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Acetazolamide and sulfonamide allergy


68-year-old woman that will be traveling to Machu Picchu in 6 months. She is concerned about altitude sickness and wants to take acetazolamide with her. She has a history of an adverse reaction to a "sulfa" antibiotic as an infant or toddler but does not recall the exact reaction and is concerned. Do you think an oral challenge in the office would suffice?


All sulfonamide antibiotics have the structure, in which the R1 is an arylamine, benzene ring attached to a nitrogen, and R2 or R3 is usually a substituted ring structure. The arylamine, is important in the specific metabolism of sulfonamides.

The Acetazolamide structure is not an arylamine as there is no 6 carbon benzene ring attached to a nitrogen or amino group. This difference reduces the likelihood of cross-reactivity.

Cross-reactivity among sulfonamide antibiotics and other sulfonamides or sulfur containing compounds is based upon theory more than data. A published paper in the New England Journal of Medicine concluded the following (1)

“Thus, although a history of allergy to sulfonamide antibiotics is a marker of increased risk on subsequent exposure to sulfonamide nonantibiotics, our results suggest that this risk is not unique to sulfonamide antibiotics. Indeed, patients with a history of hypersensitivity to sulfonamide antibiotics are at even greater risk for subsequent reactions to penicillins, a biochemically distinct group, than to nonantibiotic sulfonamides. Prescribers should understand that patients with a history of allergic reactions to drugs may be at increased risk for all drug-induced adverse events that appear to be allergic in nature.”

I have included copies of questions from the archives of Ask the Expert discussing potential cross-reactivity among sulfonamides. The consensus is that a history of sulfonamide allergy does not specifically increase risk of reaction to non-antibiotic sulfonamide or sulfonamide without an arylamine structure (benzene ring attached to the nitrogen group), such as acetazolamide.

In summary, the risk of reaction to acetazolamide in a patient with sulfonamide allergy is low. However, acetazolamide is listed as possibly cross-reacting with sulfonamide in drug information and the package insert. I would discuss with the patient that although the risk is low you cannot exclude a reaction without challenge. Since there are limited options for altitude sickness, I would document a shared decision-making discussion and recommend, if the patient agrees, a clinic drug challenge (do not feel a graded challenge is needed but simple administration under observation), observation for one to two hours and treatment for several days to exclude a delayed reaction. If all of this is negative, then I would be comfortable with the patient using the acetazolamide during travel.

1. Strom BL, Schinnar A, Apter AJ et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628-35.

I hope this information is of help to you and your practice.

All my best.
Dennis K. Ledford, MD, FAAAAI

5/16/2017: Lack of cross reactivity between sulfonamide antibiotics and nonantibiotic sulfonamides
Question: I am seeing a 66 year-old gentleman with severe glaucoma who was referred to me by his ophthalmologist to determine if he is allergic to acetazolamide (Diamox). He has failed many other medications for treatment of his glaucoma and at this time declines surgical intervention. He is unsure if he ever took sulfa containing antibiotics but was advised at age 6 to avoid them for unknown reasons. Since Diamox is not a sulfonamide antibiotic, does he need to be skin tested to this medication or is the risk of cross reaction so low that this is not necessary?

Answer: From the Drug Allergy: An Updated Practice Parameter, October, 2010, see below, testing is not indicated.
"There are data suggesting that patients with a history of allergy to sulfonamide antibiotics are at slightly increased risk of reacting to nonantibiotic sulfonamides, although this does not appear to be due to immunologic cross reactivity but rather a nonspecific predisposition to react to drugs. Although all sulfonamides contain a NH2-SO2 moiety, sulfonamide antibiotics also contain an aromatic amine at the N4 position and a substituted ring at the N1 position, and these groups are believed to be essential for various types of allergic reactions to sulfonamide antibiotics."

We hope this helps.
Patricia McNally, MD, FAAAAI

11/12/2001: Cross reactivity between sulfonamide antimicrobials and other agents
Question:I'm looking for a list of suspect agents to tell my sulfa sensitive patients to avoid and to carefully consider for cross reactivity besides certain diuretics. I have a new patient with a history of sulfa anaphylaxis and subsequent serum sickness that I think is flaring from artificial sweeteners.

Answer: My response has been delayed slightly because I wished to obtain input from Dr. Rebecca Gruchalla of the Univ. of Texas, one of the outstanding investigators of the mechanisms involved in adverse reactions to sulfa antimicrobials. Her response is enclosed below. I should say that I have the same impression from my reading of some of the relevant literature,- the cross reactivity between sulfa antimicrobials and other agents is more theoretical than proven.

Dr. Gruchalla's response
"I have enclosed a list of agents that may theoretically cross react with sulfonamides....I am attaching it....does this help?

All of these are theoretical cross reactivities...I doubt too many physicians ask their pts about sulfa reactions before they prescribe hydrochlorothiazide! Regarding the cross reactivity between Celebrex and data!...however, I am inserting an abstract from Neil Shear's group that addresses this issue:

The BIG question:
Can sulfonamide-allergic individuals take Dapsone, HydroDIURIL, Lasix, Micronase, Pediazole, Celebrex, Diamox, Vioxx, Trusopt, or Azulfidine?
Physician Desk Reference 2000 Drug Contraindications:
1. Dapsone - Hypersensitivity to Dapsone and/or its derivatives
2. HydroDIURIL (hydrochlorothiazide) - Hypersensitivity to this product or to other sulfonamide-derived drugs
3. Silvadene (silver sulfadiazine) - Hypersensitivity to silver sulfadiazine or any of the other ingredients in the preparation
4. Furosemide - Hypersensitivity to furosemide (a change from previous PDR recommendation)
5. Micronase (glyburide) - Hypersensitivity to the drug
6. Pediazole (erythromycin ethylsuccinate and sulfisoxazole acetyl) - Hypersensitivity to either of its components
7. Diamox (acetazolamide) - Hypersensitivity to this agent, other carbonic anhydrase inhibitors, sulfonamides or thiazide diuretics
8. Trusopt (dorzolamide) - (precaution not a contraindication) - Hypersensitivity to this agent, other carbonic anhydrase inhibitors, sulfonamides or thiazide diuretics
9. Blephamide (sulfacetamide and prednisolone) - Hypersensitivity to any of the ingredients of this preparation, to other sulfonamides and to other corticosteroids
10. Azulfidine (sulfasalazine) - Hypersensitivity to sulfasalazine, its metabolites, sulfonamides or salicylates
11. Celebrex (celecoxib) - Allergic-type reactions to sulfonamides
Vioxx (refecoxib) - Hypersensitivity to refecoxib or any other component of Vioxx

Drug Saf 2001;24(4):239-47
Should celecoxib be contraindicated in-patients who are allergic to sulfonamides? Revisiting the meaning of 'sulfa' allergy.
Knowles S, Shapiro L, Shear NH.
Clinical Pharmacology, Department of Medicine, Sunnybrook & Women's Health Sciences Centre, Toronto, Canada.
Celecoxib, a selective cyclo-oxygenase-2 inhibitor, is a diaryl-substituted pyrazole derivative containing a sulfonamide substitute. Because of this structural component, celecoxib is contraindicated for use in-patients who have demonstrated allergic reactions to sulfonamides. However, there is a lack of data demonstrating cross-reactivity among sulfonamide populations. A sulfonamide is any compound with an SO2NH2 moiety. The major difference between sulfonamide antimicrobials and other sulfonamide-containing medications such as furosemide, thiazide diuretics and celecoxib, is that sulfonamide antimicrobials contain an aromatic amine group at the N4 position. This allows for division of the sulfonamides into 2 groups: aromatic amines (i.e., sulfonamide antimicrobials) and nonaromatic amines. In addition, sulfonamide antimicrobials contain a substituted ring at the N1-position; this group is not found with nonaromatic amine-containing sulfonamides. Adverse reactions to sulfonamide antimicrobials include type I, or immunoglobulin (Ig) E-mediated reactions, hypersensitivity syndrome reactions, and severe skin reactions such as toxic epidermal necrolysis. The aromatic amine portion of the sulfonamide antimicrobial is considered to be critical in the development of latter 2 reactions. In susceptible individuals, the hydroxylamine metabolite is unable to be detoxified leading to a cascade of cytotoxic and immunological events that eventually results in the adverse reaction. Since celecoxib does not contain the aromatic amine, adverse reactions such as hypersensitivity syndrome reactions and toxic epidermal necrolysis would not be expected to occur at the same frequency as they do with sulfonamide antimicrobials. Similarly, for IgE-mediated reactions, the N1-substituent and not the sulfonamide moiety is important in determining specificity to antibodies. Celecoxib and other nonaromatic amine-containing sulfonamide medications do not contain the N1-substituent. Cross-reactivity among the various sulfonamide-containing medications has also not been substantiated by published case reports. In fact, conflicting information exists in the literature. Reports showing lack of cross-reactivity balance the few case reports suggesting cross-reactivity. Cross-reactivity between sulfonamide medications should be based on scientific data, including chemistry, metabolism, immune responses and clinical data. Based on the current information, there is no documentation for cross-reactivity between sulfonamide antimicrobials and other sulfonamide medications, such as celecoxib."