Practical Issues in the Management of Hypersensitivity Reactions: Sulfonamides.

ABSTRACT: Approximately 3% of the general population and 60% of patients with human immunodeficiency virus (HIV) infection have adverse reactions when treated with sulfonamide antimicrobials. The most common clinical manifestations of sulfonamide hypersensitivity are fever and a maculopapular rash 7 to 14 days after initiating therapy, though a variety of more severe manifestations may occur. The sulfonamide chemical moiety is present in many medications that are not antimicrobials, and fortunately hypersensitivity reactions to these medications are less common. The immunogenicity of sulfonamide antimicrobials may be due to the presence of an arylamine group at the N4 position of the sulfonamide molecule. No diagnostic tests are available to confirm sulfonamide hypersensitivity, and while avoidance of the drug is generally appropriate when a previous hypersensitivity reaction is suspected, desensitization protocols are available for use in HIV patients in whom Pneumocystis carinii pneumonia prophylaxis or tre atment is indicated.

DRUG-INDUCED ALLERGIC REACTIONS occur in approximately 5% of the population. These reactions are responsible for approximately 6% to 10% of all adverse drug reactions. [1,2] Although an estimated 5% of the population is allergic to one or more medications, approximately 15% of the population believe themselves to have medication allergies or have been incorrectly labeled as having a medication allergy. Because of these inaccuracies and the fear of recurrent reactions, patients may not receive optimal therapy. [3,4] In a patient having a drug reaction, optimizing short-term and long-term outcomes depends on accurate diagnosis, including clear documentation of the drug exposure and symptoms, as well as consideration of the potential for cross-reactivity with other agents that might be used.

Most medications have a 1% to 3% risk of producing immunologic manifestations. [1] Of all medication classes, [beta]-lactam antibiotics, sulfonamides, and nonsteroidal anti-inflammatory drugs comprise 80% of all reports of allergic and pseudoallergic reactions. [3] Sulfonamides provide a unique challenge for clinicians because of the variety of medication classes that possess this chemical moiety and the relative uncertainty of the potential for cross-allergenicity among agents in these classes.

The human immunodeficiency virus (HIV) pandemic has caused resurgence in the use of sulfamethoxazole due to its effectiveness in prevention and treatment of Pneumocystis carinii pneumonia (PCP). Unfortunately, HIV patients have a much higher risk of adverse reactions to the drug than other patients, which has led to exploration into the utility of sulfamethoxazole desensitization in HIV patients. This report reviews the structure of various sulfonamides and their metabolites, and then discusses the capacity for sulfonamides to cause allergic reactions, including the immunologic mechanisms and clinical manifestations. Management strategies are discussed, including both desensitization and the risk of adverse reactions to other compounds containing the sulfonamide moiety.

WHAT CONSTITUTES A SULFONAMIDE

A sulfonamide is a chemical entity characterized by a sulfur dioxide ([SO.sub.2]) and nitrogen (N) moiety directly linked to a benzene ring (Fig 1). Many medication classes contain this chemical entity including sulfonamide antimicrobials (eg, sulfamethoxazole, sulfadiazine, sulfacetamide), carbonic anhydrase inhibitors (eg, acetazolamide, methazolamide), sulfonylureas (eg, glyburide, glipizide), diuretics (eg, hydrochlorothiazide, chlorthalidone, furosemide, bumetanide), uricosurics (eg, probenecid), drugs for inflammatory bowel disease (eg, sulfasalazine), selective serotonin-1 receptor agonists (eg, sumatriptan), and the specific cyclooxygenase-2 inhibitor celecoxib. [5-7] Several structural differences exist among these medication classes. A major difference between sulfonamide antimicrobials and other sulfonamide-containing medications is the presence of an arylamine group ([NH.sub.2]) at the [N.sup.4] position. It has been hypothesized that the arylamine group is critical in producing hypersensitivity r eactions. [8] Only sulfonamide antimicrobials contain this group. Other differences are apparent in the substitutions attached to the sulfonamido group at the [N.sup.1] position of the benzene ring (Fig 2). [89]

SULFONAMIDE METABOLISM AND IMMUNOGENICITY

Sulfonamides undergo a slightly complicated metabolism, including varying degrees of acetylation, hydroxylation, and glucoronidation. [8] This results in the formation of a variety of metabolites that may be immunogenic, toxic to the body, or both. The relative amount of various metabolites determines whether adverse effects occur. The type of sulfonamide compound being metabolized, the acetylation rate, and possibly the oxidation rate all influence the likelihood of an adverse reaction to a sulfonamide.

As with most other nonproteinaceous immunogenic substances, sulfonamides act as haptens, becoming covalently linked to a carrier molecule. [10, 11] Once haptenation occurs, the body may recognize the drug as foreign and initiate an immunologic response. [5] Although this process appears simple, sulfonamide-induced hypersensitivity reactions involve a complex combination of metabolic and immunologic events, each greatly influenced by structural differences (Table 1). [8, 9, 11]

Shear et al [12] were the first to describe the importance of metabolism in the development of sulfonamide-induced hypersensitivity reactions. Their findings suggest that the reactive hydroxylamine metabolite formed through oxidation of the arylamine group is important in forming the haptenated structure recognized by the body as foreign. Because sulfonamide antimicrobials are the only sulfonamide-containing medications that have an arylamine group, they are the only medications that form the reactive hydroxylamine intermediate and the subsequent haptenaton product via this pathway. Although the potential metabolic pathways of all sulfonamide antimicrobials are similar, individual agents differ with respect to the predominance of the oxidative pathway. Thus, even individual sulfonamide antimicrobials may differ in their ability to form the reactive hydroxylamine metabolite. [8]

Haptenation pathways of other sulfonamide-containing medication classes do not occur through the arylamine group. Furosemide haptenation occurs via its furan  structure. [11] Thus, a metabolic rationale for cross-allergenicity exists among sulfonamide antimicrobials but does not exist between sulfonamide antimicrobials and other sulfonamide-containing compounds. [8]

Results of a study by Harle et al [9] indicate that the substituted sulfonamide region of sulfonamide antimicrobials is a strong determinant of immunologic recognition. The attachment of a five- or six-member aromatic heterocyclic ring with at least one nitrogen to the sulfonamido-N [1] and the presence of a single methyl group on the second carbon atom ([beta] position) from the sulfonamido substitution are important allergenic determinants. Of these features, the methyl group appears to have the more dominant allergenic role. The antigenic potential of agents without these groups or with additional substitutions to the adjacent aromatic ring (eg, methyl groups) is decreased. Because sulfamethoxazole, sulfamerazine, and sulfamethizole contain these groups, they appear to have a greater potential for cross-allergenicity than other sulfonamide antimicrobials. Since other sulfonamide-containing compounds do not contain these groups, the risk of cross-allergenicity between these compounds and sulfamethoxazole, s ulfamerazine, and sulfamethizole is reduced. [9]

INCIDENCE AND SCOPE OF REACTIONS TO SULFONAMIDES

General Population

Approximately 3% of patients in the general population have hypersensitivity reactions to sulfonamide antimicrobials. [2] Sulfonamides have been implicated in a variety of immunologic manifestations, from mild skin rashes to more serious and life-threatening reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Fortunately, the incidence of serious allergic reactions with sulfonamides is low. Overall, Stevens-Johnson syndrome and TEN occur in approximately 10 cases per million persons per year with sulfonamide antimicrobials among the most frequently cited causative agents. [13] Likewise, sulfonamide-induced IgE-mediated anaphylactic reactions also occur rarely. [8] The classic sulfamethoxazole hypersensitivity syndrome is characterized by fever, a generalized maculopapular rash, and toxicity of one or more internal organs. This syndrome usually develops 7 to 14 days after the initiation of sulfamethoxazole therapy. [8] Similarly, skin lesions should clear completely within 7 to 14 days of withdrawal of the suspected agent." Other potential immunologic sequelae are included in Table 2. [3,8,14-18]

Patients with Human Immunodeficiency Virus

In contrast to the relatively low incidence of sulfonamide hypersensitivity reactions in the general population, approximately 60% of patients with acquired immunodeficiency syndrome have adverse symptoms when treated with sulfonamides. [2] Reactions requiring drug discontinuance have been reported to be as high as 34%. [19] Because sulfonamides are a critical component in the treatment and prophylaxis of PCP, sulfonamide-allergic HIV patients pose a special therapeutic challenge. [20] Possible explanations for the greater incidence of allergic reactions among HIV-infected patients include direct cytotoxicity and/or haptenation of the hydroxylamine metabolite and glutathione deflciency. [21,22] In one study, [23] patients with CD4-to-CD8 ratios of greater than 0.10 and those with a sulfonamide treatment duration of less than 14 days were at greater risk of hypersensitivity reactions. Although the frequency of allergic reactions among this population is higher than in the general population, the clinical manif estations are essentially the same.

TREATMENT OF SULFONAMIDE HYPERSENSITIVITY REACTIONS

Generally, the more severe the clinical manifestation, the more extensive the therapeutic approach required (Table 2). A mild rash may require only the discontinuance of the suspected agent. For more serious reactions, oral antihistamines and corticosteroid therapy may be added to the treatment regimen. In the case of Stevens Johnson syndrome, patients may require hospitalization for intravenous corticosteroid therapy. Because of the extensive dermatologic involvement of TEN, patients require treatment in intensive care or bum units. Unfortunately, corticosteroids do not appear to suppress the severe cutaneous manifestations of TEN, [24] though limited data support the use of cyclosporin in this condition. [25]

Differentiating a serious reaction from one that is less serious may be difficult, particularly when evaluating a patient with a cutaneous reaction. Most morbilliform eruptions fade in a few days. However, morbilliform eruptions also may be the initial sign of more serious cutaneous reactions, such as Stevens-Johnson syndrome or TEN. Several clinical findings may help clinicians determine the potential seriousness of a cutaneous reaction, including the presence of arthralgias, skin blistering, and mucous membrane involvement (Table 3). [18]

MANAGEMENT STRATEGIES

Assessment of Risk

The most important risk for adverse drug reactions is a history of a previous drug reaction. [3,4] Patients who are allergic to one antimicrobial drug have a tenfold greater risk of reacting to another structurally unrelated antimicrobial." Several other patient subsets also are at increased risk of allergic reactions. Patients with infections appear to be at greater risk of reactions mediated through haptenation. [3,4] One study [13] suggested that some patients may have a genetic predisposition toward the development of sulfonamide-induced TEN. Because of the metabolic pathways involved in the formation of reactive intermediates, patients with the slow acetylation phenotype and those with glutathione deficiency also may be at greater risk of allergic reactions with sulfonamide antimicrobials. [12,18,26-28] Additionally, an adverse reaction involving mucosal lesions is a marker for subsequent serious reactions, and therefore subsequent therapy is contraindicated. [3,18] Some other factors to be considered in the assessment of risk include the route and frequency of drug administration. Cutaneously administered medications are more likely to induce sensitization than those administered by other routes. In addition, patients receiving frequent courses of medications are more likely to have an allergic reaction than those receiving less frequent courses of medications. [3,11,29]

Skin Testing

There are several limitations in using skin testing to determine the presence of sulfonamide hypersensitivity. First, not all immunologic reactions to sulfonamides are mediated by IgE. Second, since metabolism of sulfonamides occurs primarily in the liver, skin testing with the parent compound is not useful. A small-scale investigation has evaluated the usefulness of hapten carrier conjugates of sulfamethoxazole for skin testing. Of 44 sulfonamide-allergic patients studied, 27% had a positive result on skin testing with hapten conjugated sulfamethoxazole. No false-positive reactions occurred among the 6 patients in the control group. [26] Given the relatively low sensitivity of such testing and the lack of widespread availability of hapten conjugated sulfamethoxazole, skin testing for sulfonamide hypersensitivity currently is not a useful option.

Desensitization Protocols

Drug "desensitization" refers to the process of converting a patient from a state of sensitivity to a state in which a therapeutic dose of the drug may be administered safely. [17] This generally involves the gradual introduction of increasing amounts of the drug, starting with as little as one millionth of the therapeutic dose. Even patients who have previously had life-threatening IgE-mediated anaphylaxis may be safely treated using this technique, though the logistics often involve intensive monitoring during the procedure, informed consent, and strict adherence to the protocol used. Desensitization temporarily expends the ability of the body to react to the agent, and subsequent doses may be given safely to complete the course of therapy. Unlike allergen immunotherapy, desensitization does not result in a long-lived tolerance to the allergen, and therefore the protocol must be repeated if subsequent courses of therapy are necessary.

When beginning desensitization, the initial dose should be small enough that the potential for a serious reaction is minimal. The dose is gradually increased in twofold to tenfold increments over a matter of hours or days until a therapeutic dose is reached. The appropriate dosing interval and route of administration is determined by the characteristics of the previous reaction and the urgency for readministration of the suspected agent. Generally, the risk of anaphylactic reactions is lower with the oral route of administration. [3]

In most circumstances, desensitization should occur under controlled conditions, immediately before the anticipated course of treatment. The procedure requires that the clinician have emergency equipment on hand. If the appropriate equipment is not available or if the anticipated risk of a reaction is great, dosing in a hospital setting may be required. Before the first dose is administered, the patient should be made aware of the risks and benefits involved, and informed consent should be documented in the medical record. [5] Premedication with antihistamines or corticosteroids is not recommended, since they have not been shown to prevent reactions and may mask early signs of anaphylaxis. [1]

The best-studied agent with respect to desensitization is penicillin, a drug for which validated skin testing is available. Unfortunately, there are no practical diagnostic tests for confirming immunologic sensitization to sulfonamides. Before the HIV pandemic, treating sulfa-allergic patients with a sulfonamide-containing medication was generally contraindicated because equally effective alternative medications were usually available. However, despite the absence of accurate diagnostic testing for sulfonamide allergy, the risk of not using sulfamethoxazole in the treatment of HIV patients has led to intensive study of desensitization in this population. Accordingly, a variety of sulfonamide desensitization protocols have emerged (Tables 4 and 5). [30-33] In contrast to the classic penicillin desensitization protocols, desensitization to sulfamethoxazole in HIV patients does not necessarily require intensive monitoring, and some protocols may be completed unsupervised at home (Table 5). Relatively little inf ormation is available concerning sulfamethoxazole desensitization in immunocompetent individuals, though desensitization has been studied for sulfasalazine in patients with arthritis (Table 6). [31]

Avoiding Reactions Stemming From Cross-Allergenicity

The increased use of sulfonamide antimicrobials has spawned controversies surrounding the use of sulfonamide-containing medications in patients who have a history of sulfonamide hypersensitivity. Generally, patients who state that they have a "sulfa" allergy often are referring to sulfonamide antimicrobials, such as sulfamethoxazole. While there have been reports of individual patients having serious adverse reactions to more than one class of sulfa drug, [34,35] true immunologic cross-reactivity has not been shown.

Given the paucity of data regarding cross-allergenicity among sulfonamide-containing medications, the incidence of such cross-reactions is probably low. Potential reasons for the low incidence of cross-allergenic reactions include: structural differences, differences in haptenation pathways, metabolic differences, and site specificity requirements for immunologic recognition (Table 1). [8,11] Cross-allergenicity among various sulfonamide antimicrobials is also probably low. [9,35] As mentioned previously, the two structural features of sulfonamides that appear to be most important for the initiation of an immune response are the presence of an arylamine group (facilitating haptenation) and the presence of a single methyl group on the carbon atom [beta] to the sulfonamido substitution at the [N.sup.1] position (facilitating immune recognition). While all of the antimicrobial sulfonamides have the arylamine group and are therefore more easily haptenated, they do not all have optimally oriented methyl substituti ons.

For patients who have an established allergy to sulfonamide antimicrobials, the risk of cross-allergenicity with other sulfonamide-containing compounds (eg, diuretics, sulfonylureas) is low. [11] However, because additional drug allergies are more likely to develop in patients with a history of drug allergy, patients with a history of an adverse reaction to sulfamethoxazole may be more likely to have adverse reactions to other sulfonamides.

CONCLUSIONS

Adverse reactions to sulfonamides are relatively common and range in severity from relatively mild cutaneous manifestations to potentially life-threatening anaphylaxis. The range of clinical manifestations is in part due to the variety of mechanisms responsible for these reactions. Hepatic metabolism of sulfonamides determines both their immunogenicity as haptens and their potential to be directly cytotoxic. Unfortunately, no practical diagnostic testing is available to confirm sulfonamide allergy. Additionally, treatment of patients with sulfonamide allergies is particularly challenging because of the large number of sulfonamide-containing compounds available. Fortunately, structural features of individual sulfonamide agents strongly influence the potential for adverse reactions, and most sulfonamide agents probably do not cross-react.

As with other adverse drug reactions, the treatment of sulfonamide-allergic patients generally requires avoidance of that agent. However, the HIV pandemic has presented a unique demand for sulfonamide antimicrobials, which has led to the development of safe and practical desensitization protocols for use in immunocompromised patients.

From the Departments of Medicine and Pediatrics, Division of Allergy and Clinical Immunology, and the Allergy and Asthma Clinic, Oregon Health Sciences University, Portland.

Dr. Tilles has received an honorarium from G.D. Searle Pharmaceutical Co, the manufacturer of celecoxib.

Reprint requests to Stephen A. Tilles, MD, ASTHMA Inc, 4540 Sand Point Way NE, Suite 200, Seattle, WA 98105.

References

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(2.) Kucera CM, Greenberger PA: Adverse drug reactions: treatment and prevention. Hosp Med 1996; 32:11-24

(3.) DeSwarte RD, Patterson R: Drug allergy. Allergic Diseases. Patterson R, Grammer LC, Greenberger PA (eds). Philadelphia, Lippincott-Raven, 1997, pp 317-412.

(4.) Sullivan TJ: Drug allergy. Allergy: Principles and Practice. Middleton E, Reed CE, Ellis EF, et al (eds). St. Louis, CV Mosby Co, 1993, pp 1726-1745

(5.) Duncan C: Sulfonamide cross-allergenicity--answers to common questions. Hosp Pharm 1989; 24:666-668

(6.) Lefkowith JB: Cyclooxygenase-2 specificity and its clinical implications. Am J Ailed 1999; 106:43S-50S

(7.) Physicians' Desk Reference. Montvale, NJ, Medical Economics Co, 53rd Ed, 1999

(8.) Cribb AE, Lee BL, Trepanier LA, et al: Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicro bials: clinical syndromes and pathogenesis. Adverse Drug React Toxicol Rev 1996; 15:9-50

(9.) Harle DG, Baldo BA, Wells JV: Drugs as allergens: detection and combining site specifities of IgE antibodies to sul famethoxazole. Mol Immunol 1988; 25:1347-1354

(10.) Meekins CV, Sullivan TJ, Gruchalla RS: Immunochemical analysis of sulfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins. J Allergy Clin Immunol 1994; 94:1017-1024

(11.) Sullivan TJ: Cross-reactions among furosemide, hydrochlorothiazide, and sulfonamides. JAMA 1991; 265:120-121

(12.) Shear NH, Spielberg SP, Grant DM, et al: Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986; 105:179-184

(13.) Roujeau JC, Huynh TN, Bracq C, et al: Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol 1987;123:1171-1173

(14.) Bond CA: Skin disorders I. Applied Therapeutics: The Clinical Use of Drugs. Koda-Kimble MA, Young L (eds). Vancouver, Applied Therapeutics, 5th Ed, 1992, pp 64:1-64:16

(15.) Cheriyan S, Patterson R, Greenberger PA, et al: The outcome of Stevens-Johnson syndrome treated with corticosteroids. Allergy Proc 1995; 16:151-155

(16.) Kollef M, Goodenberger D: Critical care and medical emergencies. Manual of Medical Therapeutics. Ewald GA, McKenzie CR (eds). Boston, Little Brown and Co, 28th Ed, 1995, pp 184-235

(17.) Patterson R, DeSwarte RD, Greenberger PA, et al: Individual drugs or problems: summary of useful techniques. Drug Allergy and Protocols for Management of Drug Allergies. Providence, OceanSide Publications, 1995, pp 9-18

(18.) Roujeau JC, Stern RS: Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331:1272-1285

(19.) Montanaro A: Sulfonamide allergy. Immunology and Allergy Clinics of North America. Tilles SA (ed). Philadelphia, WB Saunders Co, 1998, pp 843-850

(20.) Greenberger PA, Patterson R: Management of drug allergy in patients with acquired immunodeficiency syndrome. J Allergy Clin Immunol 1987;79:484-488

(21.) Carr A, Tindall B, Penny R, et al: In vitro cytotoxicity as a marker of hypersensitivity to sulphamethoxazole in patients with HIV. Clin Exp Immunol 1993; 94:21-25

(22.) Gruchalla RS, Pesenk RD, Do TT, et al: Sulfonamide-induced reactions in desensitized patients with AIDS--the role of covalent protein haptenation by sulfamethoxazole. J Allergy Clin Immunol 1998; 101:371-378

(23.) Carr A, Swanson C, Penny R, et al: Clinical and laboratory markers of hypersensitivity to teimethoprim-sulfamethoxazole in patients with Pneumocystis carinii pneumonia and AIDS. J Infect Dis 1993; 167:180-185

(24.) Roujeau JC: The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: a clinical classification. J Invest Dermatol 1994; 102:28S-30S

(25.) Arevalo JM, Lorente JA, Gonzalez-Reyes J: Treatment of toxic epidermal necrolysis with cyclosporin A. J Trauma 2000; 48:473478

(26.) Gruchalla RS, Sullivan TJ: Detection of human IgE to sulfamethoxazole by skin testing with sulfamethoxazoyl-poly-L tryosine. J Allergy Clin Immunol 1991; 88:784-792

(27.) Merk HF, Baron J, Kawakubo Y, et al: Metabolites and allergic drug reactions, Clin Exp Allergy 1998; 28 (suppl 4):21-24

(28.) Rose EW, McCloskey WW: Glutathione in hypersensitivity to timethoprim/sulfamethoxazole in patients with HIV infection. Ann Pharmacother 1998; 32:381-383

(29.) Bernstein JA: Allergic drug reactions: how to minimize the risks. Postgrad Med 1995; 98:159-160, 163-166

(30.) Douglas R, Spelman D, Czarny D, et al: Successful desensitization of two patients who previously developed StevensJohnson syndrome while receiving trimethoprim-sul famethoxazole. Clin Infect Dis 1997; 25:1480

(31.) Koski JM: Desensitization to sulphasalazine in patients with arthritis. Clin Exp Rheumatol 1993; 11:169-170

(32.) Moreno JN. Poblete RB, Maggio C, et al: Rapid oral desensitization for sulfonamides in patients with acquired immunodeficiency syndrome. Ann Allergy Asthma Immunol 1995; 74:140-146

(33.) Rich JD, Sullivan T, Greineder D, et al: Trimethoprim/sul famethoxazole incremental dose regimen in human immunodeficiency virus-infected persons. Ann Allergy Asthma Immunol 1997; 79:409414

(34.) Hansbrough JR, Wedner J, Chaplin DD: Anaphylaxis to intravenous furosemide. J Allergy Clin Immunol 1987; 80:538541

(35.) Carrington DM, Earl HS, Sullivan TJ: Studies of human IgE to a sulfonamide determinant. J Allergy Clin Immunol 1987;79:442-447

TABLE 1. Considerations When Determining Cross-Allergenicity Potential Among Agents Containing Sulfonamide [8, 9, 11]

Immunologic Factors

Haptenation Pathways

Sulfonamide antimicrobials are haptenated via the [N.sup.4] arylamine group, whereas furosemide is haptenated via its furan structure.

Site Specificity Requirements for Immunologic Recognition

Sulfamethoxazole, sulfamethizole, and sulfamerazine contain a five- or six-member aromatic ring with a nitrogen and a single. methyl group attached to the carbon atom to the sulfonamido substituent. Agents with no methyl group (eg, sulfapyridine) or more than one methyl group (eg, sulfamoxole) are less likely to cross-react with the previous compounds.

Structural Factors

Presence of an Arylamine Group

Only sulfonamide antimicrobials contain an arylamine group.

Haptenation Products

Differences in haptenation pathways decrease structural similarities between sulfonamide medication classes.

Metabolic Factors

Predilection for Specific Pathways

Sulfonamide antimicrobials differ in the predominance of metabolic pathways that create reactive intermediaries (eg, hydroxylation) that are important to hapten formation and the initiation of an immunologic response.

TABLE 2.

Cutaneous and Potentially Serious Allergic Manifestations, [8,14-18]

Anaphylaxis or Anaphylactoid Reaction

Occurs within 30 minutes. Occurs most commonly after parenteral drug administration but may occur with other routes of administration. Symptoms may include pruritus; urticaria; angioedema; respiratory distress as a result of laryngeal edema, bronchospasm, or laryngospasm; wheezing; stridor; respiratory obstruction; hypotension; cardiovascular collapse; and abdominal or uterine cramping. Mortality rate is highly dependent upon rapid response to appropriate treatment.

Angioedema/Urticaria

Occurs minutes to days after initiation of therapy. Symptoms may include mucosal lesion involvement, urticaria, swelling of central part of face, respiratory distress, and cardiovascular collapse. Mortality rate ranges from 1% to 6%.

Serum Sickness or Serum Sickness--Like Reaction

Occurs 1 to 2 weeks after initiation of therapy. Delayed onset of symptoms reflects time required to form immune complexes. Symptoms may include fever, arthralgia, and morbilliform lesions, sometimes with urticaria. Mortality rate is [less than]5%.

Stevens-Johnson Syndrome

Occurs 1 to 3 weeks after initiation of therapy. Symptoms may include erosions at [greater than or equal to]2 mucosal sites, small blisters on dusky purpuric macules or atypical targets, rare areas of confluence, detachment of [less than] 10% of body surface area; 10% to 30% of cases involve fever and lesions of respiratory and gastrointestinal tracts. With prompt use of corticosteroids, mortality rate is [less than]5%.

Toxic Epidermal Necrolysis

Occurs 1 to 3 weeks after initiation of therapy. Symptoms may include erosions at [greater than or equal to]2 mucosal sites, individual lesions similar to those of Stevens-Johnson syndrome, confluent erythema, outer layer of epidermis separating readily from basal layer with lateral pressure, large sheets of necrotic epidermis, total detachment of [greater than] 30% of body surface area, fever (nearly all cases), systemic consequences of widespread injury to the skin, leukopenia, and lesions of respiratory and gastrointestinal tracts. Mortality rate ranges from 1% to 30%. Sepsis is most common cause of death.

Other Skin Eruptions

Fixed drug eruption. Occurs 30 minutes to 8 hours after reexposure to drug. Unlike other skin eruptions, fixed drug eruptions are considered characteristic of drug hypersensitivity reactions. Lesions are well-delineated, round or oval, a few millimeters to 25 to 30 cm in size, and tend to recur at the same site with each subsequent exposure. Initially, the lesion appears edematous, followed by erythema, which later darkens to a deep reddish to purple color. Occasionally, lesions may appear eczematous, urticarial, vesiculobullous, hemorrhagic, or nodular. Mucus membranes are occasionally involved. Lesions usually resolve in 2 to 3 weeks after withdrawal of suspected agent.

Photosensitivity. Generally, photosensitivity eruptions are limited to light-exposed areas. Photosensitivity is subdivided into phototoxic and photoallergic reactions. Phototoxic reactions are more common, similar to sunburn, possible with the first exposure to the drug, occur 4 to 8 hours after exposure, do not require a chemical alteration of the drug, are dose-related, and are not immunologically mediated. Photoallergic reactions are uncommon, appear eczematous, require previous sensitization, occur within 12 to 24 hours after reexposure, require a chemical alteration of the drug, are dose-independent, and are T-cell-mediated. Flares of photoallergic reactions may occur at sites distant to those involved and may reoccur with ultraviolet exposure alone.

Lupus erythematosus. Characterized by the presence of antinuclear antibodies. Symptoms include fever, malaise, arthralgia, myalgia, pleurisy, and slight weight loss. The classic butterfly rash seen with idiopathic systemic lupus erythematosus is generally not seen in cases of drug-induced lupus. Onset of symptoms may be delayed for months after initiation of therapy. After withdrawal of the offending agent, symptoms generally subside within days to weeks. However, antinuclear antibodies may be present from weeks to a year after discontinuance of the suspected agent.

TABLE 3. Signs and Symptoms That Suggest an Allergic Reaction May Become Progressively More Serious [18]

Clinical Signs/Symptoms

Arthralgia or arthritis

Blisters or epidermal detachment

Confluent erythema

Enlarged lymph nodes 

Facial edema or central facial involvement

High fever ([greater than]40[degrees]C)

Hypotension

Mucus membrane erosions

Palpable purpura 

Positive Nikolsky's sign*

Shortness of breath 

Skin necrosis

Skin pain

Swelling of the tongue

Urticaria

Wheezing

Laboratory Findings

Abnormal liver function test results

Eosinophilia ([greater than] 1,000/[mm.sup.3])

Lymphocytosis with atypical lymphocytes

(*)Outer layer of epidermis separates readily from basal layer with lateral pressure.

TABLE 4.
Sample Rapid Oral Desensitization Protocol for
Sulfamethoxazole-Trimethoprim (Dosed Every 15 Minutes) [32]
                       Volume         Dose
Concentration           (mL)          (mg)
10 ng/mL         1.0, 2.0, 4.0       0.00007
1,000 ng/mL      0.5, 1.0, 2.0, 4.0  0.00075
1 [micro]g/mL    0.5, 1.0, 2.0, 4.0   0.0075
10 [micro]g/mL   0.5, 1.0, 2.0, 4.0    0.075
100 [micro]g/mL  0.5, 1.0, 2.0, 4.0     0.75
1 mg/mL          0.5, 1.0, 2.0, 4.0      7.5
10 mg/mL         0.5, 1.0, 2.0, 4.0     75.0
40 mg/mL         2.0, 4.0, 8.0         560.0
1 DS tablet *    NA                    800.0
(*)Begin dosing 2 doubel-strength (DS) tablets every 6 hours
after last step.
NA = Note applicable.
TABLE 5.
Sample Oral Ambulatory Desensitization Protocol for
Sulfamethoxazole-Trimethoprim (Dosed Three Times Daily) [33]
      Concentration      Volume        Dose
Day      (mg/mL)          (mL)         (mg)
 1       0.00002     1.0, 3.0, 7.0    0.00007
 2        0.0002     1.0, 3.0, 7.0    0.00075
 3         0.002     1.0, 3.0, 7.0     0.0075
 4          0.02     1.0, 3.0, 7.0      0.075
 5           0.2     1.0, 3.0, 7.0       0.75
 6           2.0     1.0, 3.0, 7.0        7.5
 7          20.0     1.0, 3.0, 7.0       75.0
 8          40.0     5.0, 10.0, 20.0    560.0
 9 *     DS Tablet   NA                 800.0
(*)Begin dosing 1 double-strength (DS) tablet daily after last step.
NA = Not applicable.
TABLE 6.
Sample Desensitization Protocol for Sulfasalazine [31]
        Tablet Strength    No.
Day(s)       (mg)        Tablets
1              1            1
2              1            2
3              1            4
4              1            8
5-11          10            1
12            10            2
13            10            4
14            10            8
15-21        100            1
22           100            2
23           100            4
24           100            8

KEY POINTS

* Approximately 3% of patients in the general population have hypersensitivity reactions to sulfonamide antimicrobials, ranging from mild skin rashes to life- threatening reactions.

* The incidence of serious allergic reactions with sulfonamides is low.

* Approximately 60% of patients with acquired immunodeficiency syndrome have adverse symptoms when treated with sulfonamides.

* No practical diagnostic test is available to determine sulfonamide allergy.

* The HIV pandemic has presented a unique demand for sulfonamide antimicrobials, which has led to the development of safe and practical desensitization protocols for use in immunocompromised patients.