Sulfonamide hypersensitivity

INTRODUCTION — 

Sulfonamide-containing antibiotics are the second most frequent cause of hypersensitivity drug reactions after the beta-lactams (penicillins and cephalosporins). However, the hypersensitivity reactions caused by sulfonamides differ significantly from those attributed to beta-lactams, and the evaluation and management are distinct.

This topic review describes the most prevalent types of reactions to sulfonamides, the evaluation of patients with reported allergy, and cross-reactivity issues. Management options for patients with past reactions who require similar medications again are also presented. Most of the available literature concerns allergic reactions to antimicrobial sulfonamides, particularly trimethoprim-sulfamethoxazole (TMP-SMX). However, reactions to nonantimicrobial sulfonamides (eg, diuretics, sulfonylureas, and others) and sulfones (eg, dapsone) will be briefly addressed as well.

This review does not address the treatment of acute drug reactions. These are presented elsewhere, according to specific type of reaction. (See "Drug eruptions" and "Drug fever" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Anaphylaxis: Emergency treatment".)

TYPES OF SULFONAMIDES — 

The imprecise term "sulfa drugs" is most often applied to sulfonamide antimicrobials, although it is variably used for other medications as well. This term has contributed to ongoing confusion about relevant cross-reactivity among sulfonamide drugs. It is preferable to avoid "sulfa allergy" and instead document the specific medication that caused the adverse reaction and the symptoms that were involved.

Sulfonamide medications are drugs that contain a sulfonamide moiety (SO₂NH₂) [1]. There are two distinct groups of sulfonamides, which differ in chemical structure as well as clinical use.

Antimicrobial sulfonamides — This group includes sulfamethoxazole (in trimethoprim-sulfamethoxazole [TMP-SMX]) and other less commonly used antimicrobials (table 1) [2].

The antimicrobial sulfonamides share two essential functional groups (figure 1):

●An arylamine (an amine group linked to a benzene ring at N4)

●An aromatic (N-containing) 5- or 6-member ring attached to the sulfonamide core as an N1 substituent

The presence of both moieties is essential to their mechanism of antimicrobial action (ie, as an analog of para-aminobenzoic acid) and is also believed central to the pathogenesis of hypersensitivity reactions [3,4]. Only the antimicrobial sulfonamides contain both of these functional groups (figure 1 and figure 2) [5]. (See 'Pathogenesis of hypersensitivity' below.)

Nonantimicrobial sulfonamides — The agents in this group include diuretics (eg, furosemide, hydrochlorothiazide, acetazolamide), hypoglycemics (glyburide), antiinflammatories (celecoxib), and antimigraine agents (sumatriptan) (table 2) [2]. None of these medications contain an arylamine group or a substituted aromatic ring (figure 2).

Sulfasalazine is an important exception because, although it does not contain these moieties, it releases sulfapyridine (a cross-reactive arylamine sulfonamide) upon contact with gut flora, which can cause a cross-reaction in patients with allergies to sulfonamide antimicrobials. Thus, sulfasalazine should be avoided in patients with a significant allergy to sulfonamide antimicrobials.

Protease inhibitors — The human immunodeficiency virus (HIV) protease inhibitors darunavir, fosamprenavir, and tipranavir, as well as the hepatitis C virus protease inhibitor simeprevir, contain sulfonamide moieties but lack one or both essential functional groups implicated in sulfonamide antibiotic hypersensitivity (ie, N4 arylamine or N-containing ring substitution at N1) (table 2). Most clinical evidence confirms that they do not cross-react with antimicrobial sulfonamides [3,4]. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)

Medications that are NOT sulfonamides — The following groups of medications are not sulfonamides but are sometimes confused with them:

●Dapsone (diaminodiphenylsulphone) is a sulfone, which is a class of medication distinct from sulfonamides (figure 3). Dapsone is the only sulfone in common clinical use, and, although it is not a sulfonamide, it is included in this topic review because the hypersensitivity reactions reported to dapsone are clinically similar to those of sulfonamide antimicrobials, may have similar pathogenesis, and may have some cross-reactivity concerns as well. (See 'Dapsone' below.)

●Sulfites and metabisulfites are chemicals used to preserve certain foods, beverages, and medications. Sulfites are associated with a distinct constellation of symptoms known as sulfite sensitivity, which is primarily mediated via nonimmunologic mechanisms. Reactions to these latter medications and substances are reviewed separately. Sulfite sensitivity typically causes respiratory reactions in patients with asthma, but it is unrelated to sulfonamide hypersensitivity. (See "Allergic and asthmatic reactions to food additives".)

●Some medications contain sulfur atoms in their chemical structure but do not contain specific sulfonamide or sulfone moieties. These include amoxicillin, captopril, omeprazole, and others [3]. There is no known cross-reactivity between these medications and sulfonamides.

●Another group of medications contains sulfate ions, such as albuterol sulfate. The sulfate moieties in these compounds are not a known source of allergic or immunologic issues.

PATHOGENESIS OF HYPERSENSITIVITY — 

Metabolism of sulfonamide antimicrobials results in intermediate forms of the drug that are believed to be important in the pathogenesis of immediate and some delayed hypersensitivity reactions, although interactions between unmetabolized sulfonamide antimicrobials and T cell receptors have also been proposed [6].

There are two structural components, present only in the antimicrobial sulfonamides, which are important in metabolism and the pathogenesis of hypersensitivity reactions:

●The N4 arylamine group

●The heterocyclic aromatic ring with one or more nitrogen atoms at the sulfonamide N1 position

Between 45 and 70 percent of sulfamethoxazole becomes acetylated (via N-acetyl transferase) at the N4 arylamine moiety to form nontoxic metabolites that are excreted in the urine [7]. Alternatively, the arylamine group may undergo N-oxidation via cytochrome P450 to form reactive metabolites (figure 4) [8]. These reactive metabolites can act as haptens or small molecules that become covalently linked to large host proteins. The hapten-protein complexes may be recognized as foreign and initiate an immunologic reaction. Other intermediate metabolites may be directly cytotoxic [8].

Factors that slow metabolism, such as slow acetylation and/or glutathione deficiency states (such as HIV infection), may increase exposure to these metabolites and thus enhance the likelihood of hypersensitivity reactions [9]. (See "Drugs and the liver: Metabolism and mechanisms of injury".)

EPIDEMIOLOGY — 

There are limited data on the overall prevalence of hypersensitivity to all sulfonamides as a group, but adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMX) specifically are common and are reported in 3 to 8 percent of patients receiving oral or parenteral treatment [10]. Females are affected nearly twice as often as males.

Impact of HIV infection — The epidemiology of sulfonamide reactions changed dramatically with the appearance of HIV as patients with this infection are often prescribed this antibiotic class for Pneumocystis jirovecii pneumonia (PJP) treatment and prophylaxis. Small studies from the 1980s through the early 2000s showed that patients with HIV were markedly more susceptible to sulfonamide reactions, particularly when treating PJP [11,12]. The frequency of drug eruption after exposure to a sulfonamide antibiotic ranged from 35 to 50 percent of HIV-positive patients, with the vast majority being maculopapular eruptions with or without fever. Stevens-Johnson syndrome (SJS) was noted to occur in this population as well, but, due to the overall low numbers, it is difficult to conclude if they were truly more common than what is seen in the general population. Pharmacogenomic evaluation of 136 HIV-positive patients did not identify any polymorphisms in the major histocompatibility complex that would explain the higher reported reaction frequencies [13].

TYPES OF HYPERSENSITIVITY REACTIONS — 

A variety of hypersensitivity reactions can occur in response to sulfonamide drugs, including both immediate- and delayed-type reactions. The antimicrobial drugs cause more reactions than the nonantimicrobials. The most common reactions are delayed hypersensitivity reactions, which are defined as beginning days to weeks into therapy. Immediate reactions, which begin within minutes to a few hours of the eliciting dose, are rare with sulfonamides.

Isolated cutaneous reactions — The most common type of hypersensitivity reaction to sulfonamides is an isolated dermatologic reaction. Signs and symptoms are variable and may include morbilliform or maculopapular rash (also called morbilliform drug eruption [MDE]), diffuse erythema, delayed-onset urticaria (ie, not on the first day of treatment), and pruritus. Most of these reactions appear approximately a week into treatment, although some occur earlier or later, and symptoms resolve over a week after drug discontinuation [14,15]. The mechanisms responsible may be multifactorial and are unknown in most cases.

The following should be noted since cutaneous findings may be part of more serious types of reactions:

●The presence of fever or any systemic symptoms should be assumed to represent the beginning of a more significant systemic reaction. (See 'Morbilliform rash with fever and/or systemic symptoms' below.)

●Prominent urticaria or any other symptoms consistent with an immunoglobulin E (IgE) mediated reaction are important to note as they could also represent a possible immediate-type allergy (table 3), although immediate reactions to sulfonamides are significantly less common than delayed cutaneous reactions. (See 'Immediate-type allergy and anaphylaxis' below.)

Diagnosis — The diagnosis of MDE or exanthematous drug eruption is clinical, based on timing of initial drug administration and onset of symptoms and physical examination showing a maculopapular or morbilliform dermatitis [16]. There is no specific or reliable laboratory test to diagnose a drug eruption, and a skin biopsy is not routinely performed. MDEs can be difficult or impossible to distinguish from viral exanthema, especially in children, which is why many patients are labeled as allergic to sulfonamides during childhood. (See "Exanthematous (maculopapular) drug eruption".)

Morbilliform rash with fever and/or systemic symptoms — A more serious type of sulfonamide hypersensitivity is characterized by a pruritic, maculopapular or morbilliform rash, accompanied or preceded by fever. In some patients, this progresses to multisystem organ involvement and dysfunction. Severity can range from mild to severe to fatal. Sulfonamide antimicrobials (usually trimethoprim-sulfamethoxazole [TMP-SMX]) are most commonly implicated in this type of reaction, although nonantimicrobial sulfonamides are occasionally causative. This type of reaction is seen more routinely in patients with uncontrolled HIV infection, and it may be less familiar to clinicians today.

Symptoms generally develop one to two weeks after the start of administration, with fever usually appearing first, sometimes accompanied by flu-like symptoms such as malaise and pharyngitis. Peripheral blood smear may reveal an atypical lymphocytosis or eosinophilia [2,17]. Organ involvement may be asymptomatic or overt and can include hepatitis (abdominal pain, nausea), nephritis, pulmonary infiltrates, and cytopenias.

Once the culprit sulfonamide is discontinued, symptoms generally resolve within a few days. With reexposure, symptoms may appear more rapidly (ie, within one to two days).

Diagnosis — Patients who develop rash with fever while taking a sulfonamide drug should be evaluated for organ involvement with routine chemistries, liver function tests, a complete blood count, urinalysis, and a chest radiograph if respiratory symptoms are present.

Stevens-Johnson syndrome and toxic epidermal necrolysis — Antimicrobial sulfonamides are strongly associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In contrast, the nonantimicrobial sulfonamides (including furosemide, thiazide diuretics, and sulfonylurea hypoglycemics) are not associated with an excess risk of SJS/TEN [18].

SJS is characterized by a prodrome of malaise and fever, followed by the rapid onset of erythematous or purpuric macules and plaques and blistering of the mucous membranes (picture 1A-B). The skin lesions progress to epidermal necrosis and sloughing. TEN is a similar but more severe disorder that involves a greater percentage of the body surface area (picture 2). The diagnosis of SJS and TEN are discussed in detail separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Erythema multiforme (EM) has also been reported in association with sulfonamide antibiotics [19,20]. EM is a milder cutaneous reaction consisting of target and vesiculobullous lesions involving the mucosal membranes and favoring the extremities (and palms and soles). SJS and severe EM are viewed by many experts, although not all, as separate entities. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

Immediate-type allergy and anaphylaxis — Both sulfonamide antimicrobials and nonantimicrobials can cause type I or immediate-type hypersensitivity reactions, although they are rare (table 4) [21,22]. Type I reactions are mediated primarily by drug or metabolite-specific IgE antibodies, which trigger sensitized mast cells (and basophils) to degranulate, releasing histamine and other vasoactive mediators [23,24]. Immediate reactions begin within minutes to a few hours of the first dose. Typical symptoms include urticaria, angioedema, bronchospasm, laryngeal edema, and hypotension (table 3).

Diagnosis — Allergy skin testing with the original (unmetabolized) sulfonamide can be performed, but its utility is unknown. For sulfonamides, the relevant drug antigen is usually not the intact drug itself. Instead, reactive metabolites may become bound in large numbers to serum or cell surface carrier proteins and thereby create a multivalent immunologic stimulus, which can differ structurally from the parent drug. There is some evidence that these rare reactions involve the substituted aromatic ring rather than the arylamine portion [25]. IgE antibodies have been found to the N1-substitute of TMP-SMX and not the sulfonamide core [1,25].

Other uncommon reactions — Sulfonamide drugs, usually the antimicrobials, are infrequently associated with several other types of reactions, including serum sickness-like reaction (SSLR), hemolytic anemia, and aseptic meningitis.

Serum sickness-like reaction — SSLRs are occasionally caused by sulfonamide antimicrobials. These reactions present approximately 10 to 14 days after initiation of therapy, with fever, rash (which is often urticarial), arthralgia, and lymphadenopathy [26]. SSLR is a self-limited response following discontinuation of the drug. (See "Serum sickness and serum sickness-like reactions".)

Hemolytic anemia — Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic metabolic-type adverse drug reaction, rather than an immunologic reaction. The different sulfonamides vary in their risk of causing hemolysis in patients with G6PD deficiency (table 5). Dapsone and the sulfonylureas (eg, glipizide, glyburide) are considered high risk. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Aseptic meningitis — TMP-SMX is among the most common antibiotics to cause drug-induced aseptic meningitis [27]. The clinical presentation of aseptic meningitis involves fever and headache, sometimes accompanied by nausea and vomiting, change in mental status, photophobia, or stiff neck. Patients may display a range of other neurologic and systemic symptoms and signs. In a literature review of 41 cases, most patients developed symptoms to the combination of TMP-SMX, although cases were identified that were triggered by trimethoprim (TMP) alone or sulfamethoxazole (SMX) alone [28]. Evaluation of the cerebrospinal fluid typically showed elevated white blood cells (usually in the range of 100 to 1000/mcL) with neutrophil predominance, elevated protein, and normal glucose [28]. After the drug was discontinued, patients began to improve within 24 hours, with resolution of the headache within two to three days. Several case reports describe patients who were challenged to TMP alone after reacting to TMP-SMX and experienced recurrent symptoms. Of the 15 patients in the review who received TMP-SMX again, 91 percent developed symptoms within six hours, and all did within 24 hours, even when the initial reaction developed after days to weeks of therapy [28]. (See "Aseptic meningitis in adults".)

Drug-induced liver injury — TMP-SMX is one of the more common causes of drug-induced liver injury (DILI) [29,30]. The reaction is associated with human leukocyte antigen (HLA) B*14:01 and B*35:01 [31]. Other sulfonamide antimicrobials and nonantimicrobials have been implicated in DILI as well. (See "Drug-induced liver injury".)

CROSS-REACTIVITY

Confounding in studies of cross-reactivity — Studies of cross-reactivity among related medications are often confounded by the fact that a clinical history of drug allergy by itself identifies a subgroup of patients who are at increased risk of reactions to medications in general, even in the absence of actual cross-reactivity among the implicated drugs [32]. Patients with immunologic reactions to two or more chemically distinct types of drugs are said to have "multiple drug intolerance syndrome," although the exact definition of this syndrome is evolving, as discussed separately. (See "An approach to the patient with drug allergy".)

The propensity of certain patients to develop drug reactions was demonstrated in a large, retrospective cohort study performed on a medical database of over eight million patients spanning a 12-year period [33]. Individuals who had a documented allergic reaction to a sulfonamide antibiotic in the past did indeed react more commonly to a sulfonamide nonantibiotic (10 percent) compared with those who tolerated sulfonamide antibiotics (1.6 percent). However, those same individuals with documented sulfonamide antibiotic reactions reacted to the chemically distinct penicillins even more often (14 percent). In addition, there was a higher risk of reaction to sulfonamide nonantibiotics in those with a history of reactions to penicillins than those with a history of reactions to sulfonamide antibiotics. This strongly suggests that a predisposition to adverse drug reactions in general is a better predictor for sulfonamide allergy than a past reaction to a different type of sulfonamide.

Between sulfonamide antimicrobials and nonantimicrobials — In patients who have a past reaction to sulfonamide antimicrobials (eg, sulfamethoxazole), the nonantimicrobial sulfonamides (eg, loop diuretics, thiazide diuretics, sulfonylurea hypoglycemics, carbonic anhydrase inhibitors, and protease inhibitors) can be given normally and vice versa (table 1 and table 2). The nonantimicrobial sulfonamides do not contain the antigenic structures that are thought to be necessary for generating allergenic metabolites. There is also minimal clinical evidence of cross-reactivity between the two groups, although it is impossible to say that cross-reactivity absolutely does not occur, because the nonantimicrobial sulfonamides are implicated in hypersensitivity reactions as well, albeit rarely.

The strongest evidence supporting the lack of cross-reactivity is the large database study described in the preceding section [33]. (See 'Confounding in studies of cross-reactivity' above.)

Other evidence includes small studies and series demonstrating that most patients with a history of reacting to an antimicrobial sulfonamide will tolerate nonantimicrobial sulfonamides [4,17,21,33,34]:

●A prospective observational study of 94 hospitalized adults with reported "sulfa allergy" noted that 40 patients had taken a nonantimicrobial sulfonamide, most often furosemide, as outpatients for a median duration of 6.2 years, and nine patients had received nonantimicrobial sulfonamides as inpatients, all without adverse reactions [21].

●A retrospective series described 34 patients with reported "sulfa allergy" who were treated with furosemide and/or acetazolamide (nonantimicrobial sulfonamides) for intracranial hypertension [34]. There were no reactions in those who received furosemide. Urticaria developed in two patients treated with acetazolamide, although no patients experienced severe reactions.

Despite these data, the US Food and Drug Administration (FDA) approved product labels for many nonantimicrobial sulfonamide drugs still contain warnings concerning possible cross-reactions.

A data synthesis of the cases of suspected cross-reactions, including published reports and manufacturers' data on file from 1966 to 2004, noted that the US FDA product information for 17 of 33 nonantimicrobial sulfonamide drugs included varying statements, warnings, or actual contraindication statements against their use in patients with "sulfonamide" allergy [35]. The authors of this analysis concluded that, when subjected to closer examination, these data did not establish a reasonable probability of immunologic or hypersensitivity syndrome cross-reactivity between the two sulfonamide groups [35]. We agree with this conclusion due to the lack of conclusive reports documenting clear cross-reactivity.

Sulfasalazine is a possible exception — Sulfasalazine represents a possible exception to the general conclusion that cross-reactivity between antimicrobial and nonantimicrobial sulfonamides is unlikely. Sulfasalazine is a nonantimicrobial that releases sulfapyridine, an antimicrobial, upon exposure to gut bacteria. Sulfasalazine has been implicated in drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS), a multisystem reaction involving fever, rash, lymphadenopathy, liver involvement, cytopenias, and eosinophilia [36]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Although there is a small in vitro study demonstrating immunologic cross-reactivity between sulfonamide antibiotics and sulfasalazine [37], there remains no convincing clinical evidence. However, given the theoretic cross-reactivity, we suggest a graded challenge in patients who had past reactions to sulfonamide antimicrobials and subsequently require sulfasalazine. Protocols are provided. (See 'Needing a sulfonamide from the same group' below.)

Trimethoprim allergy — A subset of patients who react to a trimethoprim-sulfamethoxazole (TMP-SMX) combination product are sensitive to the trimethoprim (TMP) component. Types of reaction include simple morbilliform reactions and fixed drug eruption. This has mostly been documented in case reports of patients with HIV infection, in whom up to 20 percent of reactions were due to TMP allergy [38,39]. However, reactions are reported in patients without HIV infection as well [40-43]. Careful graded challenge with TMP is often required to clarify the situation.

Celecoxib — The available evidence suggests a lack of cross-reactivity between antimicrobial sulfonamides and celecoxib, a nonantimicrobial sulfonamide and selective cyclooxygenase-2 (COX-2) inhibitor [35,44-46]. Therefore, patients with past reactions of rash or immediate reactions to sulfonamide antimicrobials can receive celecoxib normally. Note that this does not apply to patients with past fever or blistering reactions to sulfonamides.

Evidence suggesting that celecoxib is not cross-reactive with antimicrobial sulfonamides includes:

●A prospective pilot study of 28 patients with a history of reactions to antimicrobial sulfonamides, in which patients were challenged with celecoxib after extensive allergy evaluation, initially with a small test dose and followed by a full dose, [44]. None experienced allergic reactions.

●A large meta-analysis of over 11,000 patients from 14 double-blinded trials of celecoxib used for arthritis, in which the rate of allergic reactions specifically to celecoxib was not statistically different from placebo or active alternate therapy (other nonsteroidal antiinflammatory drugs [NSAIDs]) [45]. Although sulfonamide hypersensitivity was part of the exclusion criteria for those trials, 135 patients were included despite histories of sulfonamide hypersensitivity. Subgroup analysis of those patients did reveal a higher rate of dermatologic reactions compared with the group as a whole. However, the three- to sixfold elevation in rate of reactions was also seen in patients receiving other NSAIDs and placebo, indicating that these patients were at higher risk for hypersensitivity drug reactions in general [45].

However, there are separate concerns in patients with past fever or blistering reactions (eg, Stevens-Johnson syndrome [SJS]/toxic epidermal necrolysis [TEN]) to sulfonamide antimicrobials because celecoxib is independently associated with SJS [47].

Evidence of an increase incidence of SJS with celecoxib includes a large retrospective review of postmarketing safety surveillance reports (from the US FDA Adverse Events Reporting System) for several of the selective COX-2 inhibitors in which there were significant increases above baseline rates of reported SJS cases [47]. Compared with an expected background rate of 1.9 cases per million annually, calculated rates were 5.7 per million in celecoxib users (based on 19 reported cases in the first two years of marketing). Twenty-one percent of these individuals had also reported "sulfa allergy." Since comparison data from appropriate control groups are not available in studies of this nature, risks of possible cross-reactivity cannot be calculated or directly inferred. Further studies are needed to define the risk of SJS with celecoxib.

Dapsone — Dapsone is a sulfone, not a sulfonamide. However, hypersensitivity to dapsone (or the "sulfone syndrome") is characterized by symptoms similar to those seen in sulfonamide reactions (such as fever and rash, sometimes accompanied by hepatitis, lymphadenopathy, and/or hemolytic anemia), and it can be even more severe [48-55].

It is unclear if there is cross-reactivity between sulfones and sulfonamide antimicrobials, and small retrospective series describe variable rates of tolerance of dapsone in patients with past TMP-SMX reactions [56-59]. As an example, in a retrospective chart review of 60 patients with HIV infection who required prophylaxis for P. jirovecii pneumonia (PJP) and had previous reactions to TMP-SMX, 70 percent were cutaneous reactions [56]. Of the 60 patients, seven were reexposed to TMP-SMX (either through normal administration, challenge, or gradual reintroduction), and five tolerated it. Another 13 patients were treated with dapsone, and all 13 tolerated dapsone. Thus, patients with past cutaneous or cutaneous with relatively mild systemic symptoms may tolerate dapsone. Of note, patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to starting dapsone (table 5). (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

More caution is warranted for patients with severe past reactions to TMP-SMX. There is some evidence that patients with HLA-B*13:01 are susceptible to severe delayed reactions to both sulfones and sulfonamides [48,49]. Pending more data, it seems prudent to avoid both types of agents whenever possible in patients who have had serious reactions (eg, rash with fever and organ involvement, SJS/TEN, serum sickness, hemolytic anemia, or drug-induced liver injury [DILI]) to one or the other.

Cross-reactivity within sulfonamide groups — It is believed that the different antimicrobial sulfonamides would cause similar hypersensitivity reactions in a susceptible patient, so patients with reactions to one antimicrobial should avoid the others.

The nonantimicrobial sulfonamides have been associated with far fewer hypersensitivity reactions. Information about cross-reactivity among various agents within this class is derived from case reports, and the paucity of such reports suggests that cross-sensitivity is very low to nonexistent [22,60]. Thus, when justified by clinical need, a patient with a past reaction to a nonantimicrobial sulfonamide can receive a different nonantimicrobial sulfonamide without additional precautions. One exception to this would be possible cross-reactivity between sulfonamide diuretics within the same class, such as thiazide diuretics, as discussed below. (See 'Needing a sulfonamide from the same group' below.)

FUTURE USE OF SULFONAMIDES

History — The general approach to information gathering in a patient with possible drug allergy (eg, clinical history and review of records) is presented separately. (See "An approach to the patient with drug allergy".)

The primary goals in taking a history of past reactions to sulfonamides are:

●Assessing what type of hypersensitivity reaction the patient likely experienced in the past, including inquiring about whether any photos were taken of the patient at the time. (See 'Types of hypersensitivity reactions' above.)

●Assuring that the reaction was not suggestive of severe forms of hypersensitivity, such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or anaphylaxis. Accordingly, patients who report emergency department visits or hospitalizations; blistering or peeling of the skin or mucous membranes; or use specific phrases, such as "anaphylaxis" or "nearly died," in association with prior sulfonamide reactions must be taken very seriously [2].

Referral — Consultation with an allergy specialist experienced in adverse drug reactions is recommended if retreatment with any type of sulfonamide is being considered in a patient with a severe or multisystem reaction to a sulfonamide in the past or who cannot provide much information.

General strategies — There are four general strategies for the future use of sulfonamide drugs in patients with past reactions to a specific agent: avoidance, drug challenge to confirm lack of allergy, and gradual reintroduction or desensitization if allergy is likely. The choice of strategy depends upon the type and severity of the past reaction and on the risks and benefits of alternative treatments. Approaches to different clinical scenarios are described briefly here and summarized in the table (table 6).

●Avoidance – Use of an alternative medication of a distinct pharmacologic class is obviously the simplest option in most patients with past sulfonamide reactions. Avoidance of sulfonamides in the same group is the only safe approach if a patient describes symptoms consistent with any type of blistering dermatitis or diffuse erythroderma, including SJS and TEN. These patients should almost never undergo test dosing or gradual reintroduction, except in very unusual circumstances. Case series have noted that SJS and TEN can recur and may be more severe with even minor reexposures [61].

●Drug challenge – Drug challenge (or test dosing) is a term used to describe the cautious administration of a medication under medical observation. Drug challenge is appropriate for patients who are unlikely to be allergic to the drug in question. It does not alter the patient's immune response to the drug, so patients who tolerate a drug challenge prove that they are not allergic to that drug. Challenges are administered without premedications, which could obscure detection of early and mild allergic symptoms. Challenge can be performed immediately before required treatment or electively when the patient is in their usual state of health for the purpose of removing drug allergy labels ("delabeling").

●Gradual reintroduction – Various multiday protocols have been developed for use in patients with past delayed reactions, particularly rash and fever. Whether these protocols alter the immune response has not been established. Although they are not technically "desensitization," because they do not clearly alter the immune response, they are often referred to as such in the medical literature. (See 'Gradual reintroduction protocols for delayed reactions' below.)

●Desensitization – The term "desensitization" is used to describe the cautious administration of small and increasing doses of a medication under careful medical observation to patients who are likely to have an immediate, IgE-mediated allergy to the drug in question. Most desensitizations take a few hours to complete. Desensitization alters the patient's underlying response to the drug, although only temporarily, as long as there is uninterrupted exposure to the medication. Desensitization is appropriate when there are no acceptable alternative medications. Unfortunately, the term "desensitization" is often applied to gradual reintroduction protocols in the medical literature.

Precautions with any form of reexposure — Consultation with an allergy specialist experienced in adverse drug reactions is recommended if drug challenge, gradual reintroduction, or desensitization are under consideration, unless the clinician is specifically experienced with these procedures. Documentation of informed consent is essential and should include a discussion of risks and benefits of the procedure.

Management of specific patient groups

No history about past reaction available — Sometimes patients report an allergy to "sulfa drugs" but have no knowledge of what the signs or symptoms of the reaction were.

In this situation, several questions are helpful in assessing risk:

●How long ago did the reaction occur? (Relevant to simple cutaneous reactions.) (See 'Previous isolated rash' below.)

●Was the drug given for an infection? (If yes, it likely was trimethoprim-sulfamethoxazole [TMP-SMX].)

Questions about the past reaction:

●Was the reaction severe enough that they required urgent treatment or hospitalization?

●Was there organ damage?

●Did the skin blister or peel off?

If the answer to the last three questions was "no" or the patient was never told of them, the reaction was likely either a simple cutaneous reaction or a cutaneous reaction with relatively mild fever +/- systemic symptoms, and the examiner can proceed under that assumption.

Previous isolated rash — An isolated morbilliform or maculopapular rash to a sulfonamide drug, without fever, blistering, or erythroderma, is considered a low-risk reaction [62].

Needing a sulfonamide from a different group — Patients with a history of previous isolated rash to a sulfonamide from one group (antimicrobial or nonantimicrobial) can safely receive a sulfonamide from the other group, and it can be given normally. For example, a patient who had isolated rash to TMP-SMX can receive hydrochlorothiazide normally. (See 'Between sulfonamide antimicrobials and nonantimicrobials' above.)

Needing a sulfonamide from the same group — If the patient requires the same drug or a drug from the same sulfonamide group, management depends upon how long ago the reaction occurred because more recent reactions are somewhat more likely to recur [63].

●Rash >5 years ago – A low-risk reaction to a sulfonamide is a reaction limited to the skin, without fever, and not involving blistering or erythroderma, which occurred more than five years ago.

For patients with a simple cutaneous reaction to a sulfonamide that happened >5 years ago, the 2022 American Drug Allergy Practice Parameter recommends a one-step (or "direct") oral challenge with the same or related drug, rather than gradual reintroduction [62]. We observe patients for one hour after the challenge. If no reaction occurs, the patient can then be discharged home and instructed to report back if any delayed symptoms develop. As an example, a patient with a morbilliform eruption to TMP-SMX that occurred 10 years ago who subsequently requires TMP-SMX could take a single dose of TMP-SMX in the office with a one-hour observation time and then be discharged home for self-monitoring.

Note that, even if the original reaction was delayed in nature, recommendations are to perform a drug challenge in a single day for the purpose of excluding an immediate reaction [62,64].

The preference for direct challenge is based on several small trials showing that one- or two-step challenges were as effective as more gradual, multistep protocols in patients both with [39,65,66] and without [63,67] HIV infection.

•In the largest study of multistep protocols in patients without HIV infection, 72 individuals underwent one of three multistep TMP-SMX readministration protocols, and their cases were reviewed retrospectively [67]. Past reactions were most commonly rash or hives (54 and 13 percent, respectively), while patients with severe delayed hypersensitivity reactions (eg, SJS, TEN, drug reaction with eosinophilia and systemic symptoms [DRESS], serum sickness, or drug-induced nephritis or hepatitis) were excluded. The time elapsed from the original reaction was not reported. The overall success rate was 90 percent, and patients subsequently took TMP-SMX for a mean of 11 months. Eight patients had reactions leading to discontinuation.

•A subsequent study evaluated the safety of shorter, one- or two-step readministration protocols in patients with (4 percent) and without (96 percent) HIV infection [63]. In this retrospective study, 204 individuals with either immediate or delayed past reactions were included, while those with severe delayed reactions were excluded. Overall, 94 percent passed the challenge, while 13 patients developed reactions, but none were severe. Time since the initial reaction was significantly associated with a lower risk of developing symptoms on challenge, with an adjusted odds ratio of 0.88 per year (95% CI 0.80-0.97). Patients with past delayed reactions were also more likely to pass challenge compared with those with past immediate reactions. Patients were contacted to determine if they were subsequently treated with TMP-SMX, and 27 percent had. Of those, 83 percent tolerated treatment, and the others had mild reactions.

●Rash within 5 years – Cutaneous reactions that occurred within the past five years are somewhat more likely to recur with reexposure to the same sulfonamide drug or a drug from the same group, so a more gradual challenge is preferred.

For patients with cutaneous reactions to a sulfonamide drug that occurred within the past five years and who need the same or a related drug again, the 2022 American Drug Allergy Practice Parameter recommends a graded challenge [62]. Graded challenges start with a dose of 1/100^th to 1/10^th of the therapeutic dose. Such doses are easily prepared by serial dilutions of a liquid preparation. The remaining amount is given as the second or third step, at time intervals that are long enough to allow for the development of immediate-type symptoms (ie, usually 30 minutes). This approach is appropriate for patients with HIV infection and those without.

As an example, a patient with isolated, delayed-onset urticaria to TMP-SMX two years ago who requires TMP-SMX could be given 1/10^th of a full dose, be observed for 30 minutes, and, if no reaction occurs, be given the remainder of the full dose followed by one hour of observation. A three-step challenge would involve 1/100^th of a dose, then 1/10^th of a dose, then the remainder of a full dose. The patient can then be discharged home and report back if there are any delayed symptoms during the treatment course.

Previous morbilliform rash with fever and/or systemic symptoms

Needing a sulfonamide from a different group — There is minimal evidence for cross-reactivity between sulfonamide antimicrobials and nonantimicrobials, as previously discussed (see 'Cross-reactivity' above). Thus, for patients requiring a drug from the other group (eg, a patient requiring furosemide who had a past rash and fever to TMP-SMX), there are two options for treatment:

●Give the drug normally – This is appropriate for the majority of patients, provided they do not have multiple drug allergies. As mentioned previously, sulfasalazine should be considered an antimicrobial because it releases an antimicrobial in the gut.

●Administration of one or more test doses of the desired drug – This is an approach preferred by some providers for the patient with multiple drug allergies as this clinical history identifies a subset of patients at higher risk for drug reactions in general. There are no data beyond clinical experience supporting this strategy. (See 'Confounding in studies of cross-reactivity' above.)

Needing a sulfonamide from the same group — There are several potential clinical scenarios that arise in which a patient with a past sulfonamide reaction requires an agent from the same group of sulfonamides and no equivalent alternative drug can be identified.

●TMP-SMX allergy in patients with HIV – Patients with HIV infection who reacted to TMP-SMX with nonblistering rash and fever +/- systemic symptoms or mild organ involvement may need TMP-SMX for P. jirovecii pneumonia (PJP) prophylaxis if alternative therapies are not available or equally effective. In this situation, a gradual reintroduction protocol can be applied. (See 'Protocols for past morbilliform rash and fever' below.)

●Sulfonamide diuretic allergy in a patient needing diuresis – Most of the potent loop diuretics (furosemide, bumetanide, torsemide) and other diuretics (including thiazides and carbonic anhydrase inhibitors, such as acetazolamide) are sulfonamides. These drugs may cause allergic reactions, as discussed previously, albeit less commonly than the antimicrobial sulfonamides [68]. The risk of cross-reactivity among them is poorly understood, although there has been a presumption of cross-reactivity among the loop and thiazide diuretics, supported by case reports [69,70].

Ethacrynic acid is the only available loop diuretic with no known potential to cross-react with sulfonamide-containing diuretics [69]. It is therefore the preferred agent for an individual who previously had a severe reaction to a sulfonamide-containing diuretic and requires diuresis again.

If ethacrynic acid is unavailable or insufficiently effective, graded challenge or gradual reintroduction protocol to one of the sulfonamide diuretics can be performed. There have been published reports of successful graded-dose challenges to torsemide and gradual reintroduction to furosemide in patients with previous reactions to sulfonamide diuretics [68,71]. Together, these reports describe three cases: one patient's initial reaction to sulfonamide diuretics was diffuse hives without other signs of anaphylaxis [68], a second had pancytopenia [68], and a third had recurrent pancreatitis with furosemide, bumetanide, and torsemide [71]. Sulfonamide diuretics were successfully reintroduced to all three patients.

●Sulfasalazine allergy in inflammatory diseases – Sulfasalazine is a prodrug that is converted into 5-aminosalicylic acid (ASA) and sulfapyridine (an arylamine sulfonamide antimicrobial) following oral administration (figure 2). It is used in the treatment of inflammatory bowel disease, psoriasis, lupus, rheumatoid arthritis, and other disorders. A history of sulfonamide hypersensitivity reactions frequently complicated the management of these conditions in the past, although newer preparations of 5-ASA, which are not sulfonamides (eg, mesalamine), and other biologic therapies have become available [72]. However, prior to these therapies, relatively successful gradual reintroduction protocols for sulfasalazine were published [73-76]. (See "Management of the hospitalized adult patient with severe ulcerative colitis".)

Previous SJS or TEN — As discussed previously, blistering rashes include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Needing a sulfonamide from a different group — In patients with past SJS/TEN to one type of sulfonamide, practice has evolved over the past few decades, and it is now felt to be safe to give sulfonamides from the other group normally. Understanding of the pathogenesis of these reactions has improved, and reports of cross-reactivity have not appeared. As an example, a patient with TEN caused by TMP-SMX could be given hydrochlorothiazide normally. Note that sulfasalazine should be considered an antimicrobial because it releases sulfapyridine in the gut.

One case report described successful reintroduction of a sulfonamide diuretic in a male patient with SJS to TMP-SMX years earlier and uncomplicated rashes with furosemide and glyburide [69]. The patient was treated for several years with ethacrynic acid, but this drug then became temporarily unavailable, and his heart failure progressed. After giving informed consent, he received underwent a gradual reintroduction protocol using torsemide, which was chosen because it was structurally more different from furosemide compared with bumetanide. He was initially given torsemide 2.5 mg daily for one week. The dose was then increased to 10 mg daily over the next six weeks. He did not diurese adequately at this dose, so the dose was increased to 40 mg daily over the ensuing month, which was effective. The patient developed no allergic symptoms.

Needing a sulfonamide from the same group — Reexposure to the culprit drug or a sulfonamide in the same group is contraindicated if a patient describes symptoms consistent with a blistering dermatitis or diffuse erythroderma. This contraindication applies to any form of reexposure. Case series have noted that SJS and TEN can recur with even small test doses and may be more severe the second time [61]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Previous immediate reactions or anaphylaxis — For patients with past reactions consistent with IgE-mediated allergy or anaphylaxis (ie, urticaria accompanied by angioedema, bronchospasm, laryngeal edema, and/or hypotension), the causative drug should be avoided.

Needing a sulfonamide from a different group — Patients with past reactions consistent with IgE-mediated allergy or anaphylaxis to an agent in one group of sulfonamide drugs can receive agents from the other group normally. There is no evidence of cross-reactivity.

Needing a sulfonamide from the same group — Patients with past reactions consistent with IgE-mediated allergy or anaphylaxis to an agent in one group of sulfonamide drugs should avoid all the other drugs in that same group. As an example, a patient who experienced apparent anaphylaxis with furosemide should not be treated with hydrochlorothiazide or other sulfonamide diuretics. If such therapy is essential, then a rapid desensitization protocol designed for type I, IgE-mediated allergy should be employed under the guidance of an allergy specialist [77]. After completing a desensitization protocol for an IgE-mediated drug reaction, the patient must continue the course of treatment without missing a single daily dose as the tolerance is temporary and dependent upon continuous ongoing exposure. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

GRADUAL REINTRODUCTION PROTOCOLS FOR DELAYED REACTIONS

Application to sulfonamide reactions — Protocols of gradual dose escalation have been developed for some non-IgE-mediated immunologic mechanisms, including sulfonamide sensitivity involving delayed morbilliform rash and fever. Unfortunately, these procedures for non-IgE-mediated skin rashes are often called "desensitizations" in the literature, despite the lack of evidence that any immune cell is downregulated as a result of the process. A more accurate term would be slow or gradual reintroduction protocols. These protocols may appear to be successful in large part because many patients lose immunologic sensitivity over time.

Protocols for past morbilliform rash and fever — Most patients with past cutaneous reactions to sulfonamides without fever will tolerate reintroduction of sulfonamide medications from the same group using a drug challenge and do not require gradual dose escalation, as described previously. However, if preferred by the clinician or patient, or if the patient does not tolerate simple reintroduction, several gradual protocols exist, which range from six hours to 10 days [62]. The protocols presented in this topic have been performed successfully by the authors, although modifications may be made based on characteristics of the individual case. In most cases, these modifications are made to escalate the dose more slowly. Clinicians should avoid altering successful protocols to render them faster or significantly shorten the time interval between doses. After reaching the desired dose, the patient should be counseled that it is important to take daily doses as scheduled as interruption may predispose the patient to breakthrough symptoms, although the likelihood of this is not well known.

Trimethoprim-sulfamethoxazole — There are a significant number of published gradual reintroduction protocols for use in patients with HIV requiring trimethoprim-sulfamethoxazole (TMP-SMX). The efficacy of these protocols has not been compared in head-to-head studies, and the optimal approach is not known [9]. Most of the published TMP-SMX protocols have used the oral route as this is presumed safer than intravenous administration.

Representative studies of TMP-SMX gradual reintroduction protocols are presented here [78-80]. All three were performed in patients requiring P. jirovecii pneumonia (PJP) prophylaxis and had a history of TMP-SMX-associated nonblistering skin rash with fever. The authors have used these three protocols successfully in patients without HIV infection with no apparent differences in outcome.

●The largest prospective published study involved 48 patients with HIV undergoing the three-day TMP-SMX protocol outlined in the table (table 7) [79]. By day 3, subjects were receiving a full (single-strength) TMP-SMX tablet, and 77 percent of those undergoing this regimen were able to tolerate the course of therapy for a mean of 16 months without adverse effects. Eleven subjects failed to complete the course of therapy, with eight stopping within the first two days. One patient experienced hypotension and acute nonfatal myocardial infarction. Higher relative and absolute CD4 counts were associated with trends toward higher risk of failure.

●A retrospective study of 52 solid-organ transplant recipients used a three-day protocol involving a total of eight dose escalations [80]. Most (92 percent) of patients completed the protocol, with 41/52 remaining on TMP-SMX at three months without adverse events. Seven patients discontinued therapy due to reported mild allergic reactions, with no episodes of anaphylaxis or severe life-threatening reactions. The authors showed significant cost savings with this approach compared with the use of alternate agents for long-term PJP prophylaxis.

●Another retrospective study of 22 patients used a longer nine-day protocol, which was successful in 87 percent of patients (table 8) [78]. Reactions occurred in eight individuals (36 percent). All of these reactions consisted of mild-to-moderate rash or fever, which resolved after a brief course of systemic glucocorticoid treatment. There were no episodes of hypotension or anaphylaxis.

Setting and safety — We initiate all gradual reintroduction protocols under medical supervision. For patients with mild fever and/or morbilliform rash in the past, we typically administer the initial doses of the multiday protocols in the clinic and then allow the patient to complete the remaining steps as an outpatient. More rapid, single-day protocols are sufficiently short that they can be administered entirely in the clinic under medical supervision [81]. This may be preferred, for example, if the patient's ability to follow a timed schedule of doses is uncertain. In contrast, the longer protocols may be better for reliable patients in whom the main concern is introducing the medication very gradually, as the success rate of these protocols is high.

●Risks – Oral gradual reintroduction protocols are generally well tolerated [9]. However, risks include but are not limited to the entire spectrum of allergic reactions. This includes dermatologic reactions, such as urticaria/angioedema or other types of rash; pulmonary reactions, such as asthma; and rare multisystem anaphylaxis. Other types of serious and life-threatening reactions have also been reported in association with these procedures, including myocardial infarction [79].

●Symptoms during reintroduction – Any symptoms that develop during gradual reintroduction must be promptly evaluated in the clinic. We typically abort the protocol if fever or systemic symptoms (eg, abdominal pain, respiratory symptoms) develop. In contrast, if a patient develops mild morbilliform rash during reintroduction, without fever, systemic symptoms, or mucosal involvement, then we typically reduce the dose to the last tolerated step and administer this dose repeatedly at the usual time intervals while simultaneously treating the rash. We treat mild rashes with antihistamines (eg, cetirizine 10 mg twice daily) and more extensive rashes with oral glucocorticoids. When the rash begins to improve, the doses can be escalated again, although we sometimes increase the doses more gradually.

Other sulfonamides — Gradual reintroduction protocols for sulfonamides other than SMX, such as sulfadiazine (for cerebral toxoplasmosis in patients with acquired immune deficiency syndrome), sulfasalazine (for patients with rheumatoid arthritis or inflammatory bowel disease), and furosemide, have been published as well [71,74,76,81].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Sulfonamide allergy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Types of sulfonamides – There are two distinct groups of sulfonamides: antimicrobial sulfonamides and nonantimicrobial sulfonamides (table 1 and table 2). Antimicrobial sulfonamides contain an arylamine group that undergoes metabolic changes believed critical to the development of hypersensitivity reactions. Medications in the nonantimicrobial group do not contain arylamine groups and are associated only rarely with hypersensitivity reactions. Dapsone is not a sulfonamide but can cause hypersensitivity reactions that are very similar to those caused by sulfonamides (figure 3). (See 'Types of sulfonamides' above.)

●Common hypersensitivity reactions – The most common reaction to sulfonamide antimicrobials is morbilliform rash, which occurs in 3 to 8 percent of exposed patients. A more severe reaction is rash sometimes accompanied by fever and/or organ involvement beginning one to two weeks after the start of therapy. This is particularly common in patients with human immunodeficiency virus (HIV) receiving trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jirovecii pneumonia (PJP). (See 'Types of hypersensitivity reactions' above.)

●Uncommon reactions – Sulfonamides less commonly cause other types of hypersensitivity reactions, including immunoglobulin E (IgE) mediated allergic reactions or drug-induced liver injury (DILI). Sulfonamide antimicrobials are highly associated with the severe blistering reactions Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), although these reactions are rare overall. (See 'Types of hypersensitivity reactions' above.)

●Cross-reactivity among sulfonamides – Once a patient has reacted to one type of sulfonamide, questions often arise about whether they can safely receive a different type (see 'Future use of sulfonamides' above):

•There is minimal evidence of cross-reactivity between the antimicrobial sulfonamides and the nonantimicrobial sulfonamides. Therefore, patients with past reactions of any type to antimicrobial sulfonamides (eg, TMP-SMX) can receive nonantimicrobial sulfonamides (eg, hydrochlorothiazide) normally. A notable exception is sulfasalazine (a nonantimicrobial), which releases sulfapyridine (an antimicrobial) in the gut and should be considered an antimicrobial and avoided in patients allergic to antimicrobial sulfonamides. (See 'Between sulfonamide antimicrobials and nonantimicrobials' above.)

•Celecoxib is a nonantimicrobial sulfonamide. It is independently associated with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and so we avoid it in patients with past blistering reactions to any drug. (See 'Celecoxib' above.)

•There is cross-reactivity among drugs within the antimicrobial sulfonamide group. In contrast, there is only anecdotal evidence of cross-reactivity within the nonantimicrobial sulfonamide group. One possible exception to this statement is the potential cross-reactivity between different sulfonamide-containing diuretics, which is suggested by case reports. (See 'Cross-reactivity within sulfonamide groups' above.)

●Indications for referral – Consultation with an allergy specialist experienced in adverse drug reactions is recommended if drug challenge, gradual reintroduction, or desensitization is under consideration, unless the clinician is specifically experienced with these procedures (eg, some HIV specialists). (See 'Precautions with any form of reexposure' above.)

●Management of patients with past reactions who need sulfonamides again – In patients with a past reaction to a sulfonamide, the use of related medications is summarized below and in the table (table 6). (See 'Future use of sulfonamides' above.)

•Past cutaneous reaction (without fever or systemic symptoms):

-Patients with past isolated rash to one group of sulfonamide drugs (eg, antimicrobial sulfonamides such as TMP-SMX) can receive agents from the other group (eg, nonantimicrobial sulfonamides such as hydrochlorothiazide) normally because there is no known cross-reactivity between these two groups of sulfonamide drugs. (See 'Needing a sulfonamide from a different group' above and 'Between sulfonamide antimicrobials and nonantimicrobials' above.)

-For patients with past isolated rash to one group of sulfonamides more than five years ago who subsequently need the same drug or a drug from the same group, we suggest a direct (ie, one-step, full-dose under observation) challenge to the desired drug, rather than a more protracted, multi-step challenge (Grade 2B). (See 'Needing a sulfonamide from the same group' above.)

-For patients with past isolated rash to one group of sulfonamides less than five years ago who subsequently need the same drug or a drug from the same group, we suggest a graded (multi-step) challenge to the desired drug, rather than a direct challenge (Grade 2C). Reactions that occurred in the near past are somewhat more likely to recur with reexposure. (See 'Needing a sulfonamide from the same group' above.)

•Past rash and fever:

-For patients with past rash and fever +/- systemic symptoms to one group of sulfonamides who subsequently need a drug from the other group, we suggest giving the desired drug normally, rather than through a challenge procedure (Grade 2C). However, challenge may be preferred in patients with multiple drug allergies. (See 'Needing a sulfonamide from a different group' above.)

-For patients with past rash and fever +/- systemic symptoms to one group of sulfonamides who subsequently need the same drug or a drug from the same group, we advise use of a gradual reintroduction procedure. (See 'Protocols for past morbilliform rash and fever' above.)

•Past SJS/TEN:

-For patients with past SJS/TEN to one group of sulfonamides who subsequently need a drug from the other group, we suggest giving the desired drug normally, rather than through a challenge or gradual reintroduction procedure (Grade 2C). (See 'Needing a sulfonamide from a different group' above.)

-Patients with past SJS/TEN to one group of sulfonamides should strictly avoid all the sulfonamide drugs in that same group. Reexposure could precipitate a more severe and potentially fatal recurrence. (See 'Needing a sulfonamide from the same group' above.)

•Past immediate reaction:

-Patients with past immediate reactions or anaphylaxis to a drug in one group of sulfonamide drugs (eg, TMP-SMX) can receive agents from the other group (eg, hydrochlorothiazide) normally. (See 'Needing a sulfonamide from a different group' above.)

-Patients with past immediate reactions or anaphylaxis to a drug in one group of sulfonamide drugs (eg, TMP-SMX) should avoid all the other drugs in that same group. If reexposure is critical, then a rapid desensitization protocol designed for type I, IgE-mediated allergy should be employed under the guidance of an allergy specialist. (See 'Needing a sulfonamide from the same group' above.)