The Metabolic Rationale for a Lack of Cross-reactivity Between Sulfonamide Antimicrobials and Other Sulfonamide-containing Drugs

Abstract

Sulfonamide antimicrobials (sulfamethoxazole) contain an arylamine group, oxidized by CYP2C9 to the hydroxylamine with subsequent auto-oxidation to a highly reactive [-nitroso-] intermediate is a necessary (if not sufficient) cause of drug hypersensitivity. Accordingly, xenobiotics that do not contain an arylamine cannot generate this reactive intermediate and do not cross react with sulfonamide antimicrobials. Despite this well-attested observation, product labeling and direct-to-consumer advertising for non-arylamine therapeutic classes of drugs containing the sulfonamido- functional group persist with a warning of the potential for cross-reactivity. It is hoped that by offering an explicit rationale for the lack of cross-reactivity will provide medical practitioners with a level comfort to proceed with prescribing medications such as thiazide diuretics and celecoxib for patients with a history of hypersensitivity to sulfonamide antimicrobials.

A Survey on Knowledge Gaps in Assessment and Management of Severe Drug Hypersensitivity Reactions: Multicenter Cross‐Sectional Study of Australian Health Care Providers

“…Nonarylamine group sulfonamides (eg, frusemide, hydrochlorothiazide, celecoxib) do not cross‐react with arylamine sulfonamides (sulfonilamide antimicrobials and sulfasalazine) 22 . However, as shown in our questionnaire, there is still significant hesitation among HCPs in prescribing or recommending medications such as thiazide diuretics and celecoxib to patients with sulfonilamide allergies 22 . Nonantibiotic sulfonamides may be prescribed for patients reporting an antibiotic sulfonamide hypersensitivity.…”

Clinical relevance of cross-reactivity between darunavir and trimethoprim-sulfamethoxazole in HIV-infected patients

“…Several previous publications have questioned the entity of sulfonamide cross-reactivity [8,9]. Pharmacological metabolization of the DRV sulfonamide group does not lead to the generation of a reactive hydroxylamine intermediate that is the cause of drug hypersensitivity [8]. That would explain the absent association of a crossreactivity between DRV and TMP-SMX in two of the three studies [4,5].…”

“…It is important to note that the latter study did not classify their allergic patients according to the Naranjo scale making interpretation more difficult. Several previous publications have questioned the entity of sulfonamide cross-reactivity [8,9]. Pharmacological metabolization of the DRV sulfonamide group does not lead to the generation of a reactive hydroxylamine intermediate that is the cause of drug hypersensitivity [8].…”