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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
*Both authors contributed equally.

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, Spain
4Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, 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, Spain
8Departamento de Medicina, Universidad de Málaga, Spain
9Facultad de Medicina, Universidad Complutense de Madrid, Spain

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

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

Key words: Amoxicillin-Clavulanic acid, Drug allergy, Immediate reaction, Intradermal test, Non-immediate reaction