Simplified drug provocation test assesses nonimmediate amoxicillin reactions in children
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A single therapeutic dose administered on the first day of a drug provocation test could be safe in diagnosing mild nonimmediate reactions to amoxicillin-clavulanic acid, according to a study published in Pediatric Allergy and Immunology.
This single dose would save time because patients would spend less time in the hospital, Giulia Liccioli, MD, of the allergy unit in the department of pediatrics at Meyer Children’s University Hospital in Florence, Italy, and colleagues wrote.
The study involved 354 patients (50.6% boys; mean age at reaction, 4.8 years; standard deviation, ± 3.7 years) with a history of mild nonimmediate reactions to amoxicillin or amoxicillin-clavulanic acid who had a drug provocation test (DPT) at Meyer Children’s University Hospital between Jan. 1, 2016, and Aug. 31, 2021.
According to the researchers, 9.6% of the children had a suspected reaction to amoxicillin, and 90.4% had a suspected reaction to amoxicillin-clavulanic acid. Also, 60% of them had tolerated the drug in the years prior to the index reaction.
There were 23 positive results among the 354 DPTs (6.5%), with two positive results for amoxicillin and 21 for amoxicillin-clavulanic acid. Eleven of these 23 participants had reactions during the first or second day of the DPT at the hospital within 2 to 8 hours of receiving the last dose, with one participant reacting about 30 minutes after the first dose.
Also, 11 of these 23 participants reacted at home between 24 and 48 hours after the last dose on the fifth day of therapy.
Only one participant reacted with urticaria 30 minutes after the first administration of one-tenth of the therapeutic dose.
The researchers further noted that 14 of these 23 participants showed the same cutaneous manifestations described in their history during the DPT. The other participants had skin rashes similar to those reported during their first visit.
These reactions all were mild, the researchers wrote, with seven requiring antihistamine treatment and 16 improving without any therapy. No other associated clinical manifestations or systemic involvement were observed.
Finally, the children with positive DPTs were evaluated a second time, with 16 of the 23 taking a lymphocyte transformation test and six of them getting a positive result. One participant had a patch test, which had a negative result.
Only one of the 354 participants had a positive intradermal test. The DPT with the culprit drug confirmed this result, the researchers found, confirming the poor utility of skin tests for nonimmediate reactions to amoxicillin or amoxicillin-clavulanic acid.
Skipping the intradermal test and directly performing a graded oral DPT is safe, according to the researchers, even when the duration of the DPT is not reported. But because most positive DPTs happened among patients with a history of reactions within 6 hours of the last drug intake, the researchers added, clinical history needs to be correctly collected at the start of the test.
Clinicians also need to pay more attention to patients with a history of reactions occurring up to 6 hours after the last drug dose, the researchers continued, because their findings could not exclude overlap between immediate reactions and nonimmediate reactions. The graded DPT protocol would be appropriate in these cases, the researchers wrote.
Prolonged DPTs increase diagnostic value for nonimmediate reactions, according to the researchers, but they also carry the risk for increases in antibiotic resistance, which is why current literature recommends a more personalized approach to testing.
Specifically, the researchers recommend a direct, single-day DPT with a full dose for patients with a clear history in terms of latency and symptom severity and a graded DPT for those reacting between 1 and 6 hours after the last drug dose.
Perspective
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These findings are mostly in line with what we know about mild skin reactions in children. The vast majority of children will tolerate a reintroduction of amoxicillin or amoxicillin-clavulanate, and skin testing is not helpful in this population. This is becoming more and more standard of practice and is an opportunity to delabel children so they may receive optimal antibiotics as children and as adults.
These findings also are in line with my experience. In the United States, we typically do not use an extended challenge protocol. We usually do a 1 day challenge and have patients monitor for symptoms. It may miss a few patients who would be identified over a challenge of 5 days, but this is typically not worth the risk of antimicrobial resistance or nonallergic antibiotic side effects. Notably, these challenges in the U.S. are done in outpatient allergy clinics, not a hospital. These low-risk evaluations do not need a hospital setting.
Finally, this study is further evidence that children should be referred for evaluation if they have an amoxicillin or amoxicillin-clavulanate allergy label. It would be interesting to follow the patients who did react over time to see if their allergy resolves.
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