Establishing Amoxicillin Allergy in Children Through Direct Graded Oral Challenge (GOC): Evaluating Risk Factors for Positive Challenges, Safety, and Risk of Cross-Reactivity to Cephalosporines

J Allergy Clin Immunol Pract. 2021 Nov;9(11):4060-4066. doi: 10.1016/j.jaip.2021.06.057. Epub 2021 Jul 19.


Background: Data on the diagnostic properties of direct oral challenges without the use of skin tests in children with suspected amoxicillin allergy are sparse.

Objective: Assess the use of direct oral challenges.

Methods: A cohort study was conducted between March 2013 and March 2020, in Montreal and Winnipeg. All children referred with reported history of benign reactions (ie, limited to the skin with no mucosal lesions and no vesicles) to amoxicillin were recruited and a 2-step graded oral challenge (GOC) was conducted. Data were collected on demographic characteristics, clinical characteristics, and comorbidities. Eligible children were followed to assess reactions to subsequent use of amoxicillin and to assess the safety of cephalexin use in children with a positive GOC.

Results: Among 1914 children recruited, 1811 (94.6%) tolerated the GOC, 42 (2.2%) developed mild immediate reactions, and 61 (3.2%) developed mild nonimmediate reactions. Among 265 participants who had a negative GOC and reused amoxicillin, 226 (85.3%) reported tolerance and 39 (14.7%) had mild cutaneous reactions. Chronic urticaria (adjusted odds ratio [aOR], 1.16; 95% CI, 1.09-1.23) and an index reaction occurring within 5 minutes of exposure (aOR, 1.09; 95% CI, 1.04-1.14) were associated with immediate reactions during the GOC. Symptoms lasting longer than 7 days (aOR, 1.05; 95% CI, 1.02-1.09) and parental drug hypersensitivity (aOR, 1.04; 95% CI, 1.03-1.06) were associated with nonimmediate reactions. Among those reacting to the GOC, 12.5% reacted with mild cutaneous reactions to cephalexin challenge.

Conclusions: Direct GOCs are an accurate and safe confirmatory to establish true hypersensitivity among children reporting benign reactions to amoxicillin.

Keywords: Amoxicillin; Cephalosporines; Cross-reactivity; Diagnosis; Hypersensitivity; Oral challenge; Pediatric; Safe; β-lactam.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amoxicillin / adverse effects
  • Anti-Bacterial Agents* / adverse effects
  • Child
  • Cohort Studies
  • Drug Hypersensitivity* / diagnosis
  • Drug Hypersensitivity* / epidemiology
  • Humans
  • Risk Factors
  • Skin Tests


  • Anti-Bacterial Agents
  • Amoxicillin

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