Abstract
In children with Epstein-Barr virus (EBV) infection, rash following amoxicillin use may resemble a viral exanthem, yet drug hypersensitivity must also be considered. We report the case of a previously healthy 13-month-old boy who developed a generalized erythematous maculopapular rash while on amoxicillin for otitis media and tonsillitis. EBV infection was confirmed by polymerase chain reaction. The rash resolved with supportive care. Three months later, the patient underwent allergy evaluation due to the severity of the initial eruption. Skin prick, intradermal tests, and specific IgE to beta-lactams were negative. However, four hours after an oral amoxicillin challenge, he developed periorificial and acral edema, consistent with a non-immediate hypersensitivity reaction. The challenge with cefuroxime was negative. This case highlights the potential of EBV to contribute as a cofactor in beta-lactam sensitization, even when the initial clinical presentation mimics a classical viral exanthem. Clinicians should consider reevaluation in children presenting with severe or atypical rashes during EBV infection, as drug provocation testing remains essential for distinguishing benign viral rashes from true allergic reactions.