Discussion

In this retrospective birth cohort study of over 360,000 children from 90 pediatric primary care practices, 0.9% of children were labeled as cephalosporin allergic, most commonly due to third-generation cephalosporin allergies. Children were labeled young, and those with a penicillin allergy label were more likely to have a cephalosporin allergy label. Children with cephalosporin allergy labels were prescribed different antibiotics for treatment of AOM than non-allergic peers.

The prevalence of cephalosporin allergy labels in this study is similar to prior studies and lower than the prevalence of penicillin allergy labels among children in this cohort. ^{Reference Macy and Poon3,Reference Taylor, Joerger and Li5} The difference in allergy labeling rates between penicillins and cephalosporins may be related to a differential propensity to cause hypersensitivity reactions among beta-lactams with differing R₁ side chains or lower rates of cephalosporin antibiotic prescribing in primary care settings. ^{9,Reference Wong, Seger, Lai, Goss, Blumenthal and Zhou11,Reference Khan, Banerji and Bernstein12} Additionally, when a child develops a rash or other adverse reaction, it is possible that pediatricians may be less likely to label a child as allergic when a cephalosporin is prescribed and place more scrutiny on a reaction given a perceived lack of alternative antibiotics to treat subsequent infections. Our study suggests that future research examining beta-lactam antibiotic allergies should distinguish between penicillin and cephalosporin allergies and avoid combining these two drug classes to better understand the differences between them.

Children with a penicillin allergy label were more likely to be labeled as cephalosporin allergic than those without a penicillin allergy label. One potential explanation for this finding is that children with a penicillin allergy label are more likely to be prescribed a cephalosporin than their non-allergic peers, which may increase the future risk of obtaining a cephalosporin allergy label. ^{Reference Joerger, Taylor, Li, Palazzi and Gerber7} In addition, since most patients labeled as penicillin allergic can tolerate penicillin antibiotics, and only 2% of children with a true penicillin allergy label are expected to have cross re-activity with cephalosporins, these dual labeled patients could represent a group of children that are more prone to viral and/or drug-mediated non-IgE rashes, or more likely to seek care for adverse events than children without these allergy labels. ^{Reference Norton, Konvinse, Phillips and Broyles4,Reference Vyles, Adams, Chiu, Simpson, Nimmer and Brousseau6} Children were also more likely to acquire a cephalosporin allergy label if they were White, had private insurance, had a complex medical condition, or increased healthcare utilization, similar to the risk factors for acquiring a penicillin allergy label. ^{Reference Taylor, Joerger and Li5} The reasons behind these racial disparities are unclear but may include differential antibiotic prescribing practices among health care providers and unequal access to healthcare. ^{Reference Gerber, Prasad and Localio13–Reference Gilliam and Joerger15}

As with children labeled as penicillin allergic, children labeled as cephalosporin allergic were infrequently de-labeled in this study. A recent study examining reported cephalosporin allergies in children seen in a pediatric emergency department found that nearly 60% had reaction histories that were low-risk for being IgE or T-cell mediated processes, indicating that a large proportion of children labeled as cephalosporin allergic would be good candidates for drug challenge and potential de-labeling. ^{Reference Zembles, Zhan, Chiu, Brousseau and Vyles16} Reasons behind low rates of cephalosporin allergy de-labeling are not clear but may include: less emphasis on cephalosporin allergies and less awareness of consequences of cephalosporin allergy labels as compared to penicillin allergy labels. Future research should determine reasons for low rates of cephalosporin allergy de-labeling and identify ways to increase rates of de-labeling. Lastly, children with both penicillin and cephalosporin allergy labels were more likely to be de-labeled than children with only cephalosporin allergy labels. We hypothesize that physicians are more likely to refer to an allergist or otherwise evaluate an allergy label when they run out of antibiotic options. This hypothesis should be further evaluated.

The American Academy of Pediatrics recommends amoxicillin as first line for AOM, except if the child has taken amoxicillin in the previous 30 days, if concurrent conjunctivitis is noted, or if the child is allergic to penicillin. ^{Reference Lieberthal, Carroll and Chonmaitree17} We hypothesized that children with third-generation cephalosporin allergies would be prescribed amoxicillin at the same rate as children without beta-lactam allergies given the limited cross-reactivity between third-generation cephalosporins and amoxicillin. ^{Reference Chaudhry, Veve and Wagner18,Reference Khan, Banerji and Blumenthal19} However, we found that nearly 30% of patients with a third-generation cephalosporin allergy were given amoxicillin/clavulanate instead of amoxicillin. Some children may have had concurrent conjunctivitis, and we cannot exclude that some patients failed amoxicillin prescribed at a clinic outside of the CHOP or TCP health systems, but we suspect these to be uncommon in this birth cohort and similar between the third-generation cephalosporin allergic and non-allergic groups. Physicians frequently prescribe broader spectrum antimicrobial agents than are needed, despite lack of benefits and increased adverse events. ^{Reference Gerber, Ross and Bryan20} Despite suboptimal antibiotic susceptibility rates and American Academy of Pediatrics guideline recommendations advising against using macrolides for AOM, macrolides were prescribed in 10% of children with a cefdinir allergy, 22% with a penicillin allergy, and 71% of children with both allergy labels. ^{Reference Lieberthal, Carroll and Chonmaitree17,Reference Hoberman, Dagan and Leibovitz21} Given the limited efficacy of macrolides against typical AOM pathogens, children with cephalosporin allergies should be referred to allergy specialists for formal evaluation in order to optimize future prescribing.

Assuming a pediatric population of 80 million, and a prevalence of 0.9%, it can be estimated that more than 700,000 children in the United States have a cephalosporin allergy label. ²² The presence of a penicillin allergy increases the rate of broad-spectrum antibiotic prescribing and antibiotic-related costs in children hospitalized with pneumonia. ^{Reference Jones, Fino, Olson and Hersh23} In adults, beta-lactam allergies also increase the rate of bacteremia treatment failure and rates of adverse events such as acute kidney injury and Clostridioides difficile infection. ^{Reference Blumenthal, Parker, Shenoy and Walensky24–Reference MacFadden, LaDelfa and Leen26} Future studies should examine the impact of cephalosporin allergy labels on children treated for outpatient infections.

The strengths of this study include its large sample size of over 300,000 children cared for in 90 primary care clinics across three states and two health systems. These patients represent a racially, socioeconomically, and geographically diverse population, which increases generalizability. Limitations of this study include its dependance on EHR data; therefore, factors that may have influenced care decisions that were not included in the variables examined cannot be accounted for. In addition, we cannot exclude that some patients received care outside of the CHOP or TCP systems, however, the birth cohort design with strict censoring criteria likely minimized this limitation.