Is Cross-Reactivity of Concern With Sulfa-Containing Medications?

Allergies to sulfa-containing drugs are common and lead to significant concern regarding alternative medications as well as cross-reactivity. The most common agent associated with this concern is sulfamethoxazole (SMX), a sulfonamide antibiotic to which an estimated 3% to 6% of the population is intolerant.¹ Allergic reactions to SMX can range from mild to severe with Stevens-Johnson syndrome and immune-mediated hypersensitivity reactions representing the most feared sequelae. Fortunately, these complications are relatively rare. As many other commonly prescribed medications contain a sulfa moiety (Table), there is often concern for cross-reactivity in patients who have a documented intolerance to sulfonamide antibiotics. 

A Case Study

ED is a 67-year-old white male who is an established patient in your practice. You are managing his hypertension, which had been well controlled on amlodipine 10 mg daily. Recently, due to dietary indiscretion and a lack of exercise, his blood pressure is no longer controlled and you are considering adding another medication—chlorthalidone 12.5 mg daily—which has been e-prescribed to his pharmacy. Note: ED is allergic to SMX.

A few hours later you receive a call from the pharmacy. The pharmacist reports that the drug interaction system is flagging the chlorthalidone as a problem due to ED’s allergy to SMX since chlorthalidone also contains a sulfa moiety. Can ED safely receive chlorthalidone?

The Evidence

While the sulfa moiety is present in both the sulfa-containing antibiotic (SMX) and nonantibiotic medication, it should be noted that structural differences within these molecules surrounding the sulfa moiety affect the potential for an allergic reaction. Sulfonamide antibiotics contain an aromatic amine substituted at the N1 position whereas the nonantibiotic sulfa-containing medications do not have this aromatic amine at the N1 position.² This aromatic amine and the resulting 3-dimensional structure of the molecule are both necessary components for an immune-mediated reaction to occur. As the nonantibiotic sulfa containing medications do not contain this aromatic amine at the N1 position, the 3-dimensional structure is not amenable to an immune-mediated reaction. While this is a logical thought process, clinical correlation is needed in order to complete the picture.

A literature search³ of published case reports and manufacturer information confirmed a lack of convincing evidence to substantiate the cross-reactivity. Only 9 case reports were identified in the search (spanning 55 years), and in all of these reports, there was insufficient information to definitively establish causality with respect to cross-reactivity. Given the lack of clinical evidence, combined with the differences in molecular structures, it appears unlikely that a true cross-reactivity between sulfonamide antibiotics and nonantibiotics exists. 

In patients who manifest intolerance to a nonantibiotic medication containing a sulfa moiety, it may be more likely they truly have intolerance to that medication rather than suffering from a true cross-tolerance. 

Clinical Application

When patients have a documented sulfa allergy, SMX-containing antibiotics should be avoided. However, given the lack of clinical evidence substantiating a cross-sensitivity and differing molecular structures, avoidance of sulfa-containing nonantibiotic medications is likely not indicated. As with any medication, patients should be monitored closely after starting a new medication for signs or symptoms of intolerance or allergy; any such event should likely be attributed to the specific agent rather than cross-sensitivity. 

Outcome of the Case

Although ED has a documented allergy to SMX, we should not be concerned of cross-sensitivity with the sulfa-containing chlorthalidone based on the available information. He should be counseled to monitor for signs of intolerance or allergy to the chlorthalidone upon initiation, but this counseling should be provided upon initiation of all medications (and therefore is not specific to this instance). The pharmacist would be counseled to dispense the medication as it is safe for the patient and will not have a cross-reaction with his allergy to SMX.

References:

1. Wulf NR, Matuszewski KA. Sulfonamide cross-reactivity: is there evidence to support broad cross-allergenicity? Am J Health Syst Pharm. 2013;70(17):1483-1494.
2. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of ‘sulfa’ allergy. Drug Saf. 2001;24(4):239-247.
3. Johnson KK, Green DL, Rife JP, Limon L. Sulfonamide cross-reactivity: fact or fiction? Ann Pharmacother. 2005;39(2):290-301. Erratum in: Ann Pharmacother. 2005;39(7-8):1373.

Eric A. Dietrich, PharmD, BCPS, graduated from the University of Florida College of Pharmacy in 2011 and completed a 2-year fellowship in family medicine where he was in charge of a coumadin clinic. He now works for the University of Florida Colleges of Pharmacy and Medicine in Gainesville, FL. 

Kyle Davis, PharmD, BCPS, graduated from the University of Florida College of Pharmacy in 2011 and completed a PGY-1 at Jackson Memorial Hospital and a PGY-2 in internal medicine at Indiana University Health and Butler College of Pharmacy. He currently works at Jackson Memorial Hospital in Miami, FL.