Penicillin allergy is an immune reaction that can range from mild manifestations, such as urticaria, to severe reactions like anaphylaxis. The present review emphasizes that penicillin allergy is often overreported, underscoring the necessity for proper diagnostic confirmation to prevent the unjustified use of alternative antibiotics, which can contribute to antimicrobial resistance. Desensitization protocols are reviewed as safe options for patients requiring penicillin therapy. The importance of careful patient management, including allergy documentation, patient education, and desensitization strategies, is underscored for optimizing clinical outcomes.

Distinguishing between true allergic reactions and non-immunological side effects is essential to avoid incorrect labeling and to expand the safe use of penicillins, which are crucial in treating severe infections. Accurate diagnosis allows for management strategies such as periodic re-evaluation, patient education, updated records, and the possibility of desensitization when necessary. Additionally, understanding the role of penicillin metabolites, especially penicilloic acid determinants-minor (5% of metabolites), namely benzylpenicillin (penicillin G), benzylpenicilloate and benzylpeniloate, which are important for understanding the pathogenesis of allergic reactions.

Recent advances in developing more precise diagnostic tests and educating healthcare professionals have been made. Nonetheless, there remain gaps in the complete understanding of immunological mechanisms, particularly regarding cross-reactivity with other beta-lactams, which calls for future research. Implementing systematic protocols and maintaining ongoing awareness are essential to improve clinical safety, reduce antimicrobial resistance, and enhance outcomes for patients with penicillin allergy.