A frequent question received by SDIS is “What drug can be used by a patient with a sulfa allergy”? The most common approach to  this problem is avoidance of all sulfonamides. Analysis of the literature, however, indicates that cross-reaction among different classes of sulfonamide drugs is unlikely to occur; thus we may be withholding appropriate therapies from patients unnecessarily.

SULFONAMIDES DEFINED

Sulfonamides are compounds than contain sulfur in a SO₂NH₂ moiety directly attached to a benzene ring.¹ Many  medications contain sulfur but are not sulfonamides, e.g., amoxicillin, captopril, omeprazole, spironolactone, sulfates and sulfites.² There is no risk of cross-reactivity between these substances and sulfonamides.²

Sulfonamides can be divided into two groups; the antibiotics (eg, sulfamethoxazole, sulfisoxazole, sulfacetamide) and the non-antibiotic sulfonamides (e.g., thiazides, furosemide, glyburide, sumatriptan, celecoxib). Certain chemical structures unique to the antibiotic group are implicated in the production of hypersensitivity reactions - an arylamine moiety at the N4 position and substitutions at the N1 position of the benzene ring.¹

HYPERSENSITIVITY ADVERSE EFFECTS

The term “sulfa allergy” is often incorrectly applied to all adverse reactions that occur with sulfonamide-containing medications and not just to those due to hypersensitivity mechanisms. Patients who experience side effects such as nausea and vomiting may interpret this as an allergy and subsequently report that they are allergic to sulfas.¹

Approximately 3 % of patients who receive sulfonamide antibiotics experience true hypersensitivity reactions.³  These include the entire range of immunologic reactions as well as idiosyncratic reactions (Table 1).⁴ Mild maculopapular or urticarial rashes are the most common symptoms.⁵ These generally occur within one week of drug therapy and disappear 7 to 14 days after the drug is discontinued.⁶  Less frequently, more serious dematologic reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis develop.⁵ Non-dermatological reactions such as drug fever, serum sickness syndrome, vasculitis, nephritis, hepatitis and hemolytic anemia have also been reported.⁵

Type 1 (immediate) anaphylactic reactions are rare.⁵ These reactions have been linked to the N-1 substituents in the antibiotic structure. As mentioned above, non-antibiotic sulfonamides do not contain these substituents.^1,4

 Idiosyncratic reactions to antibiotic sulfonamides are thought to be caused by a reactive metabolite produced by oxidation of the arylamine structure.^1,4  If not detoxified, this metabolite acts as a hapten (partial antigen) and binds to endogenous proteins to form a compound that triggers an immune reaction.² Haptenated compounds may also be directly toxic to cells.⁴ The arylamine structure is not found in non-antibiotic sulfonamides.

Table 1: Hypersensitivity Reactions to Sulfonamide Antibiotics^1,4

 CROSS-REACTIVITY AMONG SULFONAMIDES

Cross-reactivity is the likelihood that a person who has had a hypersensitivity reaction to one drug will have the same reaction to a structurally similar drug. In theory, therefore, cross-reactivity would be expected to occur among different members of the antibiotic sulfonamides but not between different classes of sulfonamides.^1,4  In fact, reports in the literature documenting the safe use of sulfonamide medications in patients with a previous history of allergy to a sulfonamide outnumber reports of adverse reactions to two or more sulfonamides.¹

 A possible explanation for reports of sulfonamide cross-sensitivity may be the tendency of certain patients to be more susceptible to hypersensitivity reactions. Patients allergic to one antimicrobial drug are reported to be 10 times more likely to react to another non-structurally related drug than patients without a history of allergy.⁷ Thus, reactions to more than one sulfonamide may actually represent multiple allergies rather than a specific allergy to sulfonamides.⁷

 RISK FACTORS FOR HYPERSENSITIVITY REACTIONS