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.

Grant Number: 7UG3AI190113-02
NIH Institute/Center: NIH
Principal Investigator: Kimberly Blumenthal