Development and Validation of a Sulfa Antibiotic Allergy Clinical Decision Rule

This cohort study describes the adaptation of a widely used penicillin allergy clinical decision tool for evaluation of trimethoprim-sulfamethoxazole allergy.


Introduction
Trimethoprim-sulfamethoxazole is first-line treatment for many infections; however, use is limited by sulfa allergy. 1 Use of trimethoprim-sulfamethoxazole is frequently required by antimicrobial stewardship programs to prevent use of more restricted antibotics. 2 Studies with nonstandardized challenge criteria suggest that those with low-risk allergy phenotypes can safely undergo direct oral challenges (OCs); however, no current risk-stratification tool exists to guide challenges. 3,4We sought to adapt PEN-FAST, a penicillin allergy clinical decision tool, for trimethoprim-sulfamethoxazole allergy. 5thods PEN-FAST (eFigure in Supplement 1) 5 was adapted as a trimethoprim-sulfamethoxazole allergy clinical decision rule (SULF-FAST) for use and validation in 2 data sets (in Australia and the US).
Patients aged 18 years or older with a trimethoprim-sulfamethoxazole allergy referred to drug allergy services in Melbourne, Australia (Austin Health, Peter MacCallum Cancer Centre; November 1, 2015, to July 31, 2022), or Nashville, Tennessee (Vanderbilt University Medical Center; October 1, 2015, to February 28, 2019), were prospectively assessed. 4,5Patients with a nonsevere sulfa or trimethoprim-sulfamethoxazole allergy (ie, excluding anaphylaxis within 5 years and severe cutaneous adverse drug reaction), 4 provided written consent to undergo OC at clinician discretion (eTable in Supplement 1).A positive test result was defined as a positive patch test (PT) result or a clinician-observed or patient-reported presumed immune-mediated reaction after the challenge.A PEN-FAST score (eFigure in Supplement 1) and its diagnostic performance were calculated for each cohort and allergy phenotype subgroup.Statistical analysis is detailed in the eMethods in Supplement 1.This study was approved by the Vanderbilt University Medical Center institutional review board and the Austin Health human research ethics committees.This study followed the STROBE reporting guideline. 6

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Open Access.This is an open access article distributed under the terms of the CC-BY License.Abbreviations: AUC, area under the curve for S-FAST score 3 or higher; NA, not applicable; NPV, negative predictive value; PPV, positive predictive value.

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a Immediate phenotype was defined as any reaction that occurred within 1 hour after exposure to initial medication dose, whereas delayed phenotype was defined as any reaction occurring beyond 1 hour, including those after multiple medication doses.Unknown phenotype includes any reaction that was nonimmune mediated and reactions with unknown timeline.

Table 1 .
Patient Demographic and Testing Characteristics of Trimethoprim-Sulfamethoxazole Allergy in Tested Derivation and Validation Cohorts a (continued) Abbreviations: NA, not applicable; OC, oral challenge; PT, patch test; SCAR, severe cutaneous adverse reaction.Includes specific antibiotic allergy label of Co-T or trimethoprim-sulfamethoxazole.Recent anaphylaxis was defined as anaphylaxis within the past 5 years; a positive allergy test result was defined as any positive allergy test finding, including positive result on patch testing or oral challenge.Prospective cohort; Austin Health (87.1% [101 of 116]) and Peter MacCallum Cancer Centre (12.9% [15 of 116]); November 1, 2015, to July 31, 2022.Testing sites were inpatient and outpatient.Excluded phenotypes were recent anaphylaxis and SCAR.Patients underwent patch testing and oral challenge testing after patch testing.Retrospective cohort; Vanderbilt University Medical Center; October 1, 2015, to February 28, 2019.Testing sites were outpatient only.Excluded phenotypes were recent anaphylaxis and SCAR.Patients underwent 1-step and 2-step oral challenge testing.Most patients with positive test reported a "trimethoprim-sulfamethoxazole" allergy (6 of 6 in the Melborne cohort and 12 of 13 in the US cohort), while 1 patient reported "unspecified sulfa" allergy.
a b c d Includes nonimmune mediated and reactions with unknown timeline.e

Table 2 .
Validation of SULF-FAST in All Validation Cohorts (Overall) With Subgroup Analysis Performed on Allergy Phenotype a