A 3/2 y/o female patient presents new prescription for hydrochlorothiazide (HCTZ - a thiazide diuretic) to the pharmacy.  The computer system alerts you this patient has documented allergy to "sulfa antibiotics". She describes signs and symptoms consistent with a 'fixed drug reaction' with blisters and peels. She also experiences hives on her body, arms and legs. Do you fill this prescription?  Why or why not?

What do you tell him?

**THANKS to MAJs (Drs.) Libby Schindler and John Dice for their help with this Pearl.**

Probably yes.

Actually, this issue has come up several times.  In my limited understanding, sulfonamide antibiotics (ex. Sulfamethoxazole) and sulfonamide non-antibiotics (ex. thiazide diuretics, sulfonylureas) are distinct entities and an allergic reaction to one group does NOT necessarily predict allergic reaction to the other.

It is estimated 3% of the general population experience hypersensitivity reactions to sulfonamide antibiotic drugs, usually to the sulfamethoxazole component of TMP-SMX.  Some sources say all sulfonamides are contraindicated in patients with a history of "sulfa allergy".  The question then becomes whether drugs with a similar structure to the sulfonamide in sulfamethoxazole (SMX) should be avoided in a patient with h/o hypersensitivity reaction to TMP-SMX.  According to CM Reinke, PharmD, MS, professor at Auburn's Harrison School of Pharmacy, "technically, a sulfonamide is the generic name for any derivative of sulfanilamide, including the various sulfonamide antibiotic agents. Most often those who refer to "sulfonamide" are referring to any compound with most of this
chemical structure (the --SO2NHR constituent). However, all sulfonamide antibiotics (i.e., SMX, sulfasoxazole, sulfapyridine, sulfamethazine, sulfamerazine, sulfamethoxazole, sulfamethizole) share an arylamine (--NH2) at the C4 position and the presence of this group appears to be essential for cross-sensitization to occur. Sulfonamides that are not antibiotics lack the arylamine substituent."  (examples are furosemide, bumetinide,
hydrochlorothiazide, sulfasalazine, glyburide, sumatriptan, celecoxib). FYI - Celecoxib [Celebrex®] is CONTRAindicated in patients with hypersensitivity (severe urticaria, asthma, other immune- based reaction) to sulfonamides.

Most data implicating cross reactivity between these groups are case reports regarding thiazides, loops, and sulfonylurea hypoglycemic agents and labeling is quite inconsistent regarding the use of these agents with a history of "sulfa allergy".  In addition, the actual reactions that occur with TMP-SMX are a consequence of the metabolism ("haptenation pathway") which is common to the sulfonamide antibiotics, but NOT to the non-antibiotics.

A recent retrospective epidemiological study by Strom BL and colleagues (Absence of Cross-Reactivity between Sulfonamide Antibiotics and Sulfonamide Nonantibiotics.  N Engl J Med 2003;349:1628-35) found an allergy to a sulfonamide antibiotic is a risk factor for a subsequent allergic reaction to a sulfa non-antibiotic, but that a history of PCN allergy is at least as strong a risk factor.  Therefore, the authors conclude their results indicate any association between an allergic reaction to a sulfonamide antibiotic and non-antibiotic is due to a general disposition to allergic reactions among certain patients vs. a specific cross reactivity between sulfa moieties.

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