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'Sulfur allergy' label is misleading |
Summary
The term 'sulfur allergy' is misleading and dangerous and should not be used. An allergy to a sulfonamide antibiotic may imply cross-reactivity with other sulfonamide antibiotics, but does not imply cross-reactivity with non-antibiotic sulfonamides or other drugs containing sulfhydryl or sulfate groups. Patients who suffer from an allergic reaction to the combination of sulfamethoxazole and trimethoprim should be considered potentially allergic to trimethoprim and/or sulfamethoxazole until proven otherwise, and not recorded simply as 'sulfur allergic'. Allergy to sulfonamides also does not imply cross-reactivity with sulfite preservatives, sulfates or elemental sulfur.
Key words: cross-reactivity, sulfonamide allergy.
(Aust Prescr 2008;31:8-10)
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Introduction
Sulfonamides were the first class of antibiotics to be introduced in the 1930s. They remain important because they are effective, relatively safe and inexpensive, but adverse effects are relatively common.
Up to 8% of hospitalised patients and 1–2% of those in the community are reported to suffer adverse effects from the combination of sulfamethoxazole with trimethoprim, although only about 3% of these are thought to represent hypersensitivity. The situation is markedly different in patients with HIV as up to 60% experience allergic adverse reactions.
While most hypersensitivity reactions are relatively mild, sulfonamides account for a disproportionate number of cases of life-threatening Stevens-Johnson syndrome and toxic epidermal necrolysis.
Allergic mechanisms
The mechanisms of hypersensitivity to sulfonamides are not completely understood, but some principles are apparent. 1 The term sulfonamide applies to a sulfone group connected to an amine group (Fig. 1). All antibiotic sulfonamides are arylamines (Table 1).
Like most small chemical allergens, sulfonamides probably require metabolism or haptenation for immunogenicity. Hepatic oxidation of the arylamine group by the cytochrome P450 system results in the formation of a hydroxylamine intermediate metabolite which can be reduced by glutathione and excreted. However, the capacity for glutathione conjugation may be exceeded. The reactive hydroxylamine is capable of haptenating endogenous proteins and has been shown to be associated with hypersensitivity. Other reactive metabolites have also been identified. These may act by forming immunogenic structures (epitopes) for antibodies or T cells and also by direct cytotoxicity to lymphocytes and other immune cells.
Cross-reactivity
Many commonly used drugs, such as thiazide diuretics, gliclazide, frusemide and celecoxib, contain a sulfonamide moiety, but none contain the arylamine group. While it has long been considered that allergic cross-reactivity may exist between sulfonamide antibiotics and other sulfonamide drugs, this is actually unlikely because of the structural differences. Reports of cross-reactivity are based on single cases or small series. 2 The co-existence of hypersensitivity reactions to several drugs does not prove cross-reactivity between them. A review of all available relevant studies concluded that the dogma of cross-reactivity between sulfonylarylamines and other sulfonamide drugs cannot be supported by the evidence. 3 In patients who have had an allergic reaction to one drug, allergic reactions to other drugs, even if entirely unrelated, occur more commonly. In support of this concept, a very large cohort study showed that the association between allergy to sulfonylarylamines and other sulfonamide drugs was no stronger than that between sulfonylarylamines and the completely unrelated penicillins. 4 The evidence therefore suggests that non-antibiotic (non-arylamine) sulfonamide drugs need not be considered as contraindicated in those with a history of hypersensitivity to antibiotic (sulfonylarylamine) sulfonamides. This conflicts with the product information of many drugs.
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Sulfonamide structure
A Basic sulfonamide structure – present in many drugs. B Sulfamethoxazole. The arylamine moiety, and also probably the 5-member ring containing a nitrogen atom, is thought to be important for hypersensitivity reactions. |
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