Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children | Allergy and Clinical Immunology | JAMA Pediatrics | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Sidell  D, Shapiro  NL, Bhattacharyya  N.  Demographic influences on antibiotic prescribing for pediatric acute otitis media.  Otolaryngol Head Neck Surg. 2012;146(4):653-658.PubMedGoogle ScholarCrossref
Coker  TR, Chan  LS, Newberry  SJ,  et al.  Diagnosis, microbial epidemiology, and antibiotic treatment of acute otitis media in children: a systematic review.  JAMA. 2010;304(19):2161-2169.PubMedGoogle ScholarCrossref
Seitz  CS, Bröcker  EB, Trautmann  A.  Diagnosis of drug hypersensitivity in children and adolescents: discrepancy between physician-based assessment and results of testing.  Pediatr Allergy Immunol. 2011;22(4):405-410.PubMedGoogle ScholarCrossref
Guéant  JL, Guéant-Rodriguez  RM, Gastin  IA,  et al.  Pharmacogenetic determinants of immediate and delayed reactions of drug hypersensitivity.  Curr Pharm Des. 2008;14(27):2770-2777.PubMedGoogle ScholarCrossref
Bousquet  PJ, Kvedariene  V, Co-Minh  HB,  et al.  Clinical presentation and time course in hypersensitivity reactions to beta-lactams.  Allergy. 2007;62(8):872-876.PubMedGoogle ScholarCrossref
Saxon  A, Beall  GN, Rohr  AS, Adelman  DC.  Immediate hypersensitivity reactions to beta-lactam antibiotics.  Ann Intern Med. 1987;107(2):204-215.PubMedGoogle ScholarCrossref
Sampson  HA, Muñoz-Furlong  A, Campbell  RL,  et al.  Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.  Ann Emerg Med. 2006;47(4):373-380.PubMedGoogle ScholarCrossref
Pichler  WJ.  Delayed drug hypersensitivity reactions.  Ann Intern Med. 2003;139(8):683-693.PubMedGoogle ScholarCrossref
Pavlos  R, Mallal  S, Ostrov  D,  et al.  T cell-mediated hypersensitivity reactions to drugs.  Annu Rev Med. 2015;66:439-454.PubMedGoogle ScholarCrossref
Hari  Y, Frutig-Schnyder  K, Hurni  M,  et al.  T cell involvement in cutaneous drug eruptions.  Clin Exp Allergy. 2001;31(9):1398-1408.PubMedGoogle ScholarCrossref
Caubet  JC, Eigenmann  PA.  Managing possible antibiotic allergy in children.  Curr Opin Infect Dis. 2012;25(3):279-285.PubMedGoogle ScholarCrossref
Atanasković-Marković  M, Velicković  TC, Gavrović-Jankulović  M, Vucković  O, Nestorović  B.  Immediate allergic reactions to cephalosporins and penicillins and their cross-reactivity in children.  Pediatr Allergy Immunol. 2005;16(4):341-347.PubMedGoogle ScholarCrossref
Demoly  P, Adkinson  NF, Brockow  K,  et al.  International consensus on drug allergy.  Allergy. 2014;69(4):420-437.PubMedGoogle ScholarCrossref
Bourke  J, Pavlos  R, James  I, Phillips  E.  Improving the effectiveness of penicillin allergy de-labeling.  J Allergy Clin Immunol Pract. 2015;3(3):365-374.e1.PubMedGoogle ScholarCrossref
Romano  A, Warrington  R.  Antibiotic allergy.  Immunol Allergy Clin North Am. 2014;34(3):489-506, vii.PubMedGoogle ScholarCrossref
Dodiuk-Gad  RP, Laws  PM, Shear  NH.  Epidemiology of severe drug hypersensitivity.  Semin Cutan Med Surg. 2014;33(1):2-9.PubMedGoogle ScholarCrossref
Caubet  JC, Eigenmann  PA.  Diagnostic issues in pediatric drug allergy.  Curr Opin Allergy Clin Immunol. 2012;12(4):341-347.PubMedGoogle ScholarCrossref
Thong  BY, Mirakian  R, Castells  M,  et al.  A World Allergy Organization international survey on diagnostic procedures and therapies in drug allergy/hypersensitivity.  World Allergy Organ J. 2011;4(12):257-270.PubMedGoogle ScholarCrossref
Perry  TT, Matsui  EC, Conover-Walker  MK, Wood  RA.  Risk of oral food challenges.  J Allergy Clin Immunol. 2004;114(5):1164-1168.PubMedGoogle ScholarCrossref
Caubet  JC, Kaiser  L, Lemaître  B, Fellay  B, Gervaix  A, Eigenmann  PA.  The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge.  J Allergy Clin Immunol. 2011;127(1):218-222.PubMedGoogle ScholarCrossref
Romano  A, Caubet  JC.  Antibiotic allergies in children and adults: from clinical symptoms to skin testing diagnosis.  J Allergy Clin Immunol Pract. 2014;2(1):3-12.PubMedGoogle ScholarCrossref
Zambonino  MA, Corzo  JL, Muñoz  C,  et al.  Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children.  Pediatr Allergy Immunol. 2014;25(1):80-87.PubMedGoogle ScholarCrossref
Macy  E, Ngor  EW.  Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin.  J Allergy Clin Immunol Pract. 2013;1(3):258-263.PubMedGoogle ScholarCrossref
Ponvert  C, Perrin  Y, Bados-Albiero  A,  et al.  Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests.  Pediatr Allergy Immunol. 2011;22(4):411-418.PubMedGoogle ScholarCrossref
Mori  F, Cianferoni  A, Barni  S, Pucci  N, Rossi  ME, Novembre  E.  Amoxicillin allergy in children: five-day drug provocation test in the diagnosis of nonimmediate reactions.  J Allergy Clin Immunol Pract. 2015;3(3):375-380.e1.PubMedGoogle ScholarCrossref
Katta  R, Anusuri  V.  Serum sickness-like reaction to cefuroxime: a case report and review of the literature.  J Drugs Dermatol. 2007;6(7):747-748.PubMedGoogle Scholar
Hebert  AA, Sigman  ES, Levy  ML.  Serum sickness-like reactions from cefaclor in children.  J Am Acad Dermatol. 1991;25(5, pt 1):805-808.PubMedGoogle ScholarCrossref
Martin  J, Abbott  G.  Serum sickness like illness and antimicrobials in children.  N Z Med J. 1995;108(997):123-124.PubMedGoogle Scholar
Tatum  AJ, Ditto  AM, Patterson  R.  Severe serum sickness-like reaction to oral penicillin drugs: three case reports.  Ann Allergy Asthma Immunol. 2001;86(3):330-334.PubMedGoogle ScholarCrossref
Wiertsema  SP, Chidlow  GR, Kirkham  LA,  et al.  High detection rates of nucleic acids of a wide range of respiratory viruses in the nasopharynx and the middle ear of children with a history of recurrent acute otitis media.  J Med Virol. 2011;83(11):2008-2017.PubMedGoogle ScholarCrossref
Heikkinen  T, Thint  M, Chonmaitree  T.  Prevalence of various respiratory viruses in the middle ear during acute otitis media.  N Engl J Med. 1999;340(4):260-264.PubMedGoogle ScholarCrossref
Rallis  E, Balatsouras  DG, Kouskoukis  C, Verros  C, Homsioglou  E.  Drug eruptions in children with ENT infections.  Int J Pediatr Otorhinolaryngol. 2006;70(1):53-57.PubMedGoogle ScholarCrossref
Carder  KR.  Hypersensitivity reactions in neonates and infants.  Dermatol Ther. 2005;18(2):160-175.PubMedGoogle ScholarCrossref
Gómez  E, Blanca-Lopez  N, Salas  M,  et al.  Induction of accelerated reactions to amoxicillin by T-cell effector mechanisms.  Ann Allergy Asthma Immunol. 2013;110(4):267-273.PubMedGoogle ScholarCrossref
Torres  MJ, Mayorga  C, Fernández  TD,  et al.  T cell assessment in allergic drug reactions during the acute phase according to the time of occurrence.  Int J Immunopathol Pharmacol. 2006;19(1):119-130.PubMedGoogle Scholar
Régie de l’assurance maladie du Québec. Liste des médicaments. Published November 20, 2015. Accessed March 3, 2016.
Régie de l’assurance maladie du Québec. Manuel des médecins spécialistes. Published January 1, 2012. Accessed March 3, 2016.
Petit  G, De Wals  P, Law  B,  et al.  Epidemiological and economic burden of pneumococcal diseases in Canadian children.  Can J Infect Dis. 2003;14(4):215-220.PubMedGoogle ScholarCrossref
Venekamp  RP, Sanders  SL, Glasziou  PP, Del Mar  CB, Rovers  MM.  Antibiotics for acute otitis media in children.  Cochrane Database Syst Rev. 2015;6:CD000219.PubMedGoogle Scholar
Langley  J, Halperin  S.  Allergy to antibiotics in children: perception versus reality.  Can J Infect Dis. 2002;13(3):160-163.PubMedGoogle ScholarCrossref
Fölster-Holst  R, Kreth  HW.  Viral exanthems in childhood: infectious (direct) exanthems, part 1: classic exanthems.  J Dtsch Dermatol Ges. 2009;7(4):309-316.PubMedGoogle Scholar
Antunez  C, Blanca-Lopez  N, Torres  MJ,  et al.  Immediate allergic reactions to cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins.  J Allergy Clin Immunol. 2006;117(2):404-410.PubMedGoogle ScholarCrossref
Guéant  JL, Romano  A, Cornejo-Garcia  JA,  et al.  HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping.  J Allergy Clin Immunol. 2015;135(1):253-259.PubMedGoogle ScholarCrossref
Rosenfield  L, Kalicinsky  C, Warrington  R.  A retrospective comparison of false negative skin test rates in penicillin allergy, using pencilloyl-poly-lysine and minor determinants or penicillin G, followed by open challenge.  Allergy Asthma Clin Immunol. 2015;11:34.PubMedGoogle ScholarCrossref
Picard  M, Paradis  L, Bégin  P, Paradis  J, Des Roches  A.  Skin testing only with penicillin G in children with a history of penicillin allergy.  Ann Allergy Asthma Immunol. 2014;113(1):75-81.PubMedGoogle ScholarCrossref
Original Investigation
June 6, 2016

Assessing the Diagnostic Properties of a Graded Oral Provocation Challenge for the Diagnosis of Immediate and Nonimmediate Reactions to Amoxicillin in Children

Author Affiliations
  • 1Division of Clinical Epidemiology, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada
  • 2Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, Canada
  • 3Discipline of Pediatrics, Faculty of Medicine, Memorial University, St John’s, Newfoundland and Labrador, Canada
  • 4Division of Dermatology, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada
JAMA Pediatr. 2016;170(6):e160033. doi:10.1001/jamapediatrics.2016.0033

Importance  The diagnostic properties of a graded provocation challenge (PC) among children presenting with a rash in the course of amoxicillin treatment are currently unknown.

Objective  To assess the accuracy and the negative predictive value of the PC in a cohort of children referred with suspected allergy to amoxicillin.

Design, Setting, and Participants  A cohort study was conducted between March 1, 2012, and April 1, 2015, at the allergy clinic of the Montreal Children’s Hospital, Montreal, Quebec, Canada. All children referred with suspected allergy to amoxicillin were approached. In addition, 346 eligible children were followed up to assess reactions to subsequent use of amoxicillin at the time of illness in cases with negative PC results. Data were collected on clinical characteristics, suspected antibiotic exposure, personal and first-degree relatives’ comorbidities, and history of atopy and management of the reaction. Univariate and multivariate logistic regressions were compared to determine factors associated with immediate and nonimmediate reactions to the PC.

Interventions  All children had a graded PC.

Main Outcomes and Measures  Reactions to the graded PC, the negative predictive value of the PC for nonimmediate reactions, and factors associated with immediate and nonimmediate reactions to the PC.

Results  A total of 818 children were assessed (median age, 1.7 years [interquartile range, 1.0-3.9 years]; 441 [53.9%] male). Among all participants, 770 (94.1%) tolerated the PC, 17 (2.1%) developed mild immediate reactions, and 31 (3.8%) developed nonimmediate reactions. The graded PC had a specificity of 100.0% (95% CI, 90.9%-100.0%), a negative predictive value of 89.1% (95% CI, 77.1%-95.5%), and a positive predictive value of 100.0% (95% CI, 86.3%-100.0%). Among all 346 participants eligible for annual follow-up, 250 (72.3%; 95% CI, 67.2%-76.8%) responded, 55 of whom received subsequent full treatment with amoxicillin; 49 of these 55 participants (89.1%) reported tolerance to subsequent full treatment with amoxicillin, while 6 (10.9%) developed nonimmediate cutaneous reactions. History of a reaction occurring within 5 minutes of exposure was associated with immediate reactions to the PC (adjusted odds ratio = 9.6; 95% CI, 1.5-64.0), while a rash that lasted longer than 7 days (adjusted odds ratio = 4.8; 95% CI, 1.4-16.4) and parental history of drug allergy (adjusted odds ratio = 3.0; 95% CI, 1.3-6.8) were associated with nonimmediate reactions to the PC.

Conclusions and Relevance  Graded PCs provide an accurate and safe confirmatory test for skin-related reactions to amoxicillin. Further studies are required to assess factors associated with the PC outcome groups.