Original Articles
Asthma, Lower Airway Diseases
Skin testing only with penicillin G in children with a history of penicillin allergy

https://doi.org/10.1016/j.anai.2014.04.017Get rights and content

Abstract

Background

The absence of commercially available penicilloyl-polylysine (PPL) for most of the last decade severely hampered the practice of penicillin allergy evaluation because skin testing without PPL is reported to have a poor negative predictive value (NPV).

Objective

To determine the safety and NPV of skin testing without PPL using only penicillin G followed by a 3-dose graded challenge to the incriminated penicillin in children with a history of penicillin allergy.

Methods

Patients evaluated for a history of penicillin allergy at the CHU Sainte-Justine Allergy Clinic between December 2006 and December 2009 were skin tested only with penicillin G and underwent a 3-dose graded challenge to the culprit penicillin if the skin test result was negative.

Results

Among 563 patients skin tested to penicillin G, 185 (33%) had a positive skin test result. These patients had a shorter interval between the initial reaction and skin testing compared with patients with a negative skin test result (P = .03). A total of 375 of 378 patients (99%) with a negative skin test result were challenged and 18 (4.8%) reacted, translating into a NPV of 95.2% (95% confidence interval [CI], 92.5%–97.1%). Three of 17 patients with a history of anaphylaxis and a negative skin test result reacted to challenge (NPV, 82.4%; 95% CI, 59.0–93.8%). All challenge reactions were mild and resolved promptly with treatment.

Conclusion

Among children with a history of penicillin allergy, skin testing only with penicillin G followed by a 3-dose graded challenge to the incriminated penicillin is safe and yields a good NPV. This approach could be useful when PPL is unavailable.

Introduction

Approximately 5% of children and 10% of adults report a history of penicillin allergy, although only a few of these patients are truly allergic.[1], [2], [3], [4] Because history is a poor predictor of reactivity, penicillin allergy evaluation that consists of skin tests, often followed by a drug challenge, is key to identify truly allergic and nonallergic patients who can be safely treated with penicillins.[5], [6] The importance of evaluating patients with a history of penicillin allergy is increasingly recognized given that penicillin avoidance is unnecessary for most of them and leads to the use of alternative broader-spectrum antibiotics (vancomycin and fluoroquinolones), which have been associated with additional costs and significant morbidities, such as vancomycin-resistant enterococcus and Clostridium difficile–associated diarrhea.[2], [7], [8], [9]

Skin test reagents used for penicillin allergy evaluation include penicilloyl-polylysine (PPL), the major antigenic determinant, and a variety of minor determinants, the most commonly used being penicillin G.[6], [10] After a negative skin test result, a drug challenge is often performed because, depending on the population studied and skin test reagents used, up to 31% of patients require a drug challenge to identify their allergy.11 A drug challenge may also provide reassurance to patients and parents who might not be convinced that they are not allergic based on negative skin test results and may therefore continue to avoid penicillins.[12], [13]

The lack of commercially available PPL for most of the last decade in North America seriously hampered the practice of penicillin allergy evaluation.[4], [14] Skin testing without PPL is not recommended because up to 75% of patients who have a positive skin test react only to PPL; therefore, only a few allergists who had the capacity to produce their own skin test reagents were apt to perform penicillin allergy evaluation during this time.[4], [6], [15] Some groups proposed alternative approaches to palliate the absence of PPL, such as combining penicillin G skin testing with radioallergosorbent testing to PPL followed by 2 graded challenges, but none reached consensus, and in many cases the practice was abandoned.[4], [16], [17]

Given the importance of penicillin allergy evaluation, especially in patients with frequent infections and/or a history of allergic reactions to multiple antibiotics, the decision was made at our institution to perform penicillin allergy evaluation in the absence of PPL using only penicillin G for skin testing followed, if results were negative, by a 3-dose graded challenge to the penicillin incriminated in the initial allergic reaction. Preliminary results revealing a low reaction rate after a negative penicillin G skin test result led us to adopt this approach as standard practice at our institution until PPL recommericalization.18 The aim of this study was to determine the safety of this approach and the negative predictive value (NPV) of skin testing solely with penicillin G for predicting an IgE-mediated penicillin allergy.

Section snippets

Study Cohort

The study was performed at the CHU Sainte-Justine, a large Canadian pediatric university hospital, and was approved by the CHU Sainte-Justine Institutional Review Board. Written informed consent was obtained from parents or legal tutors and/or patients at the time of evaluation. All patients who underwent penicillin skin testing between December 2006 and December 2009 at the CHU Sainte-Justine Allergy Clinic were identified by medical record review. Patients with a history of reaction to any

Results

A total of 563 patients with a history of penicillin allergy were skin tested to penicillin G between December 2006 and December 2009 (Table 1). Patients were between 7 months and 21 years of age (median age, 5.8 years) at the time of evaluation, and 51% were female. Twenty-eight percent had a history of atopy and 17% had a history of asthma in line with estimates of the prevalence of these conditions in the pediatric population.[20], [21] Most patients (89%) reported a reaction to amoxicillin

Discussion

In a pediatric cohort of 563 patients with a history of penicillin allergy, the results of skin testing only with penicillin G (in the absence of PPL) were positive in 33% and yielded a NPV of 95.2% (95% CI, 92.5%–97.1%) based on challenge outcomes. After a negative penicllin G skin test result, a 3-dose graded challenge to the incriminated penicillin was found to be safe, even in patients with a history of anaphylaxis, because no patient experienced a severe reaction as a result. To our

References (60)

  • G.R. Green et al.

    Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G: a cooperative prospective study of the penicillin study group of the American Academy of Allergy

    J Allergy Clin Immunol

    (1977)
  • G.O. Solley et al.

    Penicillin allergy: clinical experience with a battery of skin-test reagents

    J Allergy Clin Immunol

    (1982)
  • E. Macy et al.

    Skin testing with penicilloate and penilloate prepared by an improved method: amoxicillin oral challenge in patients with negative skin test responses to penicillin reagents

    J Allergy Clin Immunol

    (1997)
  • P.J. Bousquet et al.

    Importance of mixture of minor determinants and benzylpenicilloyl poly-L-lysine skin testing in the diagnosis of beta-lactam allergy

    J Allergy Clin Immunol

    (2005)
  • A. Goldberg et al.

    Skin testing and oral penicillin challenge in patients with a history of remote penicillin allergy

    Ann Allergy Asthma Immunol

    (2008)
  • B.B. Wong et al.

    Clinical history as a predictor of penicillin skin test outcome

    Ann Allergy Asthma Immunol

    (2006)
  • L.M. Mendelson et al.

    Routine elective penicillin allergy skin testing in children and adolescents: study of sensitization

    J Allergy Clin Immunol

    (1984)
  • B.C. Jost et al.

    Elective penicillin skin testing in a pediatric outpatient setting

    Ann Allergy Asthma Immunol

    (2006)
  • M.E. Pichichero et al.

    Diagnosis of penicillin, amoxicillin, and cephalosporin allergy: reliability of examination assessed by skin testing and oral challenge

    J Pediatr

    (1998)
  • G.A. del Real et al.

    Penicillin skin testing in patients with a history of beta-lactam allergy

    Ann Allergy Asthma Immunol

    (2007)
  • R. Asero

    Detection of patients with multiple drug allergy syndrome by elective tolerance tests

    Ann Allergy Asthma Immunol

    (1998)
  • Drug allergy: an updated practice parameter

    Ann Allergy Asthma Immunol

    (2010)
  • C.E. Lee et al.

    The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns and emerging bacterial resistance

    Arch Intern Med

    (2000)
  • K. Sade et al.

    The economic burden of antibiotic treatment of penicillin-allergic patients in internal medicine wards of a general tertiary care hospital

    Clin Exp Allergy

    (2003)
  • V. Reddy et al.

    Drug resistant infections with methicillin-resistant Staphylococcus aureus, Clostridium difficile, and vancomycin resistant Enterococcus are associated with a higher prevalence of penicillin allergy

    J Allergy Clin Immunol

    (2013)
  • P.J. Bousquet et al.

    Oral challenges are needed in the diagnosis of beta-lactam hypersensitivity

    Clin Exp Allergy

    (2008)
  • M. Picard et al.

    Outpatient penicillin use after negative skin testing and drug challenge in a pediatric population

    Allergy Asthma Proc

    (2012)
  • R.J. Warrington et al.

    The value of routine penicillin allergy skin testing in an outpatient population

    Allergy Asthma Proc

    (2003)
  • J. Gadde et al.

    Clinical experience with penicillin skin testing in a large inner-city STD clinic

    JAMA

    (1993)
  • R. Solensky

    Evaluation of penicillin allergy without benzylpenicilloyl-polylysine

    Ann Allergy Asthma Immunol

    (2007)
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    Disclosures: Authors have nothing to disclose.

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