TOPLINE:

A 5-day amoxicillin challenge was feasible for evaluating delayed penicillin allergy, with more than 80% of participants completing the protocol; immune‑mediated reactions were uncommon but occurred more often with prolonged dosing.

METHODOLOGY:

• Investigators conducted a randomized trial enrolling 169 participants with delayed-onset (≥ 2 hours after exposure) or unknown-timing penicillin allergy who tolerated an initial single-dose oral amoxicillin challenge to assess the feasibility and safety of a prolonged vs single‑dose oral amoxicillin challenge.
• Of these participants, 120 were randomly assigned to receive either 500 mg amoxicillin administered orally twice daily for 5 days (intervention group; n = 60; mean age, 51 years; 62% women) or placebo administered orally twice daily for 5 days (control group; n = 60; mean age, 47.9 years; 78% women).
• The primary outcomes were adherence to the intervention (percentage of participants taking ≥ 80% of drug doses), need for unblinding, and recruitment feasibility (percentage of eligible patients enrolled).

TAKEAWAY:

• Overall, adherence to the intervention was 83.3%. No participants were unblinded during the trial, and the recruitment-to-eligibility ratio was 71%.
• A total of 11 immune-mediated adverse events — eight in the intervention group and three in the control group — were reported during the 14-day follow-up period.
• One serious adverse event occurred in the control group and was managed with oral antihistamines and systemic glucocorticoids.
• Positive oral challenges occurred in 11.7% of participants in the intervention group vs 5.0% of participants in the control group.

IN PRACTICE:

"Our findings support the feasibility of utilizing this trial design in future definitive trials to fully assess the efficacy of single-dose vs prolonged oral challenges in identifying delayed-onset drug allergy," the authors of the study wrote.

"Such efficacy data may support clinicians to more accurately weigh the risks and benefits of different penicillin testing strategies alongside allergy assessment accuracy, antimicrobial stewardship, and practicality and allow for more fully informed consent for their patients," they added.

SOURCE:

The study was led by Morgan Rose, PhD, Austin Health, Heidelberg, Australia. It was published online on February 24, 2026, in NEJM Evidence.

LIMITATIONS:

This study had a small sample size and was restricted to adults at an urban teaching hospital in a single country. Additionally, only a few moderate‑ or high‑risk allergy phenotypes were included.

DISCLOSURES:

This study was funded by Austin Health and supported by a fellowship award. Additionally, it was supported by the Peter MacCallum Cancer Centre (Victoria, Australia), St George Hospital (New South Wales, Australia), and the Royal Brisbane and Women's Hospital (Queensland, Australia). One author reported receiving a grant from Merck Sharp & Dohme.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.