Antibiotic Allergy: Phenotypes, Endotypes, and Mechanisms

PROJECT SUMMARY Drug allergy is the leading cause of fatal anaphylaxis in the US, with antibiotics being the most common cause of allergic reactions. For immediate penicillin allergy, evidence supports specific antigenic determinants and an immunoglobulin (lg)E-mediated mechanism. For other antibiotics, the antigenic determinants and mechanisms are not known. For some antibiotic classes, such as cephalosporins and sulfonamides, positive skin testing with non irritant concentrations supports an lgE mechanism, but for other antibiotics, such as vancomycin and fluoroquinolones, current data suggest immediate hypersensitivity reactions occur through primarily non-lgEmediated processes. Currently available tests and biomarkers for antibiotic allergy have limited utility. While fatal anaphylaxis has been associated with intravenous administration, the mechanisms supporting these observations have not yet been defined as large database studies lack accurate reaction phenotyping and structured causality assessments. Although both lgE and lgG antibodies are likely to be involved in immediate-onset allergic reactions to antibiotics, biological pathways need defining in advance of biomarker discovery given the complexity of antibiotic structures, potential epitopes, and protein and cellular interactions. In this UG3/UH3 application, we apply clinical epidemiology and translational immunology methods to enhance knowledge of immediate antibiotic allergy through extending the work of an established multi-site network of drug allergy specialists, the United States Drug Allergy Registry (USDAR) Consortium. USDAR studies include a multi-site database of participants evaluated for drug allergy (n=2,432) and a biorepository from specialistconfirmed antibiotic-allergic patients (n=28). Our overall goal is to determine the phenotypes, endotypes, and mechanisms of antibiotic allergy, including investigation of mechanistic differences according to drug route through these specific aims: 1) To describe the phenotypes and endotypes of immediate-onset allergic reactions to antibiotics, and 2) To define how delivery route impacts antibiotic anaphylaxis. We will achieve these aims through leveraging USDAR's existing research infrastructure and participants and leadership by two allergist/immunologist physician scientists with complementary methodologic expertise. This project aligns with NIH/NIAID goals to advance drug allergy research and RFA-Al-24-002 to support research that enhances understanding of the mechanisms and management of antibiotic drug allergy.