Macrolide-induced hypersensitivity reactions in the pediatric population

Macrolides are widely prescribed antibiotics in pediatric practice and are commonly used as alternatives in children with suspected or confirmed beta-lactam allergy. Although generally considered safe and associated with low allergenic potential, hypersensitivity reactions to macrolides do occur and may lead to inappropriate drug avoidance. This review critically appraises the current evidence on macrolide-induced hypersensitivity reactions in the pediatric population, focusing on clinical manifestations, diagnostic approaches, cross-reactivity, and management strategies. Hypersensitivity reactions to macrolides are estimated to occur in 0.4–3% of treatments, with immediate reactions such as urticaria and angioedema being the most frequently reported. Anaphylaxis is exceedingly rare, while delayed reactions, particularly maculopapular exanthema, represent the most common non-immediate presentations. Severe cutaneous adverse reactions, including Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, and fixed drug eruptions, have been reported but remain exceptional in children. The diagnostic workup of suspected macrolide allergy is challenging due to the limited sensitivity and poor predictive value of skin tests and the lack of validated in vitro assays. Current evidence supports the use of drug provocation tests as the gold standard for diagnosis, particularly in children with non-severe, skin-limited reactions. Recent guidelines increasingly favor direct oral challenge without prior skin testing in low-risk pediatric patients. Studies consistently demonstrate that most children with suspected macrolide allergy tolerate re-exposure, confirming that true allergy is uncommon. Cross-reactivity among macrolides appears to be infrequent in children but may occur, especially in severe reactions. Desensitization protocols, although not standardized, have been successfully applied in selected pediatric cases when macrolides are indispensable. Overall, accurate diagnosis through appropriate testing is essential to avoid unnecessary antibiotic restrictions, ensure optimal antimicrobial therapy, and reduce the burden of incorrect allergy labeling in pediatric patients.