“Sulfa” allergy cross-reactivity

Let’s start with a patient scenario.  A patient presents to the emergency room experiencing a heart failure exacerbation.  When entering the order for intravenous diuretics, you note that a cross-reactivity warning has popped up for a “sulfa” allergy.  What evidence is there for cross-reactivity between Loop diuretics and “sulfa” allergy and how should this affect your decision?

What is meant by a “sulfa” allergy?

Many patients will report that they have a “sulfa” allergy.  “Sulfa” is generally referring to medications containing a sulfonamide moiety which looks like this:

This group is actually common to many classes of medications, including those we don’t typically think about when coming across a “sulfa” allergy.  Clinical experience and in vitro data has revealed that not all sulfonamide-containing medications share the same immunogenicity.  Sulfonamide medications are divided primarily into two main groups – sulfonamide antibiotics and sulfonamide nonantibiotics.

Examples of sulfonamide-containing medications/classes (not all inclusive):

Sulfonamide antibiotics	Sulfonamide nonantibiotics
Sulfacetamide, sulfadiazine, sulfamethoxazole, sulfanilamide, sulfapyridine, sulfasalazine	Thiazide diuretics, Loop diuretics, sulfonylureas, COX-2 inhibitors, carbonic anhydrase inhibitors, triptans, tamsulosin

The distinction between these two groups is important because the sulfonamide antibiotics contain additional groups (an arylamine and another nitrogen-containing ring) at two of the R- substitutions seen above.  These substituted groups are actually the target of the immune response (not the sulfonamide component) as either the parent drug or, more commonly, as a hapten after metabolism.  None of the sulfonamide nonantibiotics contain both of these substitutions and do not form the immunogenic metabolites.

Risk of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics

A large study frequently referenced concerning this issue was by Strom et al. who conducted a retrospective cohort study of the UK General Practice Research Database.  They identified 969 patients with a documented allergic reaction after a sulfonamide antibiotic.  Of these, 9.9% developed an allergic reaction after receiving a sulfonamide nonantibiotic.  To put this into context compared to a baseline group who did not experience an allergic reaction to a sulfonamide antibiotic, only 1.6% experienced allergic reactions after receiving a sulfonamide nonantibiotic.  While this may seem like a concerning finding, it was notable to find that for patients originally with an allergy to sulfonamide antibiotic, 14% subsequently developed an allergic reaction after receiving a penicillin-based antibiotic.  The results didn’t change when broken into subgroups including Loop diuretics.

Therefore, one of the points of the results of this study was that patients who had an allergic reaction to a sulfonamide antibiotic were more likely to also have an allergy to a penicillin antibiotic than a sulfonamide nonantibiotic.  This supports the hypothesis that patients may tend to have a general predisposition to allergic reactions rather than a true cross-reaction between medications.

Regarding Loop diuretics specifically, there are only six case reports involving Loop diuretics with sulfonamide allergies.  Not all of these allergic reactions were conclusive but two did include anaphylaxis.

Back to the patient case

The patient should be questioned as to what her reaction was and what specific agent elicited her reaction.  The response will likely be a sulfonamide antibiotic because of the increased immunogenicity of this group and because if the reaction was from a sulfonamide nonantibiotic like celecoxib or hydrochlorothiazide, that agent would likely be listed itself, not “sulfa”.  If the reaction was to SMX/TMP (Bactrim) and not severe (anything other than anaphylaxis or SJS/TEN), a sulfonamide nonantibiotic can most likely be given without incident.  Looking back at the study by Strom et al, it’s more justified to be concerned if you needed to give the patient a penicillin like piperacillin/tazobactam than the intravenous furosemide for their HF.  If they report the reaction was from a sulfonamide nonantibiotic, there is a potential for cross-reactivity with any of the sulfonamides but there were no studies to quantify this risk.  A completely safe alternative is ethacrynic acid since it lacks any sulfonamide group.

Note:  There are additional small studies, both clinical and in vitro, supporting the hypothesis that the immune response is to the substituted groups on the sulfonamide and not the sulfonamide itself.  Essentially, the antibiotics and nonantibiotics should be considered completely different classes of medications.  The reason for the warnings in the prescribing information was that many of the sulfonamide nonantibiotics were approved decades ago.  At this time, there was no viable immunologic explanation available so many drugs received the blanket label of “Contraindicated with sulfa allergy” based solely on the chemical structure.

Take home points:

• There are two distinct groups of sulfonamides.  The antibiotics contain reactive substitutions that the nonantibiotics do not.
• When an allergy is disclosed, inquire about the specific agent and reaction and likewise, document new allergies by drug name, not class.
• When an allergy occurs to a sulfonamide antibiotic, cross-reactivity to many classes of medications is higher when compared to patients without any allergies.
• Ethacrynic acid is a sulfonamide-free Loop diuretic that is an option if history of a severe reaction (anaphylaxis, SJS/TEN) is a possibility.
• Sulfates, sulfur, and sulfites are chemically unrelated to sulfonamide and do not cross-react (eg. morphine sulfate)

References:

Wulf NR, Matuszewski KA.  Sulfonamind cross-reactivity: Is there evidence to support broad cross-allergenicity?  Am J Health-Syst Pharm  2013;70:1483-94.

Strom BL, Schinnar R, Apter AJ, et al.  Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics.  N Engl J Med  2003;349:1628-35.