Clinicians often come across a label titled ‘sulfur allergy’ in a clinical setting. This imprecise term can be misleading and should be avoided. Sulfur is a natural element found in various forms including sulfates, sulfites, and sulfonamides. Many patients who have suffered adverse reactions to sulfonamide antibiotics are unfortunately loosely labeled ‘sulfur allergic’. This labelling creates confusion as these patients may assume they are at risk of adverse effects from sulfates, sulfites, and even elemental sulfur.

Sulfonamides

Sulfonamides were the first antibiotics to be used systemically. Introduced in the 1930s, they still play an important role in primary care today due to their relative safety, efficacy, and economic advantages. Sulfonamide antimicrobial agents used in Australia include sulfamethoxazole, combined with trimethoprim as co-trimoxazole; and sulfacetamide, used topically to treat eye infections. These medicines are effective and inexpensive. However, allergic reactions are relatively common compared to other antimicrobial agents. Allergic reactions have been estimated to occur in three out of 100 patients, with the prevalence drastically increased to 60% in patients who are HIV positive. Reactions are usually mild. However, there is a risk of a serious and life-threatening hypersensitivity reaction such as Stevens-Johnson Syndrome or toxic epidermal necrolysis.

Mechanisms of hypersensitivity

A sulfonamide is a compound that contains a sulfone group connected to an amine group (see Figure 1). Sulfonamide antibiotics have chemically distinct structures to non-antibiotic sulfonamides as all sulfonamide antibiotics contain an arylamine group (see Figure 1.b). Allergies are more commonly observed with sulfonamide antibiotics compared to arylamine deficient sulfonamides. It is this arylamine moiety that is associated with the allergies and hypersensitivities of sulfonamide antibiotics. As all sulfonamide antibiotics contain this arylamine moiety, cross-reactivity is likely. The use of all arylamine sulfonamides should, therefore, be avoided in patients with a history of allergy to any arylamine sulfonamide.

Figure 1. Sulfonamide structure.

A Sulfonyl group, basic structure – present in many drugs
B Sulfamethoxazole. The arylamine moiety, and also the 5-member ring containing a nitrogen atom, is thought to be important for hypersensitivity reactions.

Cross-reactivity between sulfonamide antibiotics and other sulfonamide drugs

Cross-reactivity between sulfonamide antibiotics and other sulfonamide medicines has historically been a concern. It is a concept that has been challenged by studies in recent years. Commonly prescribed medicines such as thiazide diuretics, gliclazide, frusemide and celecoxib are all sulfonamides, however, lack the arylamine moiety. Table 1 shows non-antibiotic sulfonamides commonly used in Australia.

Table 1. Non-antibiotic sulfonamides commonly used in Australia

Medication Class Medication
Carbonic Anhydrase Inhibitors Acetazolamide

Dorzolamide

Loop Diuretics Bumetanide

Frusemide

Thiazide Diuretics Chlorthalidone

Hydrochlorothiazide

Sulfonylureas Glibenclamide

Gliclazide

Glimepiride

Glipizide

Triptans Naratriptan

Sumatriptan

Other Agents Celecoxib

Dapsone

Probenecid

Sotalol

Sulfasalazine

Topiramate

 

It has been argued that the structural differences between sulfonamide antibiotics and non-antibiotic sulfonamides make true cross-reactivity rare. This concept is further supported by a large cohort study from Strom et al. This study reviewed 969 patients with sulfonamide antibiotic allergy and 19,257 patients without sulfonamide antibiotic allergy. Both groups subsequently received sulfonamide non-antibiotics. While results showed that patients allergic to sulfonamide antibiotics were more likely than non-allergic patients to react to sulfonamide non-antibiotics (9.9% and 1.1% respectively), it was found that the rate of allergy was even greater among patients allergic to penicillin who received non-antibiotic sulfonamides (14.2%). Based on the fact that penicillins do not have any sulfonamide moiety, researchers demonstrated that cross-sensitivity between sulfonamide antibiotics and other sulfonamide medicines is no stronger than that between non-antibiotic sulfonamide medicines and the unrelated penicillins. Strom and his colleagues concluded that sulfonamide cross-reactivity is predominately associated with a greater predisposition to allergic reactions in general than to specific sulfonamide sensitivity.

Sulfate and sulfite allergies

Sulfites have long been used as preservatives in pharmaceuticals, foods and fermented beverages such as beer and wine. The most commonly reported allergic reactions to sulfites are respiratory reactions, ranging from mild wheezing to potentially life-threatening asthmatic attacks. Approximately 10% of patients with asthma are sulfite sensitive. Other adverse reactions to sulfites include anaphylaxis, headaches, rash, seizures and death in hypersensitive patients. Patients who are sensitive to sulfite should avoid products that contain sulfur dioxide, potassium bisulfite, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Sulfates, on the other hand, are commonly used in the manufacturing of medicines. The prevalence of allergy to these compounds is very rare. Patients who have had allergic reactions to sulfonamide medicines do not need to avoid sulfites, sulfates or sulfur.

Conclusion

The term ‘sulfur allergy’ is non-specific and its use should be avoided. Allergic reactions to medications should be clearly documented in the patient’s file with the name of the medicine and the specific nature of the reaction. Allergies and hypersensitivity issues are commonly seen with sulfonamide antibiotics.

Sulfonamide antibiotics are chemically unique from other sulfonamides due to the presence of an arylamine group. This arylamine moiety is thought to be associated with these allergy and hypersensitivity reactions. Cross-reactivity between arylamine sulfonamides is high. Therefore, the use of all arylamine sulfonamides is contraindicated in patients with a history of allergy or hypersensitivity to any sulfonamide antibiotic. Non-antibiotic sulfonamides do not contain the arylamine group. Cross-reactivity between arylamine sulfonamides and non-arylamine sulfonamides is rare. Non-arylamine sulfonamides may be used with caution in patients with a history of allergy or hypersensitivity to arylamine sulfonamides. However, close monitoring by the physician is mandatory.

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References:

  1. Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of ‘sulfa’ allergy. Drug Saf. 2001; 24 (4): 239–47. 
  2. Otten H (1986). Domagk and the development of the sulphonamidesJ Antimicrob Chemoth. 1986; 17 (6): 689–696.
  3. Slatore CG, Tilles SA. Sulfonamide hypersensitivity. Immunol Allergy Clin N Am. 2004; 24(3): 477–90.
  4. Smith WB, Katelaris CH. ‘Sulfur allergy’ label is misleading. Aust Prescr. 2008; 31(1): 8-10.
  5. Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. New Engl J Med. 2003; 349:1628-35.
  6. Tilles SA. Practical issues in the management of hypersensitivity reactions: sulfonamidesSouth Med J. 2001 94(8): 817–24.

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