an outcome for antibiotic duration trials. An endpoint incorporating a measure of antimicrobial resistance may better reflect trade-offs between different antibiotic strategies.

Methods — We constructed a novel endpoint, DOOR-FRAME (Framework for Resistance Assessment and Microbiologic Evaluation), and applied it as a proof-of-concept in a post hoc analysis of the BALANCE trial comparing 7- versus 14-day antibiotic duration for uncomplicated non-Staphylococcus aureus bloodstream infection (BSI). The DOOR comprised mortality, readmission, and reinfection, while the FRAME component was a quantitative composite measure of incident Clostridioides difficile infection (CDI) and positive cultures for antibiotic-resistant organisms (AROs). We included BALANCE patients in Ontario who consented to data linkage to provincial health administrative databases. We calculated the probabilistic index (PI), the probability of a randomly selected patient in the 7-day group having a better outcome at 180 days.

Results — Two hundred seventy-one participants were included. The DOOR distributions were similar between the 7- and 14-day groups, with PI of 46.8% (95% CI 40.4%–53.2%) using DOOR alone. Nine (6.9%) and 12 (8.5%) patients in the 7 and 14-day group respectively had ARO/CDI within 180 days. Probabilistic index was 53.6% (95% CI 46.7%–60.4%) with DOOR-RADAR and 47.4% (95% CI 40.9%–53.8%) with DOOR-FRAME.

Conclusions — There were no significant differences in DOOR outcomes at 180 days between patients with uncomplicated BSI treated with 7 versus 14-day antibiotic duration. Incorporating a novel measure of antimicrobial resistance did not change interpretation of the trial.