[Skip to Content]
[Skip to Content Landing]

Development and Validation of a Penicillin Allergy Clinical Decision Rule

Educational Objective
Review research on evaluating penicillin allergy risk and severity.
1 Credit CME
Key Points

Question  Can a clinical decision rule risk stratify penicillin allergies and identify low-risk phenotypes amenable to point-of-care delabeling?

Findings  In this diagnostic study of 622 patients, a penicillin allergy decision rule (PEN-FAST) was derived from a prospective cohort of penicillin allergy–tested patients in 2 primary Australian sites and was subjected to internal and external validation in 3 local and international cohorts. PEN-FAST was found to be a practical tool with a high negative predictive value of 96.3% that uses penicillin allergy history to identify low-risk allergies.

Meaning  PEN-FAST may aid the risk stratification of patients with penicillin allergy to facilitate implementation of delabeling strategies and safe β-lactam prescribing.


Importance  Penicillin allergy is a significant public health issue for patients, antimicrobial stewardship programs, and health services. Validated clinical decision rules are urgently needed to identify low-risk penicillin allergies that potentially do not require penicillin skin testing by a specialist.

Objective  To develop and validate a penicillin allergy clinical decision rule that enables point-of-care risk assessment of patient-reported penicillin allergies.

Design, Setting, and Participants  In this diagnostic study, a multicenter prospective antibiotic allergy–tested cohort of 622 patients from 2 tertiary care sites in Melbourne, Australia (Austin Health and Peter MacCallum Cancer Centre) was used for derivation and internal validation of a penicillin allergy decision rule. Backward stepwise logistic regression was used to derive the model, including clinical variables predictive of a positive penicillin allergy test result. Internal validation of the final model used bootstrapped samples and the model scoring derived from the coefficients. External validation was performed in retrospective penicillin allergy–tested cohorts consisting of 945 patients from Sydney and Perth, Australia, and Nashville, Tennessee. Patients who reported a penicillin allergy underwent penicillin allergy testing using skin prick, intradermal, or patch testing and/or oral challenge (direct or after skin testing). Data were collected from June 26, 2008, to June 3, 2019, and analyzed from January 9 to 12, 2019.

Main Outcomes and Measures  The primary outcome for the model was any positive result of penicillin allergy testing performed during outpatient or inpatient assessment.

Results  From an internal derivation and validation cohort of 622 patients (367 female [59.0%]; median age, 60 [interquartile range{IQR}, 48-71] years) and an external validation cohort of 945 patients (662 female [70.1%]; median age, 55 [IQR, 38-68] years), the 4 features associated with a positive penicillin allergy test result on multivariable analysis were summarized in the mnemonic PEN-FAST: penicillin allergy, five or fewer years ago, anaphylaxis/angioedema, severe cutaneous adverse reaction (SCAR), and treatment required for allergy episode. The major criteria included an allergy event occurring 5 or fewer years ago (2 points) and anaphylaxis/angioedema or SCAR (2 points); the minor criterion (1 point), treatment required for an allergy episode. Internal validation showed minimal mean optimism of 0.003 with internally validated area under the curve of 0.805. A cutoff of less than 3 points for PEN-FAST was chosen to classify a low risk of penicillin allergy, for which only 17 of 460 patients (3.7%) had positive results of allergy testing, with a negative predictive value of 96.3% (95% CI, 94.1%-97.8%). External validation resulted in similar findings.

Conclusions and Relevance  In this study, PEN-FAST was found to be a simple rule that accurately identified low-risk penicillin allergies that do not require formal allergy testing. The results suggest that a PEN-FAST score of less than 3, associated with a high negative predictive value, could be used by clinicians and antimicrobial stewardship programs to identify low-risk penicillin allergies at the point of care.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: February 1, 2020.

Corresponding Author: Jason A. Trubiano, MBBS, PhD, Centre for Antibiotic Allergy and Research, Department of Infectious Diseases, Austin Health, 145 Studley Road, Heidelberg, Victoria, Australia 3084 (jason.trubiano@austin.org.au).

Published Online: March 16, 2020. doi:10.1001/jamainternmed.2020.0403

Author Contributions: Drs Trubiano and Vogrin had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Trubiano, Stone, Phillips.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Trubiano, Stone, Groenendijk, Phillips.

Critical revision of the manuscript for important intellectual content: Trubiano, Vogrin, Chua, Bourke, Yun, Douglas, Stone, Yu, Holmes, Phillips.

Statistical analysis: Trubiano, Vogrin, Stone.

Obtained funding: Trubiano.

Administrative, technical, or material support: Trubiano, Chua, Yun, Douglas, Stone, Groenendijk, Phillips.

Supervision: Trubiano, Stone, Phillips.

Conflict of Interest Disclosures: Dr Stone reported receiving grant 1K12HS026395-01 from the Agency for Healthcare Research and Quality (AHRQ) during the conduct of the study. Dr Phillips reported receiving grants from the National Institutes of Health (NIH) and National Health and Medical Research Council (NHMRC) and personal fees from UpToDate, Inc and BioCryst Pharmaceuticals, Inc outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by a grant from the Austin Medical Research Foundation (AMRF); postgraduate scholarship GNT 1139902 from the NHMRC (Dr Trubiano); a postgraduate scholarship from the National Centre for Infections in Cancer (Dr Trubiano); grants 1P50GM115305-01, R21AI139021, R34AI136815, and 1R01HG01086301 from the NIH (Dr Phillips); the NHMRC (Dr Phillips); and grant 1K12HS026395-01 from the AHRQ (Dr Stone).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The departments of Infectious Diseases at Austin Health and Peter MacCallum Cancer Centre assisted with the antibiotic allergy testing services, for which they were not compensated.

Trubiano  JA , Chen  C , Cheng  AC , Grayson  ML , Slavin  MA , Thursky  KA ; National Antimicrobial Prescribing Survey (NAPS).  Antimicrobial allergy “labels” drive inappropriate antimicrobial prescribing: lessons for stewardship.   J Antimicrob Chemother. 2016;71(6):1715-1722. doi:10.1093/jac/dkw008 PubMedGoogle Scholar
Blumenthal  KG , Peter  JG , Trubiano  JA , Phillips  EJ .  Antibiotic allergy.   Lancet. 2019;393(10167):183-198. doi:10.1016/S0140-6736(18)32218-9 PubMedGoogle Scholar
MacFadden  DR , LaDelfa  A , Leen  J ,  et al.  Impact of reported beta-lactam allergy on inpatient outcomes: a multicenter prospective cohort study.   Clin Infect Dis. 2016;63(7):904-910. doi:10.1093/cid/ciw462 PubMedGoogle Scholar
Trubiano  JA , Leung  VK , Chu  MY , Worth  LJ , Slavin  MA , Thursky  KA .  The impact of antimicrobial allergy labels on antimicrobial usage in cancer patients.   Antimicrob Resist Infect Control. 2015;4:23. doi:10.1186/s13756-015-0063-6 PubMedGoogle Scholar
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 PubMedGoogle Scholar
Trubiano  JA , Thursky  KA , Stewardson  AJ ,  et al.  Impact of an integrated antibiotic allergy testing program on antimicrobial stewardship: a multicenter evaluation.   Clin Infect Dis. 2017;65(1):166-174. doi:10.1093/cid/cix244 PubMedGoogle Scholar
Trubiano  J , Phillips  E .  Antimicrobial stewardship’s new weapon? a review of antibiotic allergy and pathways to “de-labeling”.   Curr Opin Infect Dis. 2013;26(6):526-537. doi:10.1097/QCO.0000000000000006 PubMedGoogle Scholar
Bourke  J , Pavlos  R , James  I , Phillips  E .  Improving the effectiveness of penicillin allergy de-labeling.   J Allergy Clin Immunol Pract. 2015;3(3):365-34.e1. doi:10.1016/j.jaip.2014.11.002PubMedGoogle Scholar
Marwood  J , Aguirrebarrena  G , Kerr  S , Welch  SA , Rimmer  J .  De-labelling self-reported penicillin allergy within the emergency department through the use of skin tests and oral drug provocation testing.   Emerg Med Australas. 2017;29(5):509-515. doi:10.1111/1742-6723.12774 PubMedGoogle Scholar
Trubiano  JA , Beekmann  SE , Worth  LJ ,  et al.  Improving antimicrobial stewardship by antibiotic allergy delabeling: evaluation of knowledge, attitude, and practices throughout the emerging infections network.   Open Forum Infect Dis. 2016;3(3):ofw153. doi:10.1093/ofid/ofw153 PubMedGoogle Scholar
Collins  GS , Reitsma  JB , Altman  DG , Moons  KGM .  Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD).   Ann Intern Med. 2015;162(10):735-736. doi:10.7326/L15-5093-2 PubMedGoogle Scholar
Charlson  ME , Pompei  P , Ales  KL , MacKenzie  CR .  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.   J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8 PubMedGoogle Scholar
Trubiano  JA , Douglas  AP , Goh  M , Slavin  MA , Phillips  EJ .  The safety of antibiotic skin testing in severe T-cell-mediated hypersensitivity of immunocompetent and immunocompromised hosts.   J Allergy Clin Immunol Pract. 2019;7(4):1341-1343.e1. doi:10.1016/j.jaip.2018.09.014PubMedGoogle Scholar
Rawlins  MDTJ .  Textbook of Adverse Drug Reactions. Oxford University Press; 1977.
Pichler  WJ . Drug sensitivity reactions: classification and relationship to T-cell activation. In: Pichler  WJ , ed.  Drug Hypersensitivity. S Karger Pub; 2007:168-189. doi:10.1159/000104199
Austin  PC , Tu  JV .  Bootstrap methods for developing predictive models.   Am Stat. 2004;58(2):7. doi:10.1198/0003130043277 Google Scholar
Steyerberg  EW , Harrell  FE  Jr , Borsboom  GJ , Eijkemans  MJ , Vergouwe  Y , Habbema  JD .  Internal validation of predictive models: efficiency of some procedures for logistic regression analysis.   J Clin Epidemiol. 2001;54(8):774-781. doi:10.1016/S0895-4356(01)00341-9 PubMedGoogle Scholar
Duong  TA , Valeyrie-Allanore  L , Wolkenstein  P , Chosidow  O .  Severe cutaneous adverse reactions to drugs.   Lancet. 2017;390(10106):1996-2011. doi:10.1016/S0140-6736(16)30378-6 PubMedGoogle Scholar
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.2019.02.040PubMedGoogle Scholar
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 PubMedGoogle Scholar
Blumenthal  KG , Lu  N , Zhang  Y , Li  Y , Walensky  RP , Choi  HK .  Risk of methicillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study.   BMJ. 2018;361:k2400. doi:10.1136/bmj.k2400 PubMedGoogle Scholar
Derrick  MI , Williams  KB , Shade  LMP , Phillips  EJ .  A survey of drug allergy training opportunities in the United States.   J Allergy Clin Immunol Pract. 2018;6(1):302-304. doi:10.1016/j.jaip.2017.08.003 PubMedGoogle Scholar
Banks  TA , Tucker  M , Macy  E .  Evaluating penicillin allergies without skin testing.   Curr Allergy Asthma Rep. 2019;19(5):27. doi:10.1007/s11882-019-0854-6 PubMedGoogle Scholar
Trubiano  JA , Smibert  O , Douglas  A ,  et al.  The safety and efficacy of an oral penicillin challenge program in cancer patients: a multicenter pilot study.   Open Forum Infect Dis. 2018;5(12):ofy306. doi:10.1093/ofid/ofy306 PubMedGoogle Scholar
Stevenson  B , Trevenen  M , Klinken  E ,  et al.  Multicenter Australian study to determine criteria for low- and high-risk penicillin testing in outpatients.   J Allergy Clin Immunol Pract. 2020;8(2):681-689.e3. PubMedGoogle Scholar
Chiriac  AM , Wang  Y , Schrijvers  R ,  et al.  Designing predictive models for beta-lactam allergy using the drug allergy and hypersensitivity database.   J Allergy Clin Immunol Pract. 2018;6(1):139-148.e2. doi:10.1016/j.jaip.2017.04.045PubMedGoogle Scholar
Siew  LQC , Li  PH , Watts  TJ ,  et al.  Identifying low-risk beta-lactam allergy patients in a UK tertiary centre.   J Allergy Clin Immunol Pract. 2019;7(7):2173-2181.e1. doi:10.1016/j.jaip.2019.03.015PubMedGoogle Scholar
Ramsey  A , Caubet  JC , Blumenthal  K .  Risk stratification and prediction in beta-lactam allergic patients.   J Allergy Clin Immunol Pract. 2019;7(7):2182-2184. doi:10.1016/j.jaip.2019.05.045 PubMedGoogle Scholar
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.2019.05.037PubMedGoogle Scholar
Phillips  EJ , Bigliardi  P , Bircher  AJ ,  et al.  Controversies in drug allergy: testing for delayed reactions.   J Allergy Clin Immunol. 2019;143(1):66-73. doi:10.1016/j.jaci.2018.10.030 PubMedGoogle Scholar
Devchand  M , Urbancic  KF , Khumra  S ,  et al.  Pathways to improved antibiotic allergy and antimicrobial stewardship practice: The validation of a beta-lactam antibiotic allergy assessment tool.   J Allergy Clin Immunol Pract. 2019;7(3):1063-1065.e5. doi:10.1016/j.jaip.2018.07.048PubMedGoogle Scholar
Trubiano  JA , Worth  LJ , Urbancic  K ,  et al; Australasian Society for Infectious Diseases Clinical Research Network; Australasian Society of Clinical Immunology and Allergy.  Return to sender: the need to re-address patient antibiotic allergy labels in Australia and New Zealand.   Intern Med J. 2016;46(11):1311-1317. doi:10.1111/imj.13221 PubMedGoogle Scholar
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.


My Saved Courses

You currently have no courses saved.