Direct challenges are safe and effective in children with low-risk allergies to oral cephalosporins

Cephalosporin allergy labels (CALs) affect 0.5% to 3% of children, and many are acquired by age 4 years.¹ Cephalosporins are the most common alternative antibiotic choice for those with a penicillin allergy label (PAL), and approximately one third of those with a CAL have a dual PAL and CAL, which can significantly limit antibiotic choices.¹ The optimal evaluation strategy for CAL is not well established. Skin testing with cephalosporins is not validated or studied to the same degree as penicillin skin testing.² β-Lactam skin testing can have higher false-positive rates compared with direct challenge, especially in children.³ There may be a lower pretest probability of IgE-mediated reactions to oral cephalosporins compared with parenteral cephalosporins.⁴ Therefore, skin testing may not be an ideal diagnostic tool for children with non-anaphylactic reactions to oral cephalosporins. Direct oral challenge without preceding skin testing has been established as safe, effective, and recommended in evaluating non—high risk PAL.⁵ This approach has been applied to pediatric CAL at single centers.^6–8 However, broader studies evaluating the safety and efficacy of this approach are lacking. We undertook a multicenter study evaluating the safety and efficacy of direct challenges to oral cephalosporins in children at four institutions in the United States.

We completed a retrospective chart review for children seen between January 2018 and December 2024 who underwent a direct oral challenge with culprit cephalosporins per institution protocol. Cincinnati Children’s protocol includes single-dose challenge to cefdinir and two-step graded challenge to cefprozil. Phoenix Children’s, University of Texas Southwestern’s, and Vanderbilt University Medical Center’s protocols consist of two-step graded challenges, with standardized weight-based dosing published by Accarino et al.⁹ All challenges were completed in outpatient allergy clinics under the supervision of allergy specialists (physicians or advanced practice providers). Using a risk-stratification approach, as described by Koo et al,⁷ children were eligible for direct oral challenge if they were not considered to be at high risk by the history obtained and by the clinical judgment of the allergy specialist during evaluation. High risk was defined as a history of anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, fixed drug eruption, or end-organ damage.⁷ We conducted a descriptive statistical analysis. The study was approved by the institutional review boards across all participating institutions with waiver of consent for chart review and approval to share deidentified information for multisite comparison.

Across four institutions, 313 children underwent 314 direct oral challenges to culprit cephalosporins median age 7.5 years; interquartile range, 7.3 years; nearly equal females and males; 77% self-reported as White, 17% as Hispanic or Latino, and 6% as Black (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org). Multiple drug allergy labels were seen in 214 children (68%), including 181 with both PAL and CAL (58%) and 80 with an additional non—β-lactam antibiotic allergy label (26%). Sixty-seven (21%) reported a family history of drug allergy. The most frequent indication for taking the cephalosporin was acute otitis media. Moreover, 99 children (32%) experienced the reaction in the past year. Most children (95%) reported nonimmediate cutaneous symptoms (>1 hour after dose) such as urticaria, maculopapular eruption, or other rashes (Table I). Interestingly, 73 children (23%) reported a history of chronic spontaneous urticaria, dermatographism, or acute urticaria with infections. This cohort included 20 children (6.4%) who initially received a diagnosis of acute urticarial disorders typical with joint involvement (formerly known as serum sickness-like reaction), 13 (4.1%) with acute urticarial disorders fixed (urticaria multiforme or erythema multiforme), and 47 (15%) with angioedema as part of the index reaction. Cefdinir (263 of 314; 84%) was the most frequently challenged, followed by cephalexin (14%).

Of the 314 challenges, 306 were asymptomatic (97.5%). All eight children developed symptoms mild cutaneous-only reactions and five were treated with oral antihistamines (Table II). No patients required epinephrine. Through chart review, 54 children (17%) were identified who tolerated subsequent courses of cephalosporin antibiotics after the challenge, without relabeling.

To our knowledge, this is the largest report of direct oral cephalosporin challenges reported in children, and the generalizability is strengthened by its multisite protocol. These results are reassuringly similar to other reported cohorts of asymptomatic direct cephalosporin challenges in children: Sillcox et al⁶ in Canada (123 of 136; 90.4%), Koo et al⁷ in the United States (105 of 106; 99%), and Kuzucu et al⁸ in Turkey (123 of 128; 96.1%). Unlike other cohorts, which excluded high-risk histories, Sillcox et al included two children with an index reaction of anaphylaxis, one of whom developed anaphylaxis on cephalexin rechallenge. Thus, growing evidence supports that children with a low-risk oral cephalosporin allergy can be challenged directly without the need for skin testing, in alignment with the suggested guidance in the revised drug allergy practice parameters.⁵

In terms of limitations, as a retrospective chart review, information regarding the reaction history and medical and family history may have been incomplete. The requirement for patients, caregivers, and health care providers to agree to the oral challenge may have resulted in bias toward those with milder symptoms. The high asymptomatic challenge rate observed may in part reflect selection bias, which is inherent in risk stratification strategies and may not be generalizable across all cephalosporin index reaction phenotypes. Further studies evaluating all children with CALs may provide additional insight regarding the degree of this bias. Because these institutions are referral centers, the number of children tolerating subsequent courses may have been underestimated. Many patients returned to community care, had no further visits after delabeling, and were not observed beyond the initial period that captured nonimmediate symptoms after challenge. With children who had a symptomatic challenge, it is interesting that the reaction was different from what was reported as the index reaction. Whether this indicates errors in recall, it suggests noncausality of the medication, or it provides information about the mechanisms involved in pediatric drug allergy needs further exploration.

This study demonstrates that direct cephalosporin oral challenges can be safe, practical, and effective in delabeling children who report a cephalosporin allergy without a high-risk history of anaphylaxis or severe cutaneous adverse reactions. This evaluation is crucial for children to allow for appropriate antibiotic prescribing, because we saw a high rate of multiple antibiotic labels in these children. We encourage a proactive approach to CALs in children given the low rate of confirmation.