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J Allergy Clin Immunol Pract. 2019 Jan;7(1):236-243. doi: 10.1016/j.jaip.2018.05.008. Epub 2018 May 23.

Safety and Outcomes of Oral Graded Challenges to Amoxicillin without Prior Skin Testing.

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Division of Allergy and Immunology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
Division of Allergy and Clinical Immunology, Johns Hopkins Hospital, Baltimore, Md.
Department of Otorhinolaryngology, Montefiore Medical Center, Bronx, NY.
Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY.
Division of Allergy and Immunology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. Electronic address:



Unconfirmed penicillin allergy poses substantial public health consequences. The most widely accepted protocol to evaluate penicillin allergy is skin testing followed by an amoxicillin challenge.


To evaluate the safety of direct oral graded challenges to amoxicillin.


A prospective single-blind clinical trial with historical controls of patients ≥7 years old with historical non-life-threatening reactions to penicillin was conducted. Patients received placebo followed by a 2-step graded challenge to amoxicillin. The allergic reaction rate was compared with the rate observed in our previous study that included skin testing and with the currently reported penicillin allergy prevalence in the US population.


Of the 155 participants who completed an amoxicillin challenge, 120 patients (77.4%) experienced no reaction whereas 31 patients (20%) experienced nonallergic reactions to either placebo (n = 16) or amoxicillin (n = 15). Four patients (2.6%) developed mild allergic reactions. Significantly (P = .03) fewer patients (4 of 155, 2.6%, 95% confidence interval [CI]: 1.0%, 6.5%) were determined to be allergic compared with 14 of 170 subjects (8.2%, 95% CI: 5.0%, 13.4%) in our previous study where patients were determined to be allergic based on either positive skin tests (n = 11) or allergic challenge reactions after negative skin tests (n = 3). This 2.6% reaction rate was also significantly less than the 10% reported US prevalence of penicillin allergy (P = .003).


Placebo-controlled oral graded challenges to amoxicillin without prior skin testing may be safe for patients ≥7 years old with non-life-threatening historical reactions to penicillin. Amoxicillin can be tolerated by the majority of patients with self-reported penicillin allergy.


Adverse drug reaction; Drug provocation test; Graded challenge; Hypersensitivity reaction; Penicillin allergy; Placebo


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