Sulfonamide hypersensitivity

Sulfa allergy: which drugs cross-react and which do not

Two groups, one word

What “sulfonamide” means — and what “sulfa” does not

Sulfonamide = any compound with an SO₂NH₂ moiety; two groups — antimicrobials and non-antimicrobials
Antimicrobials carry an aromatic amine at N4 and a nitrogen heterocycle at N1; most non-antimicrobials have neither
“Sulfa” means the antimicrobials — some patients hear it as everything with “sulf-” in the name
Sulfur, sulfites and sulfates (penicillins, captopril, omeprazole, metabisulfite, morphine sulfate, ferrous sulfate) are not sulfonamides — no cross-sensitivity
Numbers on these slides are from Khan 2019 unless marked¹

Sulfamethoxazole ballicule — decagon mechanism diagram — Sulfamethoxazole

Sulfasalazine ballicule — decagon mechanism diagram — Sulfasalazine

Celecoxib ballicule — decagon mechanism diagram — Celecoxib

Furosemide ballicule — decagon mechanism diagram — Furosemide

The three parts of a sulfa antimicrobial

Figure 1 of Khan 2019, on the library’s own structure — click a phrase or an atom

The N4 aromatic amine is acetylated or — in slow acetylators, via CYP2C9 — oxidized to the hydroxylamine and nitroso metabolites behind the non-IgE reactions. The sulfanilamide SO₂NH is what every “sulfonamide” shares. The N1 heterocyclic ring, an isoxazole with a methyl on the carbon beta to the nitrogen, is the IgE epitope.

IgE: specificity comes from the N1 substituent, not the sulfonamide group — a nitrogen heterocycle at N1, and a methyl on the carbon beta to the sulfonamide
Non-IgE: 45–70% of sulfamethoxazole is N4-acetylated (harmless); the rest is N4-hydroxylated by CYP2C9 — more so in slow acetylators — to a reactive nitroso compound
The nitroso metabolite is directly cytotoxic or binds T cells → SJS/TEN; without the aromatic amine, non-antimicrobials cannot make it

What the non-antimicrobials lack

The sulfonamide moiety itself does not trigger the serious reactions

A primary sulfonamide on a benzene ring whose para position carries the pyrazole, not an amine: no N4 aromatic amine, nothing on the sulfonamide nitrogen — neither the metabolite route nor the IgE epitope of the antimicrobials.

SO₂NH₂ alone does not cause DRESS or SJS/TEN — the aromatic amine does; furosemide, celecoxib and acetazolamide lack it
No N1 substituent either, so no shared IgE epitope
Monograph advice to avoid non-antimicrobial sulfonamides rests on little evidence; label wording runs from no warning to a contraindication

The diuretics

Thiazide-type and loop diuretics carry the warning without the chemistry

The benzothiadiazine dioxide core folds one of the two sulfonamide groups into a ring; the other is a free SO₂NH₂ on the chlorinated benzene edge. The only ring nitrogen is a secondary amine inside the thiadiazine — no N4 aromatic amine, no N1 heterocycle.

No or weak evidence of cross-reactivity: hydrochlorothiazide, chlorthalidone, indapamide, metolazone, diazoxide, furosemide, bumetanide
In the library’s non-antibacterial class because each label warns; torsemide’s does not, and ethacrynic acid has no sulfonamide at all⁷
Diazoxide’s label is contraindicated with hypersensitivity to “other thiazides” — the word sulfonamide never appears⁶

The sulfonylureas

Same bridge, three different labels

The sulfonamide nitrogen is acylated into a urea — the sulfonylurea bridge — and the phenyl ring carries an alkyl chain, not an amine, para to the sulfonyl. Glimepiride’s label contraindicates it after an allergic reaction to sulfonamide derivatives; glipizide’s and glyburide’s, with the same bridge, say nothing.

Glimepiride, glyburide and gliclazide: no or weak evidence of cross-reactivity
Glimepiride is label-contraindicated after a sulfonamide-derivative reaction; glipizide and glyburide, same bridge, are label-silent — so only glimepiride sits in the class

What cross-reactivity really looks like

Strom, NEJM 2003 — the number behind every modern review

Prior sulfonamide-antibiotic allergy: 96 of 969 (9.9%) reacted to a later sulfonamide non-antibiotic; without it, 315 of 19,257 (1.6%) — adjusted OR 2.8²
The same patients reacted to penicillin even more often (OR 3.9); their risk from a sulfonamide non-antibiotic was LOWER than from a penicillin (OR 0.7)²
Reads as a reaction-prone patient, not a shared structure — the pattern seen with cephalosporins after penicillin allergy
No conclusive case report documents antimicrobial-to-non-antimicrobial cross-reactivity

Penicillin V ballicule — decagon mechanism diagram — Penicillin V

After a reaction to TMP-SMX — avoid

Table II of Khan 2019

Every sulfonamide antimicrobial, any route — sulfacetamide eye drops and silver sulfadiazine cream included
Sulfasalazine: metabolized to sulfapyridine, a sulfonamide antimicrobial
Trimethoprim: no way to know which component reacted, and trimethoprim itself causes anaphylaxis
After SERIOUS reactions, prudent to avoid the aromatic-amine drugs too: dapsone (a sulfone), fosamprenavir, darunavir, sulfasalazine

Trimethoprim ballicule — decagon mechanism diagram — Trimethoprim

Dapsone ballicule — decagon mechanism diagram — Dapsone

Darunavir ballicule — decagon mechanism diagram — Darunavir

Dapsone — a sulfone with two arylamines

Conflicting data; avoid after severe reactions

A sulfone — SO₂ between two carbons, no nitrogen — bridges one phenyl ring and a second, each carrying an aromatic amine: two primary amines. Not a sulfonamide, but the arylamines can form the same hydroxylamine and nitroso metabolites.

Cross-reactivity evidence is conflicting; avoidance suggested, especially after severe reactions
In HIV, often tolerated after TMP-SMX intolerance — all 13 patients given dapsone in one series tolerated it⁴
RegiSCAR DRESS: dapsone 3 cases, sulfasalazine 7% — TMP-SMX only 2 of 115

Darunavir — the antiretroviral exception

The one non-antibacterial in the library that carries the N4 aromatic amine

The sulfonamide sits on a benzene ring whose para position carries a primary aromatic amine: 4-aminobenzenesulfonamide, the sulfanilamide fragment of the antimicrobials, built into an HIV protease inhibitor. The bis-tetrahydrofuran core and carbamate are the protease-binding end.

Label: contains a sulfonamide moiety; use with caution in known sulfonamide allergy³
Fosamprenavir is a sulfanilamide derivative; many sulfonamide-allergic patients tolerate darunavir, but caution at initiation
Khan’s text credits only fosamprenavir and amprenavir with the N4 arylamine; darunavir’s structure carries the same 4-aminobenzenesulfonamide — hence “all but darunavir” on the class card

Sulfasalazine — sulfapyridine in disguise

An antibacterial sulfonamide prescribed for the bowel and the joints

A pyridine ring on the sulfonamide nitrogen — the N1 heterocycle of sulfapyridine. Colonic bacteria cleave the azo bond to the salicylate phenyl ring, releasing sulfapyridine (a sulfonamide antimicrobial, its N4 amine now free on the other phenyl ring) and 5-ASA.

Avoid after a sulfonamide-antimicrobial reaction: it releases sulfapyridine and 5-ASA
The attributed drug in 7% of RegiSCAR DRESS cases

After a reaction to TMP-SMX — no need to avoid

Table I of Khan 2019: no or weak evidence of cross-reactivity

Tamsulosin · ibutilide, sotalol · topiramate · acetazolamide, methazolamide, dorzolamide, brinzolamide
Celecoxib · furosemide, bumetanide · glimepiride, glyburide, gliclazide · hydrochlorothiazide, chlorthalidone, indapamide, metolazone, diazoxide · sumatriptan, naratriptan
Sulfur, sulfates, sulfites: no sulfonamide moiety, no cross-reactivity
The library’s class is drawn by LABEL, not evidence: zonisamide, almotriptan, simeprevir and dichlorphenamide warn and are in; Khan does not name them

Tamsulosin ballicule — decagon mechanism diagram — Tamsulosin

Acetazolamide ballicule — decagon mechanism diagram — Acetazolamide

Glimepiride ballicule — decagon mechanism diagram — Glimepiride

Hydrochlorothiazide ballicule — decagon mechanism diagram — Hydrochlorothiazide

Sumatriptan ballicule — decagon mechanism diagram — Sumatriptan

Sotalol ballicule — decagon mechanism diagram — Sotalol

After a reaction to a NON-antimicrobial sulfonamide

Celecoxib, furosemide — what the evidence allows

No evidence that the antimicrobials or the other non-antimicrobials cross-react
After a celecoxib reaction, no data say furosemide or TMP-SMX must be avoided
After SJS/TEN or DRESS some clinicians avoid every sulfonamide — understandable, unsupported

Labels — from no warning to a contraindication

Why the library splits the class by label text

Labeling on prior sulfonamide allergy is inconsistent — no warning to contraindication
Glimepiride contraindicated, glipizide and glyburide silent · almotriptan warns, sumatriptan and naratriptan silent · zonisamide contraindicated, topiramate (a sulfamate) silent · probenecid, sotalol, ibutilide, torsemide silent
Ethacrynic acid is the loop diuretic without a sulfonamide — the classic alternative, rarely needed

Glipizide ballicule — decagon mechanism diagram — Glipizide

Almotriptan ballicule — decagon mechanism diagram — Almotriptan

Zonisamide ballicule — decagon mechanism diagram — Zonisamide

Topiramate ballicule — decagon mechanism diagram — Topiramate

Probenecid ballicule — decagon mechanism diagram — Probenecid

Topiramate — a sulfamate, not a sulfonamide

The one drug on Khan’s list that is not, strictly, in the class

The sulfamate group is O–SO₂–NH₂: the sulfur sits on an oxygen of the fructopyranose acetal, not on a carbon. A sulfamate, not a sulfonamide; the label carries no sulfonamide warning.

Listed by Khan among non-antimicrobial sulfonamides with no evidence of cross-reactivity
Chemically O–SO₂–NH₂, sulfur on oxygen not carbon; label silent, so the library keeps it out of both classes

Immediate reactions

Less common than delayed reactions, occasionally fatal

Urticaria or angioedema to anaphylaxis — rarely fatal
Topical sulfacetamide eye drops: contact urticaria progressing to anaphylaxis
Trimethoprim alone can cause anaphylaxis

Delayed reactions — the skin

Benign exanthems are common; SCARs are the fear

Boston, 1,121 inpatients on TMP-SMX: 3.3% cutaneous reactions — half within 72 h, the rest at 4–13 days, clearing on withdrawal; more frequent at ≥4 tablets/day
191 Thai patients: maculopapular 36.6%, fixed drug eruption 22%, urticaria 12%, anaphylaxis 1%; SCAR 11.5% (16 SJS, 6 DRESS)
Also: Sweet syndrome, SDRIFE, psoriasiform dermatitis, AGEP, linear IgA disease
DRESS (RegiSCAR): TMP-SMX 1.7% · SJS/TEN (EuroSCAR): co-trimoxazole 6.3%, the commonest antibiotic · US TEN series: TMP-SMX 36.6% of 82
Hospitalized erythema multiforme or SJS: 1.7 (UK) and 2.8 (US) per 100,000 prescribed — a relatively common SJS/TEN culprit, not a frequent cause of DRESS

Delayed reactions — beyond the skin

Liver, kidney, marrow, meninges

Liver: among the commonest single causes of drug-induced liver injury; onset 2–12 days, mixed hepatocellular-cholestatic, sometimes part of DRESS
Marrow: neutropenia, thrombocytopenia, pancytopenia — hospitalization 0.9–5.6 per 100,000
Kidney: AKI in 11.2% of 573 veterans, mostly asymptomatic and reversible; interstitial nephritis poorly documented
Meninges: the commonest antibiotic cause of aseptic meningitis (41 cases reviewed 2014) — headache, stiff neck, fever within hours to days, gone 2–3 days after stopping

HIV

Where sulfonamide hypersensitivity is commonest

Cutaneous reactions in 33–50% of AIDS patients in the 1980s series
136 HIV-positive patients on sulfonamides: 35% developed an eruption, median day 9 — 85% maculopapular, one SJS
No link to slow-acetylator status or MHC polymorphisms; concomitant steroids did not protect

Diagnosis

Table III of Khan 2019 — skin and in-vitro tests rarely help

Immediate: an SMX–poly-L-tyrosine conjugate was positive in 29% (never marketed), and IgE wanes within a year; native TMP-SMX can be used intradermally at 1:100 of the 16/80 mg per mL IV solution — reserved for convincing anaphylaxis histories
Delayed: prick, intradermal and patch tests almost always negative; open application in DMSO positive in 25 of 27 fixed drug eruptions
In-vitro assays: not recommended
Challenge: 1- to 2-step for immediate histories, full dose for delayed; never after SCAR or organ-specific reactions

Desensitization versus full-dose challenge

More than 20 protocols, and a question about what they do

Most protocols succeed: 95% tolerance at 10 months with a 6-hour protocol; 93–98% across 15-minute to 10-day protocols in 72 non-HIV patients
Head to head, full dose ≈ desensitization: 72% vs 79% (Italy); 91.5% vs 93.8% at 6 days in a double-blind US trial, same rash rate, more continuing at 6 months on the escalation arm
Cochrane: fewer discontinuations with desensitization — but the hypersensitivity rate is similar, so these are likely just prolonged challenges
Authors’ advice: full-dose rechallenge for a typical benign exanthem; treat through a benign rash with antihistamines under close watch

References

Every number on these slides is quoted from one of these

[1] Khan DA, Knowles SR, Shear NH. Sulfonamide hypersensitivity: fact and fiction. J Allergy Clin Immunol Pract 2019;7:2116–2123
[2] Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628–1635
[3] PREZISTA (darunavir) prescribing information, section 5.4 Sulfa allergy
[4] May SM, Motosue MS, Park MA. Dapsone is often tolerated in HIV-infected patients with history of sulfonamide antibiotic intolerance. J Allergy Clin Immunol Pract 2017;5:831–833
[5] Brackett CC, Singh H, Block JH. Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group. Pharmacotherapy 2004;24:856–870
[6] PROGLYCEM (diazoxide) prescribing information, Contraindications
[7] Prescribing information of each member of the library’s two sulfonamide classes (DailyMed, read 2026-10-20): the non-antibacterial class is the set whose label contraindicates or warns on sulfonamide hypersensitivity
[8] Apter AJ, Kinman JL, Bilker WB, et al. Is there cross-reactivity between penicillins and cephalosporins? Am J Med 2006;119:354.e11–e19

This is a topic, not a peg. The library keeps two classes — Antibacterials (sulfonamides) and Sulfonamide-derived drugs (non-antibacterial) — and every drug named here carries its own Sulfonamide section; this presentation is what they link to.

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