Version July 2025
| Type of past reaction | Signs and symptoms/historical information | What medication does patient need now? | How can it be given safely? | |
| A | Patient does not know details of past reaction, just that they are allergic to "sulfa" | Ask patient:
If patient answers no to last 3 questions (or does not know), can assume the reaction was likely simple cutaneous or cutaneous with fever +/– systemic symptoms. TMX-SMX is most likely causative drug if given for infection. Follow advice in rows B or C below. | N/A | N/A |
| N/A | N/A | |||
| Delayed hypersensitivity reactions (beginning after days to weeks of therapy) | ||||
| B | Simple cutaneous reaction (no fever or systemic symptoms) to a sulfonamide antimicrobial (eg, TMP-SMX) | Maculopapular or morbilliform eruption, mild erythema, delayed-onset urticaria, or pruritus appearing in the first few days of treatment and resolving upon drug discontinuation. Note that an immediate reaction should also be considered in patients with isolated urticaria. Refer to row E. | Sulfonamide nonantimicrobial (eg, furosemide, hydrochlorothiazide, acetazolamide, glyburide, sumatriptan, protease inhibitor, others) | Give normally. |
| Sulfonamide antimicrobial (eg, TMP-SMX or related): | Use nonsulfonamide instead or consider challenge if there is no equivalently effective nonsulfonamide alternative. | |||
| One-step (direct) challenge with desired drug (eg, TMP-SMX) under medical supervision.¶ | |||
| Graded challenge with desired drug under medical supervision.¶ | |||
| C | Cutaneous reaction with fever and/or systemic symptoms to a sulfonamide antimicrobial (eg, TMP-SMX) | Maculopapular or morbilliform eruption with fever and/or systemic symptoms appearing 1 to 2 weeks after start of treatment and resolving 1 to 2 weeks after discontinuation. May involve hepatitis, nephritis, pulmonary infiltrates, cytopenias. Atypical lymphocytosis or eosinophilia possible. | Sulfonamide nonantimicrobial | Give normally with the exception of sulfasalazine. Another possible exception is the patient with multiple drug allergies as this history may identify a subset of patients at higher risk for drug reactions in general. Direct or graded challenge could be performed instead.¶ |
| Sulfasalazine is a nonantimicrobial that releases sulfapyridine, an antimicrobial, upon exposure to gut bacteria. Avoid in patients with past serious reactions to TMP-SMX or involve a drug allergy specialist.¶ | |||
| Sulfonamide antimicrobial (TMP-SMX or other) | If no other equivalent medication is available, a gradual reintroduction protocol can be performed. Success is mixed. Involve a drug allergy specialist when possible.¶ | |||
| DapsoneΔ | Avoid if there are alternatives. If critical to give, involve a drug allergy specialist and explain risks/benefits to patient.¶ | |||
| D | SJS/TEN or erythema multiforme to a sulfonamide antimicrobial (eg, TMP-SMX) | Fever, malaise, blistering rash, mucous membrane involvement, desquamation | Sulfonamide nonantimicrobial (eg, furosemide) | Give normally with the exception of sulfasalazine and celecoxib. |
| Sulfasalazine is a nonantimicrobial that releases sulfapyridine, an antimicrobial, upon exposure to gut bacteria. Avoid in patients with past serious reactions to TMP-SMX or involve a drug allergy specialist.¶ | |||
| Celecoxib is a nonantimicrobial sulfonamide and selective COX-2 inhibitor. It is independently associated with SJS, so avoid in patients with any history of blistering drug reactions or involve a drug allergy specialist.¶ | |||
| Sulfonamide antimicrobial (eg, TMP-SMX or other) | Contraindicated. Avoid all drugs in the same sulfonamide group. Reaction could recur and possibly be more rapid and severe.¶ | |||
| DapsoneΔ | Avoid if there are alternatives. If critical to give, involve a drug allergy specialist and explain risks/benefits to patient.¶ | |||
| Immediate hypersensitivity reactions (beginning within minutes to 2 hours of the first dose) | ||||
| E | Immediate allergy and anaphylaxis (pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, hypotension) Rare with sulfonamides but can occur with drugs from either group (ie, antimicrobials or nonantimicrobials) | Urticaria, angioedema, pruritus, bronchospasm, hypotension | Sulfonamide from the other group | Give normally. |
| Sulfonamide from the same group | Avoid causative drug and all sulfonamides in the same group (antimicrobial or nonantimicrobial). Skin testing is not validated. Could only give the same or a related drug through a rapid desensitization protocol. Refer to UpToDate content on rapid drug desensitization for immediate-type drug hypersensitivity.¶ | |||
COX-2: cyclooxygenase 2; HLA: human leukocyte antigen; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; TMP-SMX: trimethoprim-sulfamethoxazole.
¶ Involvement of a drug allergy specialist is advised, if possible, for the management options shaded in yellow (can be given with caution) or orange (do not give) . Challenge procedures are described in the UpToDate topic on sulfonamide hypersensitivity.
Δ Dapsone is not a sulfonamide but a sulfone. Dapsone can cause a severe hypersensitivity reaction ("sulfone syndrome") that is similar to severe delayed reactions to sulfonamides. The degree of cross-reactivity with TMP-SMX is unclear, but certain patients are at increased risk for reacting to both drugs (possibly due in part to HLA-B*13:01).
