Direct Challenge Safely Replaces Skin Testing for Pediatric Penicillin Allergy

A recent study showed that a direct drug provocation test can safely replace penicillin skin testing in children who have immediate and delayed reactions.1

“In our study, [drug provocation tests] were positive in three out of twenty patients with a history of immediate reactions and in one patient with a delayed reaction,” wrote investigators, led by Halime Yağmur, from the department of pediatric immunology and allergy at Dokuz Eylul University, in Türkiye. “Considering these findings, in pediatric populations, it may be reasonable to consider omitting certain diagnostic steps, particularly in cases of mild, skin-limited immediate reactions such as urticaria, in order to minimize painful procedures for children.”

A parallel, 2-arm, open-label, multicenter trial had previously shown the safety and efficacy of a direct oral penicillin challenge to assess low-risk penicillin allergies. Participants were eligible if they had a score of < 3 on the PEN FAST, a clinical tool to predict low-risk penicillin allergies. However, the study only included participants aged ≥ 18 years.2

Another recent study showed that direct challenges are just as safe as penicillin skin testing in low-risk pregnant patients.3 100% of patients undergoing a 2-step direct challenge and 93.2% undergoing penicillin skin testing, respectively, received a negative evaluation for penicillin allergy.

Yağmur and colleagues sought to assess the safety and efficacy of direct drug provocation testing without penicillin testing among children aged 0 – 18 years.1 Participants had a suspected penicillin allergy between 2020 and 2023. Investigators collected data on hypersensitivity reaction history, laboratory tests, PEN-FAST scores, and drug provocation test records.

The sample included 75 patients (61.3% males; median age, 4 years [range, 1 – 15 years) with suspected penicillin allergy. Most reactions occurred at home (98.7%) after an oral administration, antihistamines being the most common (56%). Females had significantly more immediate reactions (P < .05).

Urticaria (30.7%) was the most frequent manifestation in immediate reactions, and maculopapular exanthema (33.7%) was the most frequent in delayed reactions. The most frequently implicated drug was amoxicillin-clavulanic acid (85.3%).

Laboratory tests showed the sample had a median total IgE level of 56 IU/mL, a median eosinophil count of 100 mm3/L, and a median eosinophil percentage of 1.6%. Every patient had negative penicillin V- and penicillin G-specific IgE results.

The PEN-FAST scoring algorithm demonstrated a diagnostic performance with an area under the ROC curve (AUC) of 0.701 (95% confidence interval [CI], 0.59 – 0.90). This indicated that the tool could correctly identify true allergy cases in approximately 70% of cases. The PEN-FAST test (cutoff at scores ≥ 3) had a sensitivity of 100%, a specificity of 35%, a positive predictive value of 8%, and a negative predictive value of 100%.

A total of 78 drug provocation tests were performed, and 4 patients tested positive for a penicillin allergy. These patients all experienced mild, non-life-threatening cutaneous reactions. At the 3-month follow-up, 90.7% of patients tolerated betalactam antibiotics; 4% chose not to take them despite their negative drug provocation test.

The team concluded that the findings show drug provocation tests can be performed without skin testing in immediate and delayed reactions. However, they noted that this excludes children with a history of severe reactions.

“We emphasize the need for this strategy to be supported by larger, multicenter studies,” investigators wrote. “As is well known, drug reactions in this age group may often be misdiagnosed due to overlap with infection-related exanthems. Considering the increasing use of alternative antibiotics and the associated risk of resistance, the procedural difficulties children face during in vivo testing, and the implementation of the PEN-FAST scoring system, we believe our study offers a valuable perspective for both clinicians and patients.”

References

1. Yağmur H, Atay Ö, Bakır DB, et al. Evaluation of drug provocation tests without prior skin testing in children with suspected penicillin allergy and correlation with PEN-FAST: A single-center study. Eur J Pediatr. 2025;184(8):488. Published 2025 Jul 17. doi:10.1007/s00431-025-06301-7

2. Copaescu AM, Vogrin S, James F, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023;183(9):944-952. doi:10.1001/jamainternmed.2023.2986

3. Derman, C. 2-Step Direct Amoxicillin Challenge Found Safe in Low-Risk Pregnant Patients. HCPLive. July 21, 2025. https://www.hcplive.com/view/2-step-direct-amoxicillin-challenge-found-safe-in-low-risk-pregnant-patients. Accessed July 22, 2025.

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