Impact Assessment of the Allergy Fact Checker, a Clinical Decision Support Tool for Noninvasive Beta-Lactam Antibiotic Allergy Label Delabeling: Protocol for a Multicenter Crossover Cluster-Controlled Study.

Background: Beta-lactam allergy labels (BLALs), especially penicillin allergy labels, are frequently recorded in hospitalized patients and are associated with increased use of broad-spectrum and second-line antibiotics. Most BLALs are incorrect, but current allergy workups require invasive testing and specialized resources. We recently developed a strictly noninvasive, electronic patient record-embedded clinical decision support tool, the Allergy Fact Checker (AFC), which proactively identifies potentially incorrect BLALs by detecting uneventful re-exposures to the culprit or other beta-lactams since introduction of the BLAL. Objective: This study aims to evaluate the clinical, antimicrobial, and economic impact of the AFC in hospitalized adults with BLALs compared to the standard of care (no AFC). Methods: We are conducting a multicenter, open-label, crossover cluster-controlled study in 9 hospitals in Flanders, Belgium. All hospitalized adults with a BLAL are eligible, excluding patients in palliative care, discharged within 24 hours, or previously enrolled. Each hospital will alternate between intervention (use of the AFC) and control (standard practice) phases, separated by washout periods. The primary endpoint is cumulative guideline-concordant prescribing of first-line and/or narrow-spectrum beta-lactams following local antibiotic treatment guidelines, across predefined care windows up to day 100, expressed as a weighted per-patient proportion. Secondary endpoints include delabeling or refinement rate, beta-lactam tolerance, antibiotic switching, hospital length of stay, in-hospital and 3-month mortality, intensive care unit admission, readmission, multidrug-resistant organism colonization or infection, and costs. Based on prior data, we calculated that a total of 3285 participants are required to achieve 80% power to detect superiority of the intervention (4.6% vs 9.9% appropriate prescribing). Recruitment started in March 2025 and is ongoing. Results: The primary outcome will be analyzed using hierarchical mixed-effect models accounting for hospital-level clustering and period effects. Data collection will continue until 200 days after the last patient is discharged. This trial is expected to conclude in 2026. Ethical approval was obtained from the institutional review board in November 2024. Recruitment started in March 2025 and is ongoing. As of manuscript submission, more than 3000 participants have been enrolled across the participating hospitals. According to the prespecified protocol, an interim assessment of nuisance parameters will be performed in the following month to evaluate the initial design assumptions. Data collection is expected to continue until the end of 2026. The main study results are anticipated to be reported in 2027. Conclusions: This is the first multicenter European study evaluating a strictly noninvasive BLAL delabeling approach. If successful, this AFC tool could improve antimicrobial stewardship, reduce costs, and provide a scalable model for centralized allergy label management.