Sulfonamide allergy in HIV-uninfected patients

INTRODUCTION — Sulfonamide-containing antibiotics are the second most frequent cause of allergic drug reactions, after the beta-lactams (penicillins and cephalosporins). In one large study, the incidence of reactions to trimethoprim-sulfamethoxazole (TMP-SMX) was 34 per 1000 patients exposed, compared with 51 per 1000 for amoxicillin [1]. However, the adverse reactions caused by sulfonamides differ significantly from those attributed to beta-lactams, and the evaluation and management of sulfonamide reactions are distinct. The pathophysiology of allergic (or hypersensitivity) reactions to sulfonamides is complex and poorly understood.

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 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 "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug eruptions" and "Anaphylaxis: Emergency treatment" and "Drug fever".)

TERMINOLOGY — 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.

Types of sulfonamides — Sulfonamide medications are drugs that contain a sulfonamide moiety (SO₂NH₂) [2]. There are two distinct groups of sulfonamides that 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: an arylamine (an amine group linked to a benzene ring at N4) and an aromatic (N-containing) 5 or 6 member ring attached to the sulfonamide core as an N1 substituent (figure 1). 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]. The only agents that contain both moieties and produce the reactive intermediates implicated in hypersensitivity are the antimicrobial sulfonamides (figure 1 and figure 2) [5].

Nonantimicrobial sulfonamides — The agents in this group include diuretics, hypoglycemics, anti-inflammatories, and antihypertensive agents, such as furosemide, hydrochlorothiazide, acetazolamide, sumatriptan, glyburide, celecoxib, and sulfasalazine (table 2) [2]. The nonantimicrobial sulfonamides do not contain an arylamine group or a substituted aromatic ring (figure 2).

One important exception is sulfasalazine, which can cause a cross-reaction in patients with allergies to sulfonamide antimicrobials because it releases sulfapyridine (a cross-reactive arylamine sulfonamide) as a result of contact with gut flora. Thus, sulfasalazine should be avoided in patients with a significant allergy to sulfonamide antimicrobials.

Protease inhibitors — The 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)'.)

Sulfones — Sulfones are a distinct class of medications from sulfonamides. Dapsone (diaminodiphenylsulphone) is the only sulfone in common clinical use (figure 3). Although dapsone 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.

Medications unrelated to sulfonamides — The following groups of medications are unrelated to sulfonamides but are sometimes confused with them:

●Some medications contain sulfur atoms in their chemical structure but do not contain specific sulfonamide or sulfone moieties. These include amoxicillin, captopril, omeprazole, ranitidine (no longer available in the US), 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.

●Finally, sulfites 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".)

EPIDEMIOLOGY — Adverse reactions to trimethoprim-sulfamethoxazole occurred in 8 percent of 1121 hospitalized patients receiving oral or parenteral treatment [6]. Women were affected twice as often as men. This study was published before the HIV epidemic.

Impact of HIV infection — The epidemiology of sulfonamide reactions changed dramatically with the appearance of HIV, as patients with this infection are markedly more susceptible to sulfonamide reactions [7,8]. However, this review focuses on sulfonamide allergy in patients without HIV infection.

TYPES OF HYPERSENSITIVITY REACTIONS — A variety of hypersensitivity reactions can occur in response to sulfonamide drugs.

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 erythema, maculopapular or morbilliform rash, urticaria, and pruritus. Most of these reactions appear within the first three days of therapy and resolve promptly after drug discontinuation [6]. The mechanisms responsible 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 systemic symptoms' below.)

●Prominent urticaria or any other symptoms of an immunoglobulin (Ig)E-mediated reaction should take into consideration a possible immediate-type allergy. (See 'Immediate-type allergy and anaphylaxis' below.)

Morbilliform rash with fever and 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.

Symptoms generally develop one to two weeks after the start of administration, with fever usually appearing first, sometimes accompanied by malaise and pharyngitis. Peripheral blood smear may reveal an atypical lymphocytosis or eosinophilia [2,9]. Organ involvement may be asymptomatic or overt and can include hepatitis, nephritis, pulmonary infiltrates, and cytopenias. Symptoms generally resolve one to two weeks after discontinuation. With re-exposure, symptoms may appear within one to two days.

Immediate-type allergy and anaphylaxis — Sulfonamide antimicrobials can cause type I, or immediate-type hypersensitivity reactions, although this is not common [10]. Type I reactions are mediated primarily by specific IgE antibodies, which trigger sensitized mast cells (and basophils) to degranulate, releasing histamine and other vasoactive mediators (table 3) [11,12]. Typical symptoms include urticaria, angioedema, bronchospasm, laryngeal edema, and hypotension.

There is some evidence that these rare reactions involve the substituted aromatic ring, rather than the arylamine portion [13]. Nonantimicrobial sulfonamides have also been implicated but not convincingly documented [14].

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. Thus, the utility of skin testing with the original (unmetabolized) sulfonamide is unknown.

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 [15].

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. 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. The immunologic mechanisms of SJS/TEN remain enigmatic. These disorders are discussed in detail separately. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Erythema multiforme (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. EM has also been reported in association with sulfonamide antibiotics [16,17]. (See "Drug eruptions".)

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

Serum sickness — Serum sickness, a type III immunologic reaction, is occasionally caused by sulfonamide antimicrobials (table 3). These reactions present approximately 10 days to 14 days after initiation of therapy, with fever, rash (which is often urticarial), arthralgia, and lymphadenopathy [18]. Serum sickness 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 generally considered a contraindication to the use of sulfonamide drugs, as these agents can cause hemolytic anemia. This 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. Several of the antimicrobials are considered high risk (table 1), whereas few of the nonantimicrobials are. Probenecid is one exception that is considered high risk (table 2). Dapsone also carries significant risk. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Aseptic meningitis — TMP-SMX is among the most common antibiotics to cause drug-induced aseptic meningitis [19]. 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 and SMX, although cases were identified that were triggered by TMP alone or SMX alone [20]. 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 [20]. 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 the TMP-SMX again, 91 percent developed symptoms within 6 hours, and all did within 24 hours, even when the initial reaction developed after days to weeks of therapy [20]. (See "Aseptic meningitis in adults".)

PATHOPHYSIOLOGY — The pathophysiology of the most prevalent type of sulfonamide hypersensitivity reaction (ie, fever and nonblistering rash) has not been conclusively defined and is likely multifactorial [3,9,21]. Metabolism of sulfonamide antimicrobials results in intermediate forms of the drug that are believed to be critical in the pathogenesis of some reactions, although interactions between unmetabolized sulfonamide antimicrobials and T cell receptors have also been proposed [22]. It is unclear if the mechanisms described herein are involved in fever and nonblistering rash only or also in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), although cytotoxic mechanisms are likely more prominent in SJS/TEN. (See "Drug allergy: Pathogenesis", section on 'Pharmacologic interaction of drugs with immune receptors (the p-i concept)' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Sulfonamide metabolism — Sulfonamide antimicrobials are metabolized along several pathways. Some of the drug becomes acetylated (via N-acetyl transferase) at the arylamine moiety to form nontoxic metabolites that are excreted in the urine. Alternatively, the arylamine group may undergo N-oxidation via cytochrome P450 to form reactive metabolites (figure 4) [21,23]. These reactive metabolites can act as haptens or small molecules that become covalently linked to large host proteins. These hapten-protein complexes may be recognized as foreign and initiate an immunologic reaction. Other intermediate metabolites may be directly cytotoxic [21,23].

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 (figure 4) [24]. (See "Drugs and the liver: Metabolism and mechanisms of injury".)

CROSS-REACTIVITY — There is minimal evidence of cross-reactivity between sulfonamide antimicrobials and nonantimicrobials. However, the available information about cross-reactivity between these two groups is limited to observational studies, as there are no validated skin tests or serologic tests to diagnose or confirm sulfonamide allergy. (See 'Evaluation and diagnosis' below.)

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 [25]. Patients with immunologic reactions to two or more chemically distinct types of drugs are said to have "multiple drug allergy 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 [26]. 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 of drug hypersensitivity 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 — Available evidence does not support the existence of cross-reactivity between sulfonamide antimicrobials (eg, sulfamethoxazole) and nonantimicrobials (eg, loop diuretics, thiazide diuretics, sulfonylurea hypoglycemics, carbonic anhydrase inhibitors, and protease inhibitors) (table 1 and table 2). The strongest evidence supporting this statement is the large database study described in the preceding section [26]. (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 [4,9,10,26,27]:

●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 [10].

●A retrospective series described 34 patients with reported "sulfa allergy" who were treated with furosemide and/or acetazolamide (nonantimicrobial sulfonamides) for intracranial hypertension [27]. 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 information for many nonantimicrobial sulfonamide drugs contains warnings concerning possible cross-reactions (table 2).

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 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 [28]. 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 [28]. We agree with this conclusion.

Sulfasalazine — 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. Although there is a small in vitro study demonstrating immunologic cross-reactivity between sulfonamide antibiotics and sulfasalazine [29], there remains no convincing clinical evidence. However, given the theoretic cross-reactivity, our suggested approach is to do graded challenge/desensitization in sulfonamide reactors who require sulfasalazine.

Celecoxib — The available evidence suggests a lack of cross-reactivity between antimicrobial sulfonamides and celecoxib, a nonarylamine sulfonamide selective cyclooxygenase-2 (COX-2) inhibitor [28,30,31]. However, there are separate concerns about the selective COX-2 inhibitors and Stevens-Johnson syndrome (SJS) that warrant caution in patients with past febrile or blistering reactions to sulfonamide antimicrobials [32].

●A prospective pilot study of 28 patients with a history of reactions to antimicrobial sulfonamides were challenged with celecoxib, initially with a small test dose and followed by a full dose, after extensive allergy evaluation [30]. None experienced allergic reactions.

●In a large meta-analysis of over 11,000 patients from 14 double-blinded trials of celecoxib used for arthritis, the rate of allergic reactions specifically to celecoxib was not statistically different from placebo or active alternate therapy (other nonsteroidal anti-inflammatory drugs [NSAIDs]) [31]. 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 [31].

Of note, there is concern about celecoxib and an increased incidence of SJS. A large retrospective review of postmarketing safety surveillance reports (from the FDA Adverse Events Reporting System) for several of the selective COX-2 inhibitors documented significant increases of reported SJS above baseline rates [32]. 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.

In light of the above studies, we would consider the use of celecoxib in patients with past sulfonamide cutaneous reactions that were mild, although we would avoid celecoxib in a patient with past fever to sulfonamides. Because of the possible association between celecoxib and SJS, we would probably avoid celecoxib in a patient with past blistering reactions to any medication.

Between sulfonamide antimicrobials and dapsone — As previously mentioned, 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 [33-36]. It is unclear if there is cross-reactivity between sulfones and sulfonamide antimicrobials, but it seems prudent to avoid both types of agents whenever possible in patients who have had serious reactions (eg, SJS/toxic epidermal necrolysis, rash with fever and systemic symptoms, serum sickness, or hemolytic anemia) to one or the other.

Among nonantimicrobial sulfonamides — The nonantimicrobial sulfonamides have been associated with far fewer immunologic 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 [14,37]. Thus, when justified by clinical need, a patient with a past nonanaphylactic reaction to a nonantimicrobial sulfonamide can receive a different nonantimicrobial sulfonamide using a graded challenge protocol. (See 'Needing a sulfonamide from the same group' below.)

EVALUATION AND DIAGNOSIS — A thorough and detailed history is the most important component of the evaluation of a patient who reports sulfonamide allergy because there are no definitive in vivo or in vitro tests for either confirming or excluding the allergy to these medications.

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 about past reactions to sulfonamides are:

●Assessing what type of reaction the patient likely experienced in the past. (See 'Types of hypersensitivity reactions' above.)

●Assuring that the reaction was not suggestive of severe forms of hypersensitivity, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/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 significant or multisystem reaction to a sulfonamide in the past or who cannot provide much information.

Testing — There are no reliable, valid, and practical testing techniques to evaluate patients with past sulfonamide reactions, although a variety of immunologic testing techniques have been tried experimentally, including in vivo tests, such as skin testing and patch testing, as well as in vitro tests, such as lymphocyte toxicity assays, enzyme-linked immunosorbent assays, radioallergosorbent tests, and drug-specific IgG and IgE testing [38-43].

Trimethoprim allergy — A subset of patients who react to a trimethoprim-sulfamethoxazole (TMP-SMX) combination product are sensitive to the TMP component. This has mostly been documented in HIV-infected patients, in whom up to 20 percent of reactions were due to TMP allergy [44,45]. However, both generalized erythematous skin eruptions and fixed drug eruption in response to TMP have been reported in patients without HIV infection [46-49]. Careful graded challenge with TMP is often required to clarify the situation.

Diagnosis — The diagnosis of the most common forms of sulfonamide allergy (ie, simple rash and rash with fever) are made clinically [50]. (See 'Morbilliform rash with fever and systemic symptoms' above.)

SJS and TEN are also clinical diagnoses supported by compatible histologic findings. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Issues surrounding the diagnosis of other types of allergic reactions to sulfonamides are discussed separately. (See "Serum sickness and serum sickness-like reactions".)

FUTURE USE OF SULFONAMIDES

General strategies — There are three general approaches to the future use of sulfonamide drugs in patients with past reactions to a specific agent: avoidance, test dosing to confirm lack of allergy, and desensitization if allergy is likely [51]. The choice of strategy depends upon the type and severity of the past reaction and on the risks and benefits of alternative treatments. (See 'Patients with previous morbilliform rash (+/- fever)' below and 'Patients with previous SJS or TEN' below.)

●Avoidance – Use of an alternative medication of a distinct pharmacologic class is obviously the safest and simplest option in most patients with past sulfonamide reactions. Avoidance is the only safe approach if a patient describes symptoms consistent with any type of blistering dermatitis or diffuse erythroderma. These patients should almost never undergo test dosing or desensitization, except in very unusual circumstances. Case series have noted that Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can recur and may be more severe with even minor re-exposures [52].

●Test dosing – "Test dosing" (or graded drug challenge) is a term used to describe the cautious administration of small and increasing doses of a medication under medical observation. Test dosing 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 graded challenge prove that they are not allergic to that drug.

The starting dose used is influenced by the severity and remoteness of the past reaction and may range from 1/1000^th to 1/10^th of the therapeutic dose [51,53]. This amount is then gradually increased by 3- to 10-fold at each step. The steps are administered at time intervals that are long enough to allow for the development of symptoms, and these intervals are determined by the nature of the past reaction.

As an example, a patient who had previously developed a maculopapular rash in response to hydrochlorothiazide and subsequently required glyburide would be an appropriate candidate for test dosing, as cross-sensitivity between these two nonantimicrobial sulfonamides is unlikely but not impossible. If the patient reports that the rash to hydrochlorothiazide had appeared within two to four hours of the last administered dose, then it would be appropriate to give test doses at intervals of six to eight hours, beginning at 1/10^th of the target dose. In this example, a relatively large initial dose is acceptable because the original reaction to hydrochlorothiazide was not severe.

●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 be allergic to the drug in question. 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. Desensitization is most often used in patients with IgE-mediated, type I hypersensitivity reactions, although in the case of sulfonamide drugs, protocols have been developed for use in patients with the more common presentation of rash and fever. (See 'Desensitization' below.)

Precautions with any form of re-exposure — Consultation with an allergy specialist experienced in adverse drug reactions is recommended if either test dosing or desensitization are under consideration, unless the clinician is specifically experienced with these procedures. Precautions regarding both test dosing and desensitization include the following:

●These procedures are performed immediately before required treatment.

●Medications are administered without premedication, which could obscure detection of early and mild allergic symptoms.

●Documentation of informed consent, including a thorough discussion of risks and benefits of the procedure, is essential.

Patients with previous morbilliform rash (+/- fever) — In most patients with fever and nonblistering rash in response to a sulfonamide drug in the past, the use of chemically distinct medication is the most prudent option. However, if there is no equivalent alternative medication and another sulfonamide medication is required, then both test dosing and desensitization may be considered. These situations require clinical judgment and clear communication with the patient.

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 trimethoprim-sulfamethoxazole [TMP-SMX]), there are two options for treatment:

●Simply give the drug normally – This is appropriate in a patient who does not have multiple drug allergies and whose past reaction to the sulfonamide from the other group was limited to morbilliform rash or rash and fever.

●Administration of one or more test doses of the desired drug – This is our preferred approach for the patient with multiple drug allergies, as this clinical history identifies a subset of patients at higher risk for drug reactions in general. (See 'Confounding in studies of cross-reactivity' above.)

The specific test dose protocol would be based upon the patient's past reaction. If the original reaction involved delayed-onset rash, initial test doses can be repeated for several days without dose escalation in order to ensure that any reactions have sufficient time to develop. As an example, a patient with past hypersensitivity to TMP-SMX who required furosemide could take one-half of the lowest strength tablet available once daily for a week as an initial test dose. Even lower initial test doses can be obtained by diluting commercially available oral solutions. If no symptoms developed, then the patient could be advanced stepwise to the full therapeutic dose.

Needing a sulfonamide from the same group — There are several potential clinical scenarios that may 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 a patient needing TMP-SMX again – Desensitization is appropriate in this setting. Desensitization to TMP-SMX is best studied in HIV-infected patients, although the author and editors have performed TMP-SMX desensitization in HIV-uninfected patients with similar success. (See 'Desensitization' 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 [54]. The risk of cross-reactivity among them is poorly understood, although there has been a presumption of cross-reactivity among the thiazide diuretics, supported by case reports.

Ethacrynic acid is the only available loop diuretic with no known potential to cross-react with sulfonamide-containing diuretics [55]. It is therefore the preferred agent for an individual who previously reacted to a sulfonamide-containing diuretic and requires diuresis again.

Desensitization to one of the sulfonamide diuretics is useful if ethacrynic acid is unavailable or insufficiently effective. There have been published reports of successful graded-dose challenges to torsemide and desensitizations to furosemide in patients with previous reactions to sulfonamide diuretics [54,56]. Together, these reports describe three cases: one patient's initial reaction to sulfonamide diuretics was diffuse hives without other signs of anaphylaxis [54], a second had pancytopenia [54], and a third had recurrent pancreatitis with furosemide, bumetanide, and torsemide [56]. 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 (table 4 and figure 2). It is used in the treatment of inflammatory bowel disease, psoriasis, lupus, and rheumatoid arthritis. 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 immunomodulatory therapies have become available [57]. However, prior to these therapies, relatively successful protocols for sulfasalazine reintroduction were published [58-61]. (See "Management of the hospitalized adult patient with severe ulcerative colitis".)

●Sulfonylurea allergy in diabetes – Some oral hypoglycemic agents used in the management of type 2 diabetes mellitus are nonantimicrobial sulfonamides, known as sulfonylurea hypoglycemics. These include glyburide, glipizide, glimepiride, and a few other insulin secretagogues that are no longer commonly used (table 2). Sulfonylureas occasionally cause adverse reactions with presumed immunologic mechanisms, most commonly dermatologic reactions, such as urticaria, photosensitive rash, and leukocytoclastic vasculitis. Sulfonylurea hypoglycemics can be safely given to patients with past reactions to sulfonamide antimicrobials (such as TMP-SMX), although there is little in the published medical literature addressing issues of possible cross-reactivity between sulfonylureas and other types of nonantimicrobial sulfonamides.

There is some evidence of cross-allergenicity within the sulfonylurea group itself [14]. Thus, in a patient with a past allergic reaction to one sulfonylurea hypoglycemic, it is best to avoid other similar medications and treat with an unrelated, nonsulfonamide medication. The issue of sulfonylurea allergy has become less of a concern over time, as numerous other agents of different classes and mechanisms have been developed for the management of diabetes. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)

Patients with previous SJS or TEN — As discussed previously, blistering rashes include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Re-exposure 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 both test dosing and desensitization. Case series have noted that SJS and TEN can recur with even minor re-exposures and may be more severe the second time [52].

Needing a sulfonamide from a different group — Our practice is to avoid all sulfonamides and sulfones in patients with past SJS or TEN. However, rare situations may arise in which a sulfonamide from a different group is needed for a life-threatening condition. Consultation with an allergy specialist experienced in adverse drug reactions would be essential in this setting. One report described successful reintroduction of a sulfonamide diuretic in a patient with SJS to TMP-SMX years earlier and uncomplicated rashes with furosemide and glyburide [55]. He was treated for several years with ethacrynic acid, but this drug then became temporarily unavailable, and his heart failure progressed. After giving informed consent, the patient received a graded challenge 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. The patient developed no allergic symptoms.

Patients with past anaphylaxis — For patients with past reactions consistent with IgE-mediated allergy or anaphylaxis (ie, hives, angioedema, bronchospasm, laryngeal edema, and/or hypotension), the causative drug should be avoided. In addition, all sulfonamides within the same group should also be avoided. 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 desensitization protocol designed for type I, IgE-mediated allergy should be employed under the guidance of an allergy specialist. (See 'Desensitization' 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 in whom allergic reactions are considered probable. Desensitization may be attempted for some types of reactions when there are no medically acceptable alternatives.

The term "desensitization" usually refers to procedures designed to allow patients with a history of type I (IgE-mediated, immediate-type hypersensitivity) drug allergy to temporarily tolerate readministration of a medication, such as penicillin [24]. Patients must continue to take the medication regularly (usually at least daily) following a successful desensitization procedure. Because of the temporary nature of the effect, the term "hyposensitization" is preferred by some allergy experts.

Protocols have also been developed for a small number of other medication reactions that result from non-IgE-mediated immunologic mechanisms, including sulfonamide sensitivity involving delayed maculopapular rashes and fever. Unfortunately, these procedures for non-IgE-mediated skin rashes are also called desensitizations, despite the lack of evidence that any immune cell (eg, T lymphocyte) is downregulated as a result of the process. Despite these uncertainties, desensitization is the commonly used term for sulfonamide re-exposure protocols, and this review uses the term as well. These protocols may appear to be successful in large part because many patients lose immunologic sensitivity over time.

Protocols for past rash/fever — The protocols described in this section are intended to be performed in patients with past morbilliform rash with or without fever, for whom there is no equivalent alternative treatment.

Drug desensitization protocols vary, although all are based upon administering increasing doses of medication in an uninterrupted and stepwise manner, beginning with very low doses. The protocols presented here have been performed successfully by the author, 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 change the time interval between doses.

Trimethoprim-sulfamethoxazole — There are a significant number of published desensitization protocols for use in HIV-positive patients requiring trimethoprim-sulfamethoxazole (TMP-SMX), 11 of which were compared in detail in a review on drug desensitization [24]. The efficacy of these protocols has not been compared in head-to-head studies, and the optimal approach has not been determined. Most of the published TMP-SMX desensitization trials have used the oral route, as this is presumed safer than intravenous administration.

Two prospective trials of TMP-SMX desensitization are presented in detail here [42,62]. Both were performed in HIV-positive patients who required pneumocystis pneumonia prophylaxis and had a history of TMP-SMX-associated fever or nonblistering skin rash. The author has used these two protocols successfully in patients without HIV infection, with no apparent differences in outcome.

●The largest published study of TMP-SMX desensitization in HIV-positive patients involved 48 patients undergoing the protocol outlined in the table (table 5) [62]. 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.

●Another study of 22 patients used a longer nine-day protocol, which was successful in 87 percent of patients (table 6) [42]. 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.

We initiate all desensitization protocols under medical supervision. For patients with mild fever and/or morbilliform rash in the past, we typically administer the first three doses of this protocol in the clinic and then allow the patient to complete the remaining steps as an outpatient. The three-day protocol is sufficiently short, and it can be administered entirely in the clinic under medical supervision. This may be preferred, for example, if the patient's ability to follow a timed schedule of doses is uncertain. In contrast, the longer nine-day protocol may be better for reliable patients in whom the main concern is introducing the medication very gradually, as the success rate of this protocol was high.

Symptoms during desensitization — Any symptoms that develop during desensitization must be promptly evaluated in the clinic. If a patient develops mild morbilliform rash during desensitization 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 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.

We typically abort the desensitization protocol if fever or systemic symptoms develop.

More rapid protocols have also been published for TMP-SMX [63]. These may warrant additional caution for potentially increased risks.

Risks — These types of oral desensitizations are generally well-tolerated [24]. However, risks of drug desensitization procedures 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 [62].

Duration of efficacy — Desensitization may be effective only as long as the allergic individual is continuously exposed to the drug. 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 [64]. Whether the same is true for patients desensitized to TMP-SMX, however, is speculative. Patients should be counseled that they may have a recurrent reaction if they forget to take their daily dose on one or more consecutive days.

Other sulfonamides — Desensitization 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 [56,59,61,63].

Protocols for past anaphylaxis — Desensitization protocols for patients with past anaphylaxis should only be done under the guidance of an allergy specialist with experience in such procedures. Such desensitizations are usually performed in a medically supervised setting, with proper monitoring in place and immediate availability of rescue medications and equipment to treat anaphylaxis. The techniques involved are discussed in detail separately. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

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".)

SUMMARY AND RECOMMENDATIONS

Clinical characteristics and pathophysiology:

●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 'Terminology' above.)

●Hypersensitivity reactions to sulfonamide antimicrobials most commonly present as fever and morbilliform rash, sometimes accompanied by organ involvement, beginning one to two weeks after the start of therapy. (See 'Types of hypersensitivity reactions' above.)

●Sulfonamides less commonly cause other types of immunologic drug reactions, including serum sickness-like reactions and immunoglobulin (Ig)E-mediated allergic reactions. Sulfonamide antimicrobials are highly associated with the rare blistering reactions Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN). (See 'Types of hypersensitivity reactions' above.)

Issues of cross-reactivity:

●There is minimal evidence of cross-reactivity between the antimicrobial sulfonamides and the nonantimicrobial sulfonamides. A notable exception is sulfasalazine (a nonantimicrobial), which releases sulfapyridine (an antimicrobial) in the gut and should be avoided in patients allergic to antimicrobial sulfonamides. However, it is impossible to say that cross-reactivity absolutely does not occur between the two groups, because the nonantimicrobial sulfonamides are implicated in hypersensitivity reactions as well, albeit rarely. (See 'Between sulfonamide antimicrobials and nonantimicrobials' above.)

●There is minimal evidence for cross-reactivity between antimicrobial sulfonamides and celecoxib, and patients who react to both appear to be rare. However, celecoxib may be independently associated with a higher incidence of SJS. (See 'Celecoxib' above.)

●There is only anecdotal evidence of cross-reactivity among different nonantimicrobial sulfonamides. One important exception to this statement is the potential cross-reactivity between different sulfonamide-containing diuretics, which is suggested by case reports. (See 'Among nonantimicrobial sulfonamides' above.)

Evaluation and diagnosis – The evaluation and diagnosis of a patient with a past sulfonamide reaction is based solely upon a detailed clinical history because there are no useful in vitro or in vivo tests for the diagnosis of sulfonamide allergy. (See 'History' above.)

Management of patients with past reactions – In patients with a past reaction to a sulfonamide, the use of an alternative medication is the most suitable option in most cases, although the potential consequences of treatment failure with a "second-best" therapy must also be considered. (See 'Future use of sulfonamides' above.)

●An allergy specialist should be consulted (if possible) when any form of readministration of the culprit agent or a similar medication is being considered, unless the clinician is experienced in these procedures (eg, HIV specialists). (See 'General strategies' above.)

Fever and nonblistering rash – Patients with a history of sulfonamide hypersensitivity (characterized by fever and nonblistering morbilliform rash) should avoid the causative agent and other agents in the same group (eg, within the antimicrobial arylamine group) whenever acceptable alternatives are available. (See 'Patients with previous morbilliform rash (+/- fever)' above.)

●If the culprit agent or another agent within the same group is clinically required, we suggest performing a desensitization protocol (rather than simple readministration or test dosing) (Grade 2B). Each case requires careful consideration of risks versus benefits, particularly if the original reaction involved extracutaneous organ inflammation. (See 'Needing a sulfonamide from the same group' above.)

●Desensitization has been best studied in HIV-positive patients who require readministration of trimethoprim-sulfamethoxazole (TMP-SMX), although we have successfully desensitized patients without HIV infection to TMP-SMX using the same protocols (table 5 and table 6). Desensitization protocols have been published for a small number of nonantimicrobial sulfonamides, including torsemide, furosemide, and sulfasalazine, as well as for dapsone. (See 'Desensitization' above and 'Other sulfonamides' above and 'Between sulfonamide antimicrobials and dapsone' above.)

●If the patient requires a sulfonamide medication from a different group:

•For patients without other drug allergies, we suggest simply administering the desired agent normally (Grade 2C).

•For patients with other drug allergies who may be at higher risk for drug reactions in general, we suggest giving one or more test doses initially (Grade 2C). The necessity of this has not been systematically studied. (See 'Needing a sulfonamide from a different group' above.)

SJS/TEN – Patients with a history consistent with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or any blistering dermatitis due to a sulfonamide medication should strictly avoid the culprit drug and other agents in the same sulfonamide group. Re-exposure to the same agent may be fatal. Use of a sulfonamide from the other group should only be considered in rare circumstances. (See 'Patients with previous SJS or TEN' above.)