Newly-Developed Sulfa Antibiotic Allergy Clinical Decision Rule Shows Strong Results


Adaptation of penicillin allergy clinical decision tool PEN-FAST showed strong performance, indicating the potential utility of the tool for identifying patients with low-risk allergy phenotypes who may safely undergo direct oral challenges.

An allergy clinical decision rule known as SULF-FAST—an adapted version of penicillin allergy clinical decision tool PEN-FAST—shows strong performance in identifying those with low-risk trimethoprim-sulfamethoxazole allergy, according to new findings.1

The adaptation of the PEN-FAST tool, originally designed for penicillin allergy, was done in this new study given a lack of risk-stratification tools to guide individuals with low-risk allergy phenotypes who could potentially safely undergo direct oral challenges (OCs).2

This research letter was authored by Jamie L. Waldron, MD, from Austin Health’s Department of Infectious Diseases in Australia.

“Trimethoprim-sulfamethoxazole is first-line treatment for many infections; however, use is limited by sulfa allergy,” Waldron and colleagues wrote. “Use of trimethoprim-sulfamethoxazole is frequently required by antimicrobial stewardship programs to prevent use of more restricted antibotics.”

Background and Findings

The investigators adapted the PEN-FAST tool to create SULF-FAST, a clinical decision rule for trimethoprim-sulfamethoxazole (TMP-SMX) allergy. They used two datasets from Australia and the US to validate the SULF-FAST tool.

A positive test result was defined by the research team as a positive patch test (PT) result or the occurrence of a clinician-observed or patient-reported presumed immune-mediated reaction following the challenge. The PEN-FAST score, along with its diagnostic performance, was calculated by the team for each cohort and subgroup based on allergy phenotype.

The study included adult patients, 18 or older, who had reported nonsevere sulfa or TMP-SMX allergy and who consented to undergo direct oral challenges. These individuals referred to drug allergy services from November of 2015 to July of 2022, or at the Vanderbilt University Medical Center from October of 2015 to February of 2019.

The PEN-FAST score and its diagnostic performance were calculated for each cohort and subgroup.

Overall, the prevalence of positive trimethoprim-sulfamethoxazole (TMP-SMX) allergy test results was found to be 5.2% in Australia and 6.4% in the US. The investigators noted that the adapted PEN-FAST tool showed good discrimination in determining true allergy in the Australian cohort, with an area under the curve (AUC) of 0.86.

A low PEN-FAST score (<3) indicated to the team a low allergy risk (<5%), while a score of 3 or more showed a higher allergy risk (>20%). The investigators reported that the tool had a sensitivity of 66.7% and specificity of 96.4% in identifying this allergy.

In the US cohort, the tool was shown to have an AUC of 0.67, with a sensitivity of 38.5% and specificity of 89.5%. The tool also did well in identifying immediate reactions but had lower performance for the delayed phenotype.

The research team saw good performance for immediate reactions but lower for the delayed phenotype. Out of 115 individuals with long-term prescribing data, 45 received a trimethoprim-sulfamethoxazole course without any adverse reactions.

“Although single-dose challenge was protocolized, the high rate of tolerance of multiple extended trimethoprim-sulfamethoxazole treatment doses is reassuring for excluding delayed hypersensitivity. Further validation is required for widespread implementation.”


  1. Waldron JL, Rose M, Vogrin S, et al. Development and Validation of a Sulfa Antibiotic Allergy Clinical Decision Rule. JAMA Netw Open. 2023;6(6):e2316776. doi:10.1001/jamanetworkopen.2023.16776.
  2. Krantz MS, Stone CA Jr, Abreo A, Phillips EJ. Oral challenge with trimethoprim-sulfamethoxazole in patients with “sulfa” antibiotic allergy. J Allergy Clin Immunol Pract. 2020;8(2):757-760. doi:10.1016/j.jaip.2019.07.003
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