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Sulfonamides (sulfa drugs) and the skin

Last reviewed: January 2024

Authors: Dr Hyun Kyoung Lee, Medical Registrar; and Honorary Associate Professor Paul Jarrett, Dermatologist, Middlemore Hospital and Department of Medicine, The University of Auckland, Auckland, New Zealand (2024)
Previous contributors: Dr Marie Hartley, Staff Writer (2010)

Reviewing dermatologist: Dr Ian Coulson
Edited by the DermNet content department


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What are sulfonamide (sulfa) drugs?

‘Sulfa’ is a broad term used to describe medications that contain a sulfonamide (sulphonamide) functional group within their molecular structure. They can be categorised into sulfonamide antimicrobials and sulfonamide non-antimicrobials.

The term ‘sulfa’ may be confused with other drugs and products with names stemming from ‘sulfur’, although they have different meanings. Allergies to sulfates, sulfites, or sulfhydryl bear no relationship to sulfonamide allergy.

Who gets sulfonamide (sulfa) drug reactions?

Sulfonamide antibiotics have the highest incidence of drug reaction compared to other antibiotics, with approximately 3–8% of those exposed having an adverse reaction.

Cutaneous reactions are the most common adverse event associated with sulfonamide drugs, occurring in 1.5–3% of immunocompetent patients. However, the most significant risk factor for sulfonamide allergy is HIV positivity, with an incidence of approximately 27% associated with the use of trimethoprim and sulfamethoxazole (TMP-SMX) to treat Pneumocystis jirovecii pneumonia (PJP).

There are currently no validated tests available to determine the risk of sulfonamide allergy. Skin prick testing has limited value as type 1 allergic reactions are less common.

What causes sulfonamide (sulfa) drug reactions?

Sulfonamide antimicrobials contain additional groups within their chemical structure which are usually absent in non-antimicrobial sulfonamides including: N4 aryl-amine and a N1 heterocyclic ring. These additional groups are mainly responsible for reactions to sulfonamide antimicrobials rather than the sulfonamide functional group.

Type 1 immunoglobulin E (IgE)-mediated reactions may occur as the IgE antibody binds to the N1 heterocyclic ring. Non-type 1 reactions are usually associated with metabolites of the antimicrobial agents.

 

Types of sulfonamide medications

Sulfonamide antimicrobials

A commonly used sulfonamide antibiotic is sulfamethoxazole and trimethoprim (TMP-SMX). Patients who react to this drug may be allergic to trimethoprim, sulfamethoxazole, or both. It is known that trimethoprim on its own can cause type 1 allergy (anaphylaxis) and Stevens-Johnson syndrome / toxic epidermal necrolysis. Patients known to react to TMP-SMX should avoid both trimethoprim and sulfamethoxazole.

Other examples of sulfonamide antimicrobials:

  • Sulfasalazine — a drug used to treat inflammatory bowel disease and rheumatoid arthritis
  • Sulfanilamide
  • Sulfapyridine
  • Sulfathiazole
  • Sulfisoxazole
  • Sulfacetamide — used topically to treat eye infections
  • Sulfadiazine — eg, silver sulfadiazine cream, used to prevent and treat infection in burns and other types of wounds.

Non-antimicrobial sulfonamides

Examples of non-antimicrobial sulfonamides:

  • Antivirals — amprenavir
  • Carbonic anhydrase inhibitors — acetazolamide
  • COX2 inhibitors — celecoxib
  • Loop diuretics — bumetanide, furosemide
  • Sulfonylureas — glipizide
  • Thiazide diuretics — bendroflumethiazide
  • Triptans — rizatriptan, sumatriptan
  • Miscellaneous — probenecid, tamsulosin.

What are the clinical features of reactions to sulfonamide drugs?

Many adverse reactions to sulfonamides are not of an allergic nature. Types of non-allergic reactions to sulfonamide antibiotics include nausea, diarrhoea, and candidiasis.

Types of cutaneous reactions

Types of non-cutaneous reactions

Other types of adverse reactions include:

  • Nausea/vomiting, diarrhoea (common)
  • Headaches (common)
  • Hyperkalaemia
  • Rarely:
    • Hepatic injury
    • Renal injury
    • Pancreatitis
    • Cytopaenia
    • Aseptic meningitis.

Cross-reactivity

Between antimicrobial and non-antimicrobial sulfonamides

All sulfonamide antimicrobials contain the additional groups of N4 aryl-amine and the N1 heterocyclic ring which are associated with sulfonamide drug allergy. This leads to cross-reactivity among sulfonamide antibiotics.

Sulfonamide non-antimicrobials do not have a N1 heterocyclic ring as this group is responsible for antimicrobial activity and most do not contain the N4 aryl-amine.

Current evidence shows there is low risk of cross-reactivity between sulfonamide antimicrobial agents and sulfonamide non-antimicrobials. However, it is important to note that patients with true sulfonamide allergies are more likely to have allergic reactions to other medications which are not due to cross-reactivity.

Between sulfonamides and other sulfur-containing drugs

The term ‘sulfa drug’ refers to medications with the sulfonamide group within their molecular structure. However, this can cause some confusion as it can lead to avoidance of medications with a ‘sulf’ prefix that contain sulfur (sulphur). Medications that contain sulfur but lack the sulfonamide functional group have no risk of cross-reactivity to sulfonamide medications.

Examples of medications that have no relationship to sulfonamide allergy but contain sulfhydryl or sulfate:

Sulfhydryl-containing drugs (thiols) can cause unrelated adverse skin reactions such as a rash or drug-induced pemphigus (a rare autoimmune blistering disease).

Sulfate allergies are extremely rare.

Sulfites (eg, sodium sulfite) are used as preservatives in food and drugs. Allergy to sulfite preservatives can cause urticaria and exacerbate asthma.

People who have had allergic reactions to sulfonamide-containing drugs do not need to avoid sulfhydryl drugs, sulfates, or sulfites.

Other cross-reactions

People with sulfonamide allergy may cross-react with para-aminobenzoic acid (PABA) and paraphenylenediamine (PPD).

What is the treatment for cutaneous sulfonamide (sulfa) drug reactions?

The offending drug needs to be immediately discontinued. Mild cutaneous reactions will self-resolve.

Topical steroids and antihistamines may be needed. For severe reactions, hospital admission and treatment for skin failure is required. Patients with SJS/TEN are best managed in a burns unit.

An alert should be placed in the patient’s notes, the patient informed and given a record of the offending medicine for future reference; consider an alert bracelet for serious reactions.

Rechallenge of sulfonamide (sulfa) antimicrobials

If a patient is considered to need a sulfonamide medication to which they previously reacted, rechallenge and desensitisation may be appropriate for those with a mild maculopapular eruption. However, alternatives should be considered for those with a history of severe reaction.

 

Bibliography

  • Chantachaeng W, Chularojanamontri L, Kulthanan K, et al. Cutaneous adverse reactions to sulfonamide antibiotics. Asian Pacific J Allergy Immunol. 2011;29(3):284–9. PDF
  • Chow TG, Khan DA. Sulfonamide Hypersensitivity. Clin Rev Allergy Immunol. 2022;62(3):400–12. doi: 10.1007/s12016-021-08872-3. Journal
  • Dorn JM, Alpern M, McNulty C, Volcheck GW. Sulfonamide Drug Allergy. Curr Allergy Asthma Rep. 2018;18(7):38. doi: 10.1007/s11882-018-0791-9 Journal
  • Giles A, Foushee J, Lantz E, Gumina G. Sulfonamide Allergies. Pharmacy. 2019;7(3):132. doi: 10.3390/pharmacy7030132. Journal
  • Khan DA, Knowles SR, Shear NH. Sulfonamide Hypersensitivity: Fact and Fiction. J Allergy Clin Immunol Pract. 2019;7(7):2116-2123. doi: 10.1016/j.jaip.2019.05.034. Journal
  • Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333(24):1600–8. doi: 10.1056/NEJM199512143332404. Journal
  • Smith WB, Katelaris CH. ‘Sulfur allergy’ label is misleading. Aust Prescr. 2008;31:8–10. doi: 10.18773/austprescr.2008.006. Journal

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