Confirmed Multiple Drug Hypersensitivity Syndrome is Uncommon, and its Culprit Drug Spectrum Reflects Patterns of Drug Exposure

Multiple drug hypersensitivity syndrome (MDHS) is defined as confirmed hypersensitivity to two or more chemically and pharmacologically unrelated drug entities. Few studies have characterized MDHS with systematic diagnostic confirmation. We aimed to determine the frequency, culprit drug patterns, and diagnostic findings of confirmed MDHS. We retrospectively reviewed patients evaluated for suspected drug hypersensitivity at a Korean tertiary allergy center from March 2017 to April 2026. MDHS required confirmed hypersensitivity to at least two unrelated drug entities by skin testing, serum-specific IgE, or provocation testing; cross-reactive reactions were not counted separately. Among 6684 evaluated patients, 3007 underwent diagnostic testing, and 1380 were tested for multiple suspected drugs. MDHS was confirmed in 94 patients (1.4%, 3.1%, and 6.8%, respectively). Anaphylaxis was the most common manifestation (38.3%). Most patients (84.0%) reacted to two entities, whereas 12.8% and 3.2% reacted to three and four entities, respectively. Leading culprits were β-lactams (n = 34), nonsteroidal anti-inflammatory drugs (NSAIDs)/acetaminophen (n = 34), antituberculosis agents (n = 27), and histamine-2 receptor antagonists (n = 19). Recurrent combinations involved first-line antituberculosis agents and NSAIDs plus ranitidine. Of 114 entities confirmed by drug provocation, 38 had negative preceding skin tests. Delayed-reading intradermal testing was more frequently positive in drug reaction with eosinophilia and systemic symptoms (DRESS) than in maculopapular exanthema (MPE) (53.3% vs. 0.0%, P = 0.008). Confirmed MDHS was uncommon despite suspected hypersensitivity to multiple drugs. The clinical presentation resembled European cohorts, whereas the culprit spectrum reflected regional prescribing patterns. Systematically evaluating each suspected entity may preserve future treatment options.