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Deconstructing Adverse Reactions to Amoxicillin- Clavulanic Acid: The Importance of Time of Onset

Freundt-Serpa NP1,2*, Salas-Cassinello M3,4*, Gonzalo-Fernández A2, Marchán-Pinedo N1,2, Doña I3,4, Serrano-García I5, Humanes-Navarro AM6, Bogas G3,4, Labella M3,4, Sánchez-Morillas L1,2, Torres MJ3,4,7,8, Fernández-Rivas M1,2,9

1Allergy Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos -IdISSC, Madrid, Spain
2Allergy Research Group, IdISSC, Madrid, Spain
3Allergy Unit, Hospital Regional Universitario de Málaga, Málaga, Spain
4Allergy Research Group, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
5Unidad de Apoyo Metodológico a la Investigación (UAMI), IdISSC, Madrid, Spain
6Preventive Medicine and Public Health Department, Hospital Clínico San Carlos, IdISSC, Madrid, Spain
7Nanostructures for Diagnosing and Treatment of Allergic Diseases Laboratory, Andalusian Center for Nanomedicine and Biotechnology- BIONAND, Málaga, Spain
8Departamento de Medicina, Universidad de Málaga, Málaga, Spain
9Facultad de Medicina, Universidad Complutense de Madrid, Málaga, Spain
*Both authors contributed equally.

J Investig Allergol Clin Immunol 2024; Vol 34(3) : 177-187
doi: 10.18176/jiaci.0896

Background: Amoxicillin-clavulanic acid (AX-CL) is the most consumed ß-lactam antibiotic worldwide. We aimed to establish the different phenotypes of ß-lactam allergy in patients reporting a reaction to AX-CL and to investigate the differences between immediate and nonimmediate onset.
Methods: We performed a cross-sectional retrospective study at Hospital Clínico San Carlos (HCSC), Madrid and Hospital Regional Universitario de Málaga (HRUM), Málaga, Spain. We included patients reporting reactions with AX-CL who underwent the allergy workup between 2017 and 2019. Data on the reported reaction and allergy work-up were collected. Reactions were classified as immediate and nonimmediate with a 1-hour cut-off.
Results: The study population comprised 372 patients (HCSC 208, HRUM 164). There were 90 immediate reactions (24.2%), 252 nonimmediate reactions (67.7%), and 30 reactions with unknown latency (8.1%). Allergy to ß-lactams was ruled out in 266 patients (71.5%) and confirmed in 106 patients (28.5%). The final main diagnosis in the overall population was allergy to aminopenicillins (7.3%), to CL (7%), to penicillin (6.5%), and to ß-lactams (5.9%). Allergy was confirmed in 77.2% and 14.3% of immediate and nonimmediate reactions, respectively, with a relative risk of 5.06 (95%CI, 3.64-7.02) for an allergy diagnosis in those reporting immediate reactions. Only 2/54 patients with a late-positive intradermal test (IDT) result for CL were diagnosed with CL allergy.
Conclusion: Allergy was diagnosed in a minority of the study population. However, given that it was diagnosed 5 times more frequently in patients reporting immediate reactions, this classification proved useful for risk stratification. Late-positive IDT results for CL have no diagnostic value. Therefore, the late IDT reading for CL could be removed from the diagnostic work-up.

Key words: Amoxicillin-clavulanic acid, Drug allergy, Immediate reaction, Intradermal test, Nonimmediate reaction