Adverse drug reactions are frequent and potentially life-threatening occurrences. A recent meta-analysis of these reactions in hospitalized patients estimated an incidence of 6.7% and a fatality rate of 0.32% [1]. Hypersensitivity reactions to medications are reported to account for 6% to 10% of inpatient adverse drug reactions, and, of these events, fatalities occur in 1 of 10,000 [2]. Despite this high frequency, for the vast majority of drugs, the pathophysiology of the hypersensitivity reactions is not well understood. Sulfamethoxazole (SMX) is the best studied and most widely used sulfonamide, and its cost is low relative to more recently introduced antimicrobial agents. Use of sulfonamide antibiotics has declined in recent years [3] owing to the combination of a rise in drug-resistant organisms, concerns about adverse reactions, and aggressive marketing of newer antibiotic classes. Nevertheless, sulfonamides remain a cost-effective medication in many settings. They were the first class of antibiotics introduced, and they still have a broad range of indications, including infections of the urinary, respiratory, and gastrointestinal tracts. Among hospitalized patients, adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMX) occur 8% of the time, most commonly involving the skin and gastrointestinal tract [4]. Only approximately 3% of adverse reactions to TMP-SMX are thought to represent sulfonamide hypersensitivity reactions [5,6], and severe systemic reactions to TMP-SMX are even less frequent. Paradoxically, sulfonamides cause a disproportionate share of life-threatening adverse drug reactions. For example, sulfonamides account for the largest percentage of the 10 cases per million persons per year of antibiotic-induced toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome [7]. For most patients who report an adverse reaction to a sulfonamide, it is appropriate to substitute a different antibiotic for a given infection; however, simply avoiding these agents introduces a variety of potential consequences that must be considered. For example, in the past decade, the preferential use of broader-spectrum antibiotics has resulted in a large increase in the overall costs of antibiotics [8]. These more expensive agents, in turn, result in selection pressure favoring resistant organisms, a phenomenon that may limit choices of effective agents in the future. For HIV-infected patients, the risks of simply substituting a different antibiotic class for SMX are more directly apparent. TMP-SMX is the antibiotic of choice for Pneumocystis carinii pneumonia (PCP) infection, PCP prophylaxis, and toxoplasmosis prophylaxis; unfortunately, approximately 60% of HIV-infected patients experience TMP-SMX hypersensitivity reactions during their therapy [4,5,9,10]. The following sections explore several aspects of sulfonamide hypersensitivity reactions in more detail-pathophysiology, physical manifestations, diagnosis, sulfonamide desensitization, and cross-reactivity between sulfonamide antibiotics and sulfa-containing nonantibiotics.
