Sulfur Allergies

A patient’s allergy status should always be discussed, and documented if possible, before they receive any medication. The term ‘sulfur’ allergy is often documented and can be very misleading.

Sulfur is a natural element, important in everyday life, and exists in many forms; sulfur powder, sulfates, sulfites, sulfonamide antibiotics and non-antibiotic sulfonamides. Sulfur powder is commonly used in gardening and while inhalation or skin contact may cause irritation, allergy has not been described. Sulfates are common compounds found in a variety of products from drugs, such as morphine sulphate, to soaps and cosmetics. Some sulfates can be irritant to the skin and eyes, but again do not actually cause an allergic reaction. Sulfites are used as preservatives in foods and drugs, and can cause respiratory reactions and very rarely cause anaphylaxis, predominantly in asthmatics.

Sulfonamide antibiotics include sulfamethoxazole, which is used synergistically in combination with trimethoprim, sulfadiazine, sulfadoxine and sulfacetamide. Sulfasalazine, used for rheumatoid arthritis, ulcerative colitis and Crohn’s disease, is a combination of sulfapyridine (a sulfonamide antibiotic) and a salicylate.

Approximately 3% of patients have reported mild hypersensitivity to sulfamethoxazole/trimethoprim, however, sulfonamides do account for a number of cases of life-threatening Stevens-Johnson syndrome and toxic epidermal necrolysis. In addition, HIV patients are up to 60% more likely to experience allergic reaction compared to those without the condition.

A ‘sulfonamide’ is a compound that contains a sulfonyl group.

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.

The exact mechanism of allergic reactions to sulfonamides is not completely understood, but some principles are evident. The arylamine group (Figure 1) is oxidised by the cytochrome P450 system, resulting in a hydroxylamine intermediate metabolite, which can be reduced by glutathione and excreted. The reactive hydroxylamine can bind to proteins and has been shown to be associated with hypersensitivity.

Figure 2. Sulfonamides and related structures. (Click on individual images to view in new window)

SulfamethoxazoleSulfapyridine

Basic Sulfanilamide structure:
Sulfanilamide
Structures of sulfonamide antimicrobials: (all contain an arylamine group)
Structures of other sulfonamide-containing compounds: (none contain an arylamine group)
Frusemide	Celecoxib	Gliclazide
Sulfasalazine

Some medications contain the sulfonyl moiety such as frusemide, gliclazide, and celecoxib (Figure 2), but do not contain the arylamine group. Studies have shown that the association of an allergy to sulfonamide antibiotics and other sulfonamide drugs is no stronger than comparing them to penicillins. Patients who have had an allergic reaction to one medication do have a higher chance of experiencing an allergic reaction to another medication, however this does not imply cross-reactivity.

Patients should be educated on their particular allergies and not simply told “you have an allergy to sulfur”. They should know the exact medication and what the relevant reaction was. There was a case report of a patient, who had a documented sulfonamide allergy, who started legal action after being told her post-operative rash was due to morphine sulphate. It should be recognised that morphine and many other drugs can cause histamine release, which can result in flushing and itching of the skin but is not necessarily an allergic reaction. In addition, patients who have had an allergic reaction to sulfamethoxazole/trimethoprim should be treated as if allergic to both medications and not simply labelled as having a ‘sulfur’ allergy. If the reaction was mild, the patient may be challenged with trimethoprim if it is required to confirm the exact allergen.

In conclusion, an allergy to antibiotic sulfonamides does not imply cross-reactivity to non-antibiotic sulfonamides, sulfur, sulfates or sulphites. An accurate history of allergies and reactions is important to avoid both adverse effects in patients, as well as unnecessary stress due to misunderstandings.