D2.28 - When Cross-Reactivity Is Not the Answer: Immediate Multiple Drug Hypersensitivity to Aminopenicillins and Ceftriaxone

Multiple drug hypersensitivity syndrome (MDHS) is defined as confirmed hypersensitivity to two or more chemically and pharmacologically unrelated drugs, representing a distinct entity from cross-reactivity or multiple drug intolerance. MDHS is rare and classically associated with delayed, T-cell–mediated mechanisms (type IV), whereas immediate IgE-mediated MDHS remains exceptional. We report a severe immediate MDHS case involving an aminopenicillin and a third-generation cephalosporin, illustrating diagnostic complexity and clinical reasoning required.

Case Report

A 37-year-old male nurse, treated with propranolol 30 mg/day due to migraine, was prescribed amoxicillin–clavulanate for ulceronecrotic tonsillitis. Clinical deterioration prompted emergency department admission, where intravenous ceftriaxone, clindamycin, and hydrocortisone were initiated. During ceftriaxone infusion, he developed a severe anaphylaxis with mucocutaneous, respiratory and cardiovascular involvement, including hypotension, stridor and oxygen desaturation (83%). Nasofibrolaryngoscopy showed arytenoid edema without airway compromise. He had no previous known exposure to cephalosporins, although occupational exposure was relevant, as he frequently handled antibiotics without gloves. At the time, he was also taking ibuprofen and reported ingestion of amoxicillin–clavulanate approximately 15–20 minutes before ceftriaxone administration. He had subsequently tolerated ibuprofen, clindamycin and hydrocortisone, excluding these agents as culprits.

Allergy workup revealed negative specific IgE to penicillin G and V and low-positive IgE to amoxicillin (0,23kU/L, total IgE 107kU/L). Ten months after the index reaction, immediate skin tests to β-lactams were negative, with a delayed (6-hour) intradermal response to amoxicillin–clavulanate. Basophil activation test was positive for amoxicillin–clavulanate and negative for ceftriaxone and hydrocortisone. Given these results and the suspicion of a primary aminopenicillin involvement, an intravenous drug provocation test (DPT) with ceftriaxone was performed. An immediate urticarial reaction occurred, requiring intramuscular adrenaline, considering both the severity of the index reaction and concomitant beta-blocker therapy. Subsequent skin testing became positive to ceftriaxone. A DPT with meropenem (cumulative dose 1 g IV) was negative.

Conclusion

This case represents a rare presentation of immediate IgE-mediated MDHS involving aminopenicillins and third-generation cephalosporin, in the context of simultaneous exposure. Tolerance to carbapenems excludes hypersensitivity mediated by the shared β-lactam ring, favoring MDHS over classical cross-reactivity. This case highlights the critical role for structured allergological investigation and careful mechanistic interpretation of severe reactions occurring under concomitant drug administration.