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Non–B-Lactam Antibiotic Hypersensitivity Reactions

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Non–B-Lactam Antibiotic Hypersensitivity Reactions Non–b-Lactam Antibiotic Hypersensitivity Reactions Lisa Grinlington, MBBS, BPharm,a,b Sharon Choo, MBBS, FRACP FRCPA,c Noel Cranswick, MBBS, BMedSc, MSS, LLB,a,d,e Amanda Gwee, MBBS, FRACP, PhDa,d,e OBJECTIVES: Antibiotics are among the most common prescriptions in children, and non–b- abstract lactam antibiotics (NBLAs) account for almost half of those prescribed in Australian pediatric hospitals. Despite this, data on NBLA hypersensitivity in children are limited. This study describes reported hypersensitivity reactions to NBLAs in children and the results of allergy evaluation. METHODS: Children with a suspected NBLA allergy who had skin testing and/or an intravenous or oral challenge test (OCT) between May 2011 and June 2018 were included. Patients were excluded if they were .18 years old or did not complete the allergy evaluation for any reason other than allergic reaction. RESULTS: Over the 7-year study period, 141 children had 150 allergy evaluations of 15 different NBLAs. The median time from the initial reported reaction to allergy evaluation was 1.9 (range 0.1–14.9) years. Overall, 27 of the 150 (18.0%) challenge tests to NBLAs had positive results, with the rate of positive OCT results being highest for trimethoprim-sulfamethoxazole (15 of 46; 32.6%) and macrolides (8 of 77; 10.4%). Although 4 children reported initial anaphylactic reactions, no patients had severe symptoms on rechallenge or required adrenaline. Of the challenges that had positive results, the majority of children (23 of 27; 85.2%) had symptoms on repeat challenge similar to those that were initially reported. CONCLUSIONS: Overall, 8 of 10 children with NBLA allergy could be delabeled. On average, patients waited 1.9 years to be rechallenged. Timely access to allergy evaluation to delabel these patients is needed to preserve first-line antibiotics. Departments of aGeneral Medicine and cAllergy and Immunology, The Royal Children’s Hospital Melbourne, WHAT’S KNOWN ON THIS SUBJECT: Non–b-lactam Parkville, Victoria, Australia; bMonash Health, Clayton, Victoria, Australia; dDepartment of Paediatrics, The antibiotics are commonly prescribed in the pediatric University of Melbourne, Parkville, Victoria, Australia; and eMurdoch Children’s Research Institute, Parkville, population; however, data on the risk of Victoria, Australia hypersensitivity reactions are largely unknown. Drs Grinlington and Gwee analyzed and interpreted the data; Dr Choo coordinated the acquisition of WHAT THIS STUDY ADDS: This large retrospective data; and all authors conceptualized and designed the study, drafted the initial manuscript, study suggests that ∼1 in 5 children with a reported reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be –b accountable for all aspects of the work. non -lactam antibiotic allergy had a true allergy, with trimethoprim-sulfamethoxazole and macrolide DOI: https://doi.org/10.1542/peds.2019-2256 antibiotics being the most frequently implicated. Accepted for publication Oct 17, 2019 Timely access to allergy evaluation is recommended. Address correspondence to Amanda Gwee, MBBS, FRACP, PhD, Infectious Diseases Unit, Department of General Medicine, The Royal Children’s Hospital Melbourne, 50 Flemington Rd, Parkville, VIC 3052, Australia. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to To cite: Grinlington L, Choo S, Cranswick N, et al. Non–b- this article to disclose. Lactam Antibiotic Hypersensitivity Reactions. Pediatrics. 2020;145(1):e20192256 FUNDING: No external funding. Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 1, January 2020:e20192256 ARTICLE Adverse drug reactions to TABLE 1 Classification System for Allergic Reactions antiinfective agents are reported in up Immediate Nonimmediate to one-third of the pediatric Severe Respiratory compromise (including wheeze and Severe cutaneous adverse reactions 1,2 population. This has been shown to bronchospasm) Mucosal lesions impact costs to the health system Angioedema Serum sicknesslike reaction through the prescription of more Anaphylaxis Exfoliative dermatitis or extensive skin expensive drugs as well as the use of Extensive urticaria desquamation Arrhythmia or cardiovascular collapse Cytopenia second-line broad-spectrum Hypotension or symptoms of end-organ Organ involvement (eg, acute interstitial 3–5 antibiotics. Extensive pediatric hypoperfusion nephritis) data exist on drug hypersensitivity Nonsevere Isolated urticaria or mild rash Itching reactions to b-lactam antibiotics; Persistent gastrointestinal symptoms and signs Isolated exanthem (maculopapular however, studies of hypersensitivity (including vomiting and abdominal cramps) eruption or unknown childhood history) to non–b-lactam antibiotics (NBLAs) are limited. In a previous pediatric study of NBLA allergies, 4.7% of children evaluated by using an 7 years and 1 month (between May 1 hour or more intradermal test (IDT) and/or oral 2011 and June 2018). We included postadministration.4,11,12 Symptoms challenge test (OCT) had a confirmed children who had a suspected NBLA were further classified as severe or allergy. However, the rate of NBLA allergy and had a skin test (including nonsevere (Table 1).12 Patients who allergies was 15.6% when those skin prick test [SPT] or IDT) and/or had symptoms suggestive of an children who were diagnosed solely intravenous test or OCT during the immediate severe immunoglobulin E on the basis of history were included, study period. Data were entered into (IgE)–mediated allergy and/or with macrolides and sulfonamides a Research Electronic Data Capture anaphylaxis (involvement of $2 being the most frequently database. organ systems and/or hypotension) implicated.6 had skin testing before intravenous ’ The Royal Children s Hospital tests or OCT. All patients were Of all antibacterial prescriptions in 8 Melbourne is a tertiary pediatric advised to avoid antihistamines for Australian hospitals in 2015, 33.0% referral center and runs the only 7 days before any testing. were for NBLAs.7 Despite this, there is pediatric drug allergy service in a current paucity of data on the Victoria, Australia. Patients are Standard drug test volumes and clinical presentation and frequency of reviewed in an outpatient clinic concentrations were used for both true NBLA allergies in children. before admission to the day medical SPT and IDT, with isotonic saline and Furthermore, for some NBLAs, such unit for skin testing and/or histamine at 10 mg/mL being used as as sulfonamides, an inappropriate intravenous tests or OCT if indicated. positive and negative controls, 13–15 label of a drug allergy often results in respectively. After SPT, mean the exclusion of a broad range of The outpatient review includes wheal diameter was recorded at 15 other sulfur-containing drugs (such a detailed clinical history from the and 20 minutes for the histamine and as cyclooxygenase-2 inhibitors and parents or caregivers of the reported allergen, respectively, with a diameter loop and thiazide diuretics) despite reaction including the prescribed of $3 mm being considered a positive 16 the unlikely cross-reactivity with antibiotic and formulation, result. IDT for patients with nonantibiotic sulfonamide concomitant medications, indication a negative SPT result involved medications.8,9 We therefore for treatment, age at the time of intradermal injection of 0.02 mL of reviewed the clinical presentation reaction, nature and timing of the test allergen at concentrations of 1/ and results of allergy evaluation onset of symptoms, and management. 100th initially, followed by 1/10th procedures for all children who Coexisting medical conditions and of the maximum recommended 16 presented to a tertiary pediatric family history of atopy are also dose. A wheal and flare were hospital with a suspected NBLA routinely recorded. measured and recorded at time 0 and 20 minutes, with an increase in wheal allergy. Patients were classified as having an diameter of $3 mm being considered immediate reaction or nonimmediate positive.16 reaction on the basis of the timing of METHODS symptoms. An immediate reaction The inpatient oral and intravenous This was a retrospective study of was defined as symptoms developing challenge protocols are described in children ages 0 to 18 years at within 1 hour after drug Tables 2 and 3, respectively. Patients a tertiary pediatric hospital in administration.4,10,11 Nonimmediate who were thought to have rate- Melbourne, Australia, over a period of reactions were those that occurred related allergic-type symptoms Downloaded from www.aappublications.org/news by guest on September 30, 2021 2 GRINLINGTON et al TABLE 2 Inpatient Oral NBLA Challenge Protocol TABLE 4 Home Continuation Regimen for Oral NBLA Time, Min Dose Antibiotic Frequency Days Challenged 0 1/100th of top dose Daily Days 2–7: top dose daily 45 1/10th of top dose Twice daily Day 2: top dose daily 90 Top dose Days 3–7: top dose twice daily 3 times daily Day 2: top dose daily Day 3: top dose twice daily Days 4–7: top dose 3 times daily secondary to an intravenous NBLA 4 times daily or until course is Day 2: top dose daily were given a graded infusion in which completed Day 3: top dose twice daily Day 4: top dose 3 times daily the full dose was given over 4 to Days 5–7: top dose 4 times daily or until course is 6 hours, starting at a slow rate and completed increasing every 30 minutes. Patients were observed for 3 hours after the top dose, after which the antibiotic 1–2), and the median time from nonimmediate) and suspected was continued at home for 3 to 5 days reported reaction to testing was 1.9 anaphylaxis in 4 patients (Table 4). The top dose was defined (range 0.1–14.9) years. (characterized by 1 or more of the as the maximum appropriate dose as following: hypotension, respiratory recommended by the Australian The NBLAs to which an allergy was 17 compromise, involvement of the skin- Medicines Handbook.
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