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. Patients were suspected were macrolides (77 of provided with instructions to contact 150; 51.3%), trimethoprim- mucosal tissue, and/or persistent the hospital if any allergic symptoms sulfamethoxazole (TMP-SMX) (46 of gastrointestinal symptoms) requiring developed and were followed up with 150; 30.7%), fluoroquinolones (6 of adrenaline. All 4 patients were via a phone call or outpatient clinic 150; 4.0%), metronidazole (6 of 150; concomitantly treated with multiple review. Any reactions on rechallenge 4.0%), clindamycin (6 of 150; 4.0%), medications, and 3 were inpatients at were classified as previously outlined nitrofurantoin (3 of 150; 2.0%), the time, 1 of whom did not have skin for the initial reaction (Table 1). glycopeptides (2 of 150; 1.3%), testing done before an oral challenge trimethoprim (2 of 150; 1.3%), because it was presumed that the gentamicin (1 of 150; 0.7%), and hypotension was related to a surgical RESULTS doxycycline (1 of 150; 0.7%; procedure. For the 109 patients for Table 6). Of these, 70 (46.7%) whom data on concurrent infection During the study period, 141 children reported an immediate reaction, 76 were recorded, 64 (58.7%) had with 150 suspected NBLA allergies (50.7%) reported a nonimmediate symptoms suggestive of a viral were evaluated (Tables 5 and 6). In reaction, and for 4 patients, the illness. total, 149 oral or intravenous timing of symptoms in relation to challenges were completed, with 4 drug administration was not Four patients had skin testing done having skin testing done before the documented. Of the 70 patients with for suspected severe IgE-mediated challenge. One patient who had reported immediate reactions, 23 reactions before consideration of a positive IDT result did not proceed (32.9%) were taking concomitant OCT. Three of these patients required to an intravenous challenge. Fifteen medications at the time. adrenaline for anaphylaxis on initial different antibiotics were tested, with exposure to metronidazole, 9 children being challenged with 2 The overall median age at the time of vancomycin, or gentamicin, and 1 NBLAs. Of these 141 children, 80 the reported reaction was 5 (range (56.7%) were boys with a median age 0.1–17.0) years. However, 17.3% (26 patient developed a severe reaction at the time of challenge of 7.8 (range of 150) could not recall the age at to TMP-SMX with perioral 1.2–17.6) years. The median number which the initial reaction occurred. angioedema and respiratory of challenges per child was 1 (range Symptoms of reported initial compromise. One patient had 3 reactions were predominantly a borderline-positive IDT result (7 TABLE 3 Inpatient Intravenous NBLA Challenge cutaneous (135 of 150; 90.0%), 9 mm at 20 minutes) for gentamicin Protocol including urticaria (69 of 135; and did not to proceed to a challenge Times, Dose 51.1%), nonspecific rash (38 of 135; test. The remaining 3 patients had Min 28.1%), maculopapular eruption (27 negative SPT and/or IDT results for 0 1/100th of top dose of 135; 20.0%), and erythema TMP-SMX, metronidazole, and 60 1/10th of top dose multiforme (1 of 135; 0.7%). Other vancomycin with subsequent 120 Top dose as either a push or graded reported symptoms included negative oral or intravenous infusion angioedema (20 immediate and 13 challenge results.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 1, January 2020 3 TABLE 5 Patients With Immediate Severe Reactions on Rechallenge Patient Antibiotic Severity Initial Symptoms Challenge Result Challenge Symptoms 75 Bactrim NIR nonsevere Diarrhea, vomiting, and abdominal IR severe Angioedema of the face, leg cramping weakness, red conjunctiva, and abdominal cramping 161 Bactrim NIR nonsevere Generalized urticaria IR severe Chest tightness, generalized arthralgia and myalgia, red conjunctiva and photophobia, vomiting, abdominal cramps, and shortness of breath 142 Erythromycin IR severe Angioedema of the tongue and lips IR severe Angioedema of the tongue and lips 168 Teicoplanin IR severe Lethargy with generalized urticaria IR severe Itchy throat and persistent cough IR, immediate reaction; NIR, nonimmediate reaction.

Overall, 26 of the 149 (17.4%) could not recall the timing of their least 1 antimicrobial medication in challenge results for NBLAs were initial reaction had negative OCT 2015.7 b-lactam antibiotics were the positive and 123 (82.6%) were results. One patient was challenged most frequently dispensed antibiotics negative. The frequency of positive with 2 antibiotics from the same class across all ages; however, NBLAs reactions was highest for TMP-SMX and had a positive OCT result for accounted for a significant (15 of 46; 32.6%) and macrolides (8 erythromycin and a subsequent proportion, with macrolides of 77; 10.4%), all of which were to negative OCT result for accounting for 13.0%, followed by erythromycin. Of the 26 positive roxithromycin. One patient who had tetracyclines (8.0%), TMP-SMX challenge results, 10 were classified a positive challenge for TMP-SMX (5.0%), nitroimidazoles (3.0%), and as IgE-mediated hypersensitivity suspension had a negative challenge fluoroquinolones (1.0%).7 Despite reactions, 4 of which were severe and result for the tablet formulation. this, there are few guidelines on how 6 were nonsevere (Table 6). In to manage NBLA allergies. The addition, there was 1 patient who had For the 16 patients with a positive reported rates of confirmed a positive IDT result for gentamicin nonimmediate reaction on hypersensitivity reactions to NBLAs and was not challenged. TMP-SMX rechallenge, TMP-SMX was the most are highly variable and range from caused the majority of immediate common causative agent (8 of 16; 0.2% to 27.2% in the pediatric reactions on rechallenge (7 of 10; 50%), followed by erythromycin (6 of population. This variability is likely fl 70.0%), followed by erythromycin (2 16; 37.5%), cipro oxacin (1 of 16; due to the different NBLAs of 10; 20.0%) and teicoplanin (1 of 6.3%), and clindamycin (1 of 16; investigated and the various study 10; 10.0%). Patients had varying 6.3%). Nonimmediate reactions were methods used (eg, retrospective combinations of symptoms, including nonsevere in the majority (9 of 16; cohort study versus parental – persistent gastrointestinal symptoms 56.3%), with cutaneous (13 of 16; questionnaire).6,20 23 In our study, (6 of 10; 60.0%), urticaria (4 of 10; 81.3%) and/or gastrointestinal (9 of 18.0% of children had a positive 40.0%), respiratory compromise (4 of 16; 56.3%) symptoms being the most NBLA reaction on rechallenge, which 10; 40.0%), symptoms of end-organ frequently reported. One patient is similar to that previously hypoperfusion (3 of 10; 30.0%), and receiving erythromycin reported reported.6 Whereas the median time angioedema (2 of 10; 20.0%). angioedema of the larynx and lips on from reported reaction to testing was Immediate reactions were treated the fourth day of the oral challenge 1.9 years in our population, the delay with oral antihistamines in 7 of 10 that resolved with oral in confirmation or exclusion of drug patients. No patients had anaphylaxis. antihistamines. The majority of allergy extended up to 14.9 years. patients experienced recurrence of Although there are no data on the fi Of the 69 reactions for which symptoms within the rst 2 days of most appropriate timing of drug immediate symptoms were initially the challenge (11 of 16; 68.8%). challenges in children, ideally, testing reported, 11 (15.9%) had a positive should occur promptly after an initial or equivocal challenge test result, of DISCUSSION reaction. which 5 (45.5%) had immediate symptoms. For the 76 challenges for Antibiotics are the most commonly Antibiotic-allergy labeling can have which nonimmediate reactions were prescribed medications in significant implications for the reported, 15 (19.7%) had positive or children.7,18,19 The Antimicrobial Use patient, hospital, and health care – equivocal challenge test results, of and Resistance in Australia 2017 system.24 27 To date, there have been which 5 were immediate and 10 were report found that 51.0% of all no studies looking specifically at the nonimmediate. All 4 patients who children aged 0 to 4 years received at health economic impact of NBLAs.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 4 GRINLINGTON et al EITISVlm 4,nme ,Jnay2020 January 1, number 145, Volume PEDIATRICS TABLE 6 NBLA Oral and Intravenous Challenge Results Reaction Type IDT Challenge Result Final Diagnosis After Immune Evaluation Initial Reaction Result Immediate Reaction Nonimmediate Reaction Negative Severe Nonsevere Severe Nonsevere Macrolides (n = 77) Immediate No IDT IR, 2 of 77 IR severe (n =16) 1of16 ———15 of 16 NIR, 6 of 77 IR nonsevere (n = 20) ——1 of 20 1 of 20 18 of 20 Negative, 69 of 77 Nonimmediate NIR severe (n =11) — 1of11 — 1 of 11 9 of 11 — Downloaded from NIR nonsevere (n = 29) ——2 of 29 1 of 29 26 of 29 — Insufficient information on timing Nonsevere (n =1) ————1of1 — TMP-SMX (n = 46) Immediate Negative, 1 of 16 IR, 7 of 46 IR severe (n =7) — 1of7 1of7 — 5 of 7 NIR, 8 of 46 www.aappublications.org/news IR nonsevere (n =9) — 2of9 — 1 of 9 6 of 9 Negative, 31 of 46 Nonimmediate NIR severe (n =8) — 1of8 1of8 1of8 5of8 — NIR nonsevere (n = 19) 2 of 19 1 of 19 2 of 19 2 of 19 12 of 19 — Insufficient information on timing Nonsevere (n =3) ————3of3 — Fluoroquinolones (n =6) Immediate No IDT NIR, 1 of 6 IR severe (n =4) ———1 of 4 3 of 4 Negative, 5 of 6 IR nonsevere (n =1) ————1of1 — byguest on September30, 2021 Nonimmediate NIR severe (n =0) ———— — — NIR nonsevere (n =1) ————1of1 — Glycopeptides (n =2) Immediate Negative, 2 of 2 IR, 1 of 2 IR severe (n = 2) 1 of 2 ———1 of 2 Negative, 1 of 2 IR nonsevere (n =0) ———— — — Metronidazole (n =6) Immediate IR severe (n =4) NoIDT ————4 of 4 Negative, 6 of 6 IR nonsevere (n =0) ———— — — Nonimmediate NIR severe (n =2) ————2of2 — NIR nonsevere (n =0) ———— — — Nitrofurantoin (n =3) Nonimmediate NIR severe (n =3) NoIDT ————3 of 3 Negative, 3 of 3 NIR nonsevere (n =0) ———— — — 5 However, 1 retrospective study of 51 582 patients found that when compared with adults without an allergy label, those with a penicillin allergy had increased length of stay, increased use of second-line — — antibiotics, and higher rates of IR, 1 of 1 NIR, 1 of 6 Clostridium difficile 25 Negative, 2 of 2 Negative, 1 of 1 Negative, 5 of 6 infection. Furthermore, increased rates of infection with resistant bacteria, including vancomycin-resistant Final Diagnosis After Immune Evaluation Enterococcus spp. and methicillin- resistant Staphylococcus aureus,have been associated with an antibiotic- allergy labeling.25 Increased mortality

1 of 2 1 of 1 1of1 2of2 1of1 1of1 1of1 rates and intensive care admissions have also been documented.24 The clinical and economic costs to the hospital system as a result of a patient having an antibiotic allergy

1 of 2 ranged from no difference to $609 per patient compared with those without an allergy.28 These results have prompted hospital stewardship programs to incorporate the Nonimmediate Reaction Negative assessment and testing of reported

Challenge Result antibiotic allergies to optimize antibiotic prescribing.25,26 Our results highlight that through drug allergy testing evaluation in children, 8 out of 10 children with an NBLA allergy could be delabeled, therefore preserving first-line antibiotics for these patients. Immediate Reaction ——— ———— ———— ———— ———— ———— ———— — ———— — ———— — ———— — ———— ———— —

Severe Nonsevere Severe Nonsevere Current guidelines on antibiotic- allergy testing in children are highly variable, especially for NBLAs. Graded OCTs are the gold standard and are safe and effective in delabeling

IDT antibiotic allergies; however, the Result NoIDT NoIDT No IDT utility of skin testing for both Positive, 1 of 1

— , not applicable. immediate and nonimmediate reactions is controversial.10,29,30 One study of 64 children who reported cutaneous reactions to clarithromycin underwent skin testing before an OCT, with all patients having =2)

=1) =1) =0) =0) a negative SPT result and 10 having n n n n n =1) =1) =1) =1) =2)

n a positive IDT result (1 at 0.05 mg/ =2) n n n n =6) n =1) =1)

n mL and 9 at 0.5 mg/mL). Of these 10 n n patients, 3 had a positive OCT result Continued (sensitivity 75.0%). Of note, 54 of 60 IR nonsevere ( NIR nonsevere ( IR severe ( IR nonsevere ( IR severe ( IR nonsevere ( IR severe ( IR nonsevere ( IR severe ( NIR severe ( Immediate Nonimmediate Immediate Immediate Immediate children who had negative IDT results Doxycycline ( Initial Reaction Clindamycin ( Trimethoprim ( Gentamicin ( Reaction Type

TABLE 6 IR, immediate reaction; NIR, nonimmediate reaction; also had negative OCT results

Downloaded from www.aappublications.org/news by guest on September 30, 2021 6 GRINLINGTON et al (specificity 90.0%).31 More recently, medication because of ongoing A limitation of this study is its a study of 45 children with a reported concern of a potential repeat reaction retrospective design, and not all allergy to clarithromycin (9 by the patient or primary care patients who reacted to NBLAs within immediate and 36 nonimmediate physician.5,27 this time were referred (or seen) in reaction) found that of 20 children the outpatient clinic. An accurate and who had an IDT (up to 0.05 mg/mL) Data on the potential for cross- thorough documented history was before an OCT, 9 had a positive result, reactions between and within NBLA limited by poor parental recall and all of whom subsequently had classes are limited, especially in variability of detail among clinicians negative OCT results.32 The authors children. Studies of adult populations in their written records. In addition, concluded that skin testing was examining cross-reactivity between not all patients were reviewed as an poorly predictive of a positive OCT macrolide antibiotics have suggested outpatient after the home challenge. result (positive predictive value 0%, that the overall risk is low given the Patients who did not present for negative predictive value 82.0%, difference in the sizes of the lactone follow-up were deemed to have sensitivity 0%, and specificity ring.30,34–38 A study in children a negative result on the basis of the 32 50.0%). Given that skin testing is concluded that azithromycin was instructions outlined in the discharge poorly predictive of a repeat reaction, more allergenic than clarithromycin; summary to represent if the patient further studies have supported the however, it should be noted that those or family were concerned. approach of skin testing only in with positive skin test results did not patients who describe severe proceed to OCT, and patients tested CONCLUSIONS reactions (immediate or with azithromycin had more positive nonimmediate) and those with an This is the largest study of NBLA skin test results (possibly due to the unclear history before an OCT on the allergies in children and found that skin test concentration used or the basis of clinical judgment (ie, the ∼1 in 5 children with a reported properties of the drug itself clinician feels that the risk of a severe NBLA allergy had a true allergy. producing more irritation).15,39 Our hypersensitivity reaction is likely on Allergies to TMP-SMX and macrolides study included 1 patient who had reexposure to the antibiotic).4,10,12 All were the most frequent. Our study other patients would proceed to an a positive OCT result for also highlights the significant delay in OCT without previous skin testing. erythromycin but tolerated the testing and delabeling of NBLA roxithromycin. In clinical practice, it allergy in children. Improved access Studies have shown that despite is reasonable to consider an oral to standardized and reliable allergy patients having a negative challenge challenge to an alternative antibiotic testing protocols to delabel children result for a suspected antibiotic, within the same class, especially if the are urgently needed. Further studies ongoing avoidance of the drug OCT is equivocal. For sulfonamide on the risk of potential cross- continues.5,27 This, in part, is due to antibiotics, the risk of cross-reactivity reactivity within NBLA classes are failure to remove the drug allergy with nonantibiotic sulfur drugs needed, although biochemically, the label from patient files, which results appears low given the significant risk of cross-reactivity appears low. in unnecessary avoidance of the 9,40 antibiotic.33 Another reason for difference in chemical structure. ongoing drug avoidance is poor Despite this, often all sulfur drugs are ABBREVIATIONS communication between different avoided when a patient is suspected health practitioners and of having a sulfonamide antibiotic IDT: intradermal test 9,41 patients.5,27,33 In our study, a copy of allergy. In our study, 15 of 46 IgE: immunoglobulin E the discharge summary outlining the (32.6%) patients had a positive NBLA: non–b-lactam antibiotic test result was sent to the referring reaction to TMP-SMX, a sulfonamide OCT: oral challenge test doctor and the patient whenever antibiotic. These patients were SPT: skin prick test possible. Despite these efforts, 2 instructed to avoid both oral and TMP-SMX: trimethoprim- studies suggested that patients may topical forms of sulfonamide sulfamethoxazole continue to unnecessarily avoid the antibiotics only.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 1, January 2020 7 REFERENCES 1. Osowicki J, Gwee A, Noronha J, et al. 12. Blumenthal KG, Peter JG, Trubiano JA, tests. Int J Clin Pharm. 2015;37(4): Australia-wide point prevalence survey Phillips EJ. Antibiotic allergy. Lancet. 583–591 of the use and appropriateness of 2019;393(10167):183–198 23. Treadway G, Pontani D. Paediatric safety antimicrobial prescribing for children 13. Brockow K, Garvey LH, Aberer W, et al; of azithromycin: worldwide experience. in hospital. Med J Aust. 2014;201(11): ENDA/EAACI Drug Allergy Interest Group. J Antimicrob Chemother. 1996;37(suppl 657–662 Skin test concentrations for C):143–149 2. Star K, Norén GN, Nordin K, Edwards IR. systemically administered drugs -- an 24. Charneski L, Deshpande G, Smith SW. Suspected adverse drug reactions ENDA/EAACI Drug Allergy Interest Group Impact of an antimicrobial allergy label reported for children worldwide: an position paper. Allergy. 2013;68(6): in the medical record on clinical exploratory study using VigiBase. Drug 702–712 Saf. 2011;34(5):415–428 outcomes in hospitalized patients. 14. Otani IM, Kuhlen JL Jr, Blumenthal KG, Pharmacotherapy. 2011;31(8):742–747 3. Langley J, Halperin S. Allergy to Guyer A, Banerji A. A role for 25. Macy E, Contreras R. Health care use antibiotics in children: perception vancomycin epicutaneous skin testing and serious infection prevalence versus reality. Paediatr Child Health. in the evaluation of perioperative associated with penicillin “allergy” in 2002;7(4):233–237 anaphylaxis. J Allergy Clin Immunol hospitalized patients: a cohort study. Pract. 2015;3(6):984–985 4. Norton AE, Konvinse K, Phillips EJ, J Allergy Clin Immunol. 2014;133(3): Broyles AD. Antibiotic allergy in 15. Empedrad R, Darter AL, Earl HS, 790–796 pediatrics. Pediatrics. 2018;141(5): Gruchalla RS. Nonirritating intradermal 26. MacFadden DR, LaDelfa A, Leen J, et al. e20172497 skin test concentrations for commonly Impact of reported beta-lactam allergy prescribed antibiotics. J Allergy Clin 5. Vyles D, Chiu A, Routes J, et al. Antibiotic on inpatient outcomes: a multicenter Immunol. 2003;112(3):629–630 use after removal of penicillin allergy prospective cohort study. Clin Infect Dis. label. Pediatrics. 2018;141(5):e20173466 16. Australian Society of Clinical 2016;63(7):904–910 6. Guvenir H, Dibek Misirlioglu E, Immunology and Allergy. Skin prick 27. Gerace KS, Phillips E. Penicillin allergy Capanoglu M, Vezir E, Toyran M, testing for the diagnosis of allergic label persists despite negative testing. Kocabas CN. Proven non-b-lactam disease: a manual for practitioners. J Allergy Clin Immunol Pract. 2015;3(5): antibiotic allergy in children. Int Arch 2018. Available from: https://www. 815–816 Allergy Immunol. 2016;169(1):45–50 allergy.org.au/hp/papers/skin-prick- testing. Accessed November 6, 2019 7. Australian Commission on Safety and 28. Mattingly TJ II, Fulton A, Lumish RA, et al. The cost of self-reported penicillin Quality in Health Care (ACSQHC). AURA 17. Australian Medicines Handbook Pty Ltd. allergy: a systematic review. J Allergy 2017: Second Australian Report on AMH Children’s Dosing Companion. Clin Immunol Pract. 2018;6(5): Antimicrobial Use and Resistance in Adelaide, Australia: Australian 1649–1654.e4 Human Health. Sydney, Australia: Medicines Handbook Pty Ltd; 2018 ASQHC; 2017 29. Grinlington L, Cranswick N, Gwee A. 18. Justiz Vaillant AA, Zito PM. Question 1: what is the risk of a repeat 8. Strom BL, Schinnar R, Apter AJ, et al. Hypersensitivity Reactions, Immediate. reaction to amoxicillin or Absence of cross-reactivity between Treasure Island, FL: StatPearls; 2018 sulfonamide antibiotics and a cephalosporin in children with sulfonamide nonantibiotics. N Engl 19. Yan J, Hawes L, Turner L, Mazza D, a history of a non-immediate reaction J Med. 2003;349(17):1628–1635 Pearce C, Buttery J. Antimicrobial to amoxicillin? Arch Dis Child. 2017; prescribing for children in primary 102(3):285–288 9. Brackett CC. Sulfonamide allergy and care. J Paediatr Child Health. 2019; 30. Sánchez-Borges M, Thong B, Blanca M, cross-reactivity. Curr Allergy Asthma 55(1):54–58 Rep. 2007;7(1):41–48 et al. Hypersensitivity reactions to non 20. Mori F, Pecorari L, Pantano S, et al. beta-lactam antimicrobial agents, 10. Mill C, Primeau MN, Medoff E, et al. Azithromycin anaphylaxis in children. a statement of the WAO special Assessing the diagnostic properties of Int J Immunopathol Pharmacol. 2014; committee on drug allergy. World a graded oral provocation challenge for 27(1):121–126 Allergy Organ J. 2013;6(1):18 the diagnosis of immediate and nonimmediate reactions to amoxicillin 21. Ibia EO, Schwartz RH, Wiedermann BL. 31. Mori F, Barni S, Pucci N, et al. Sensitivity in children. JAMA Pediatr. 2016;170(6): Antibiotic rashes in children: a survey and specificity of skin tests in the e160033 in a private practice setting. Arch diagnosis of clarithromycin allergy. Ann Dermatol. 2000;136(7):849–854 Allergy Asthma Immunol. 2010;104(5): 11. Australian Society of Clinical 417–419 Immunology and Allergy. Antibiotic 22. Arikoglu T, Aslan G, Batmaz SB, allergy clinical update. 2015. Available Eskandari G, Helvaci I, Kuyucu S. 32. Cavkaytar O, Karaatmaca B, Yilmaz EA, from: https://www.allergy.org.au/hp/ Diagnostic evaluation and risk factors Sekerel BE, Soyer O. Testing for papers/allergic-reactions-to-antibiotics. for drug allergies in children: from clarithromycin hypersensitivity: Accessed November 6, 2019 clinical history to skin and challenge a diagnostic challenge in childhood.

Downloaded from www.aappublications.org/news by guest on September 30, 2021 8 GRINLINGTON et al J Allergy Clin Immunol Pract. 2016;4(2): 36. Romano A, Warrington R. Antibiotic clarithromycin in children with 330–332.e1 allergy. Immunol Allergy Clin North Am. suspected hypersensitivity reaction to – 33. Trubiano JA, Adkinson NF, Phillips EJ. 2014;34(3):489 506, vii macrolides. J Investig Allergol Clin Penicillin allergy is not necessarily 37. Petitto J, Chervinskiy SK, Scurlock AM, Immunol. 2015;25(2):128–132 forever. JAMA. 2017;318(1):82–83 Perry TT, Jones SM, Pesek RD. 40. Zawodniak A, Lochmatter P, Beeler A, Successful clarithromycin 34. Demoly P, Benahmed S, Valembois M, Pichler WJ. Cross-reactivity in drug desensitization in a macrolide-sensitive et al. Allergy to macrolide antibiotics. hypersensitivity reactions to Review of the literature [in French]. pediatric patient. J Allergy Clin – sulfasalazine and sulfamethoxazole. Int Presse Med. 2000;29(6):321–326 Immunol Pract. 2013;1(3):307 308 Arch Allergy Immunol. 2010;153(2): 38. Principi N, Esposito S. Comparative 35. Kruppa A, Scharffetter-Kochanek K, 152–156 Krieg T, Hunzelmann N. Immediate tolerability of erythromycin and newer reaction to roxithromycin and prick test macrolide antibacterials in paediatric 41. Dorn JM, Alpern M, McNulty C, – cross-sensitization to erythromycin and patients. Drug Saf. 1999;20(1):25 41 Volcheck GW. Sulfonamide drug clarithromycin. Dermatology. 1998; 39. Barni S, Butti D, Mori F, et al. allergy. Curr Allergy Asthma Rep. 196(3):335–336 Azithromycin is more allergenic than 2018;18(7):38

Downloaded from www.aappublications.org/news by guest on September 30, 2021 PEDIATRICS Volume 145, number 1, January 2020 9 Non β− -Lactam Antibiotic Hypersensitivity Reactions Lisa Grinlington, Sharon Choo, Noel Cranswick and Amanda Gwee Pediatrics 2020;145; DOI: 10.1542/peds.2019-2256 originally published online December 3, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/145/1/e20192256 References This article cites 36 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/145/1/e20192256#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Allergy/Immunology http://www.aappublications.org/cgi/collection/allergy:immunology_s ub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 30, 2021 Non β− -Lactam Antibiotic Hypersensitivity Reactions Lisa Grinlington, Sharon Choo, Noel Cranswick and Amanda Gwee Pediatrics 2020;145; DOI: 10.1542/peds.2019-2256 originally published online December 3, 2019;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/145/1/e20192256

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2020 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 30, 2021