Clinical Features of Penicillin Allergy

Key points

  • 10% of U.S. patients reported having a penicillin allergy. When evaluated by clinicians, less than 1% of those patients were truly allergic.
  • A penicillin allergy label can be evaluated through different methods including reviewing a patient’s allergy history, conducting a validated risk assessment, followed by penicillin skin testing and/or a direct oral challenge, as appropriate.

5 facts about penicillin allergy

  1. Approximately 10% of U.S. patients reported having an allergic reaction to a "penicillin class" antibiotic in their past. However, less than 1% of patients were truly allergic.1
  2. A penicillin allergy label can prompt a clinician to prescribe second-line broad spectrum antibiotics that may be associated with suboptimal antibiotic therapy, increased risk for antimicrobial resistance or other adverse events, and higher healthcare costs.2345
  3. Patients may have an inaccurate penicillin allergy label based on a past history of viral rashes, a family history of penicillin allergy, or intolerance to an antibiotic (e.g., diarrhea).26
  4. A true penicillin allergy may cause either an immediate hypersensitivity reaction (IgE-mediated, resembling anaphylaxis) or a delayed hypersensitivity reaction (resembling a severe rash or causing organ and blood cell injuries). For immediate hypersensitivity reactions, penicillin allergy-specific IgE antibodies may decrease over time resulting in patients tolerating penicillin-related antibiotics later in life.17
  5. Clinicians can evaluate a penicillin allergy label through different methods, including reviewing a patient's allergy history and conducting a validated risk stratification, followed by penicillin skin testing and/or a direct oral challenge, as appropriate.189

Clinical Assessment

Assessing a patient's penicillin allergy reaction history is important when deciding about next steps in allergy assessment and treatment selection.28910

Questions to ask during the examination

  • How long ago did the reaction occur?
  • What medication(s) were you taking when the reaction occurred? How many doses had you taken before the symptoms started?
  • What kind of reaction occurred? Can you describe the symptoms you experienced?
  • How was the reaction managed? Did you have to seek care for the reaction? Did you have to get any treatments for the reaction? What was the outcome?
  • Have you been prescribed amoxicillin or another penicillin since your reaction? Did you experience any side effects?

Determining Risk

Based on a patient's history, penicillin allergy risk categories can be determined. Validated risk stratification tools are available to determine the risk of a positive penicillin allergy test and guide appropriate clinical decisions.91011121314

Special consideration: delayed hypersensitivity reactions

Patients with severe delayed hypersensitivity reactions should not use the offending drug. A direct oral challenge and skin testing are not appropriate for patients with severe delayed hypersensitivity reactions such as:10

  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Drug rash with eosinophilia and systemic symptoms (DRESS)
  • Acute generalized exanthematous pustulosis
  • Multifocal bullous fixed drug eruptions
  • Drug-induced organ or blood cell injuries

High-risk patients and patients with a history of severe delayed hypersensitivity reactions should be referred to a drug allergy specialist.

Direct oral challenge

A direct oral challenge is a method used to determine if a person with a history of penicillin allergy can safely take "penicillin class" antibiotics.1215

  • Direct oral challenges are generally suitable for low-risk patients as determined through an assessment using validated risk stratification tools.
  • A direct oral challenge involves giving a controlled oral dose of amoxicillin under close medical supervision.
  • Direct oral challenges should be done with a standard protocol, in a safe setting, under observation, and with rescue medications available.
  • A negative skin test should also be followed by a direct oral challenge.

Penicillin skin testing

Penicillin skin testing involves a two-step introduction of dilute penicillin reagents into a patient's skin, compared against a normal saline negative control and a histamine-containing positive control.16

  • When correctly performed, skin testing has greater than 95% specificity for identifying IgE-mediated adverse reactions.17
  • Negative skin testing should be confirmed with a direct oral challenge test in most cases.

Training resource

The Penicillin Allergy Management training course from SHEA provides information on penicillin allergy history taking, risk assessment, penicillin allergy testing, and delabeling.
Penicillin Allergy Management - Removing Barriers to Optimal Antibiotic Prescribing

Resources

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Content Source:
National Center for Emerging and Zoonotic Infectious Diseases (NCEZID)
  1. Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: A 2022 practice parameter update. J Allergy Clin Immunol. 2022;150(6):1333-1393. doi:10.1016/j.jaci.2022.08.028
  2. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA. 2019;321(2):188-199. doi:10.1001/jama.2018.19283
  3. Blumenthal KG, Ryan EE, Li Y, Lee H, Kuhlen JL, Shenoy ES. The Impact of a Reported Penicillin Allergy on Surgical Site Infection Risk. Clin Infect Dis. 2018;66(3):329-336. doi:10.1093/cid/cix794
  4. Blumenthal KG, Parker RA, Shenoy ES, Walensky RP. Improving Clinical Outcomes in Patients With Methicillin-Sensitive Staphylococcus aureus Bacteremia and Reported Penicillin Allergy. Clin Infect Dis. 2015;61(5):741-749. doi:10.1093/cid/civ394
  5. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin "allergy" in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014;133(3):790-796. doi:10.1016/j.jaci.2013.09.021
  6. Khan DA, Solensky R. Drug allergy. J Allergy ClinImmunol. 2010;125(2)(suppl 2):S126-S137. doi:10.1016/j.jaci.2009.10.028
  7. Trubiano JA, Adkinson NF, Phillips EJ. Penicillin Allergy Is Not Necessarily Forever. JAMA. 2017;318(1):82-83. doi:10.1001/jama.2017.6510
  8. American Academy of Allergy, Asthma, and Immunology Milwaukee, Wis. Electronic address: info@aaaai.org; American Academy of Allergy, Asthma, and Immunology Milwaukee, Wis. Penicillin Allergy Evaluation Should Be Performed Proactively in Patients With a Penicillin Allergy Label. J Allergy Clin Immunol Pract. 2023;11(12):3626-3628. doi:10.1016/j.jaip.2023.09.045
  9. Devchand M, Trubiano JA. Penicillin allergy: a practical approach to assessment and prescribing. Aust Prescr. 2019;42(6):192-199. doi:10.18773/austprescr.2019.065
  10. Broyles AD, Banerji A, Barmettler S, et al. Practical Guidance for the Evaluation and Management of Drug Hypersensitivity: Specific Drugs [published correction appears in J Allergy Clin Immunol Pract. 2021 Jan;9(1):603. doi: 10.1016/j.jaip.2020.10.025] [published correction appears in J Allergy Clin Immunol Pract. 2021 Jan;9(1):605. doi: 10.1016/j.jaip.2020.11.036]. J Allergy Clin Immunol Pract. 2020;8(9S):S16-S116. doi:10.1016/j.jaip.2020.08.006
  11. Trubiano JA, Vogrin S, Chua KYL, et al. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Intern Med. 2020;180(5):745-752. doi:10.1001/jamainternmed.2020.0403
  12. Copaescu AM, Vogrin S, James F, et al. Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial. JAMA Intern Med. 2023;183(9):944-952. doi:10.1001/jamainternmed.2023.298
  13. Koo G, Stollings J, Lindsell C, et al. Low-risk penicillin allergy delabeling through a direct oral challenge in immunocompromised and/or multiple drug allergy labeled patients in a critical care setting. J Allergy Clin Immunol Pract. 2022;10(6):1660-1663 e1662.
  14. Stone C, Jr., Stollings J, Lindsell C, et al. Risk-stratified Management to Remove Low-Risk Penicillin Allergy Labels in the ICU. Am J Respir Crit Care Med. 2020;201(12):1572-1575.
  15. Mustafa SS, Conn K, Ramsey A. Comparing Direct Challenge to Penicillin Skin Testing for the Outpatient Evaluation of Penicillin Allergy: A Randomized Controlled Trial. J Allergy Clin Immunol Pract. 2019;7(7):2163-2170. doi:10.1016/j.jaip.2019.05.037
  16. Sousa-Pinto B, Tarrio I, Blumenthal KG, et al. Accuracy of penicillin allergy diagnostic tests: A systematic review and meta-analysis. J Allergy Clin Immunol. 2021;147(1):296-308. doi:10.1016/j.jaci.2020.04.058
  17. Solensky R, Jacobs J, Lester M, et al. Penicillin Allergy Evaluation: A Prospective, Multicenter, Open-Label Evaluation of a Comprehensive Penicillin Skin Test Kit. J Allergy Clin Immunol Pract. 2019;7(6):1876-1885.e3. doi:10.1016/j.jaip.2019.02.040