LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

The sulfonamides represent a large class of antibiotics that have multiple clinical uses. The sulfonamides were the first effective antibiotics to be introduced into clinical medicine and have been in use continuously since the 1930’s. They are considered bacteriostatic and appear to act by inhibition of bacterial biosynthesis of folic acid, which is needed for cell growth, at least in those bacteria that are sensitive to sulfonamides. Because humans rely upon dietary folic acid, they are usually resistant to the adverse effects of inhibition of folate synthesis. Sulfonamides have a wide range of antimicrobial activity against both gram-positive and -negative organisms. Unfortunately, bacterial resistance to sulfonamides is now common, and their use has decreased with the introduction of more potent classes of antibiotics. However, sulfonamides are still widely used especially for urinary tract infections in combination with trimethoprim and for treatment or prevention of parasitic (toxoplasmosis, pneumocystosis jiroveci) and malarial infections usually combined with trimethoprim or pyrimethamine. Sulfonamides with 5-aminosalicyclic acid are the structural components of sulfasalazine, which is widely used for long term management of inflammatory bowel disease. The combination of sulfadoxine and pyrimethamine is used as prophylaxis against chloroquine-resistant malaria. Dapsone is a sulfonamide related drug that is used for the therapy of leprosy and dermatitits herpetiformis. The sulfonamides are well known to cause idiosyncratic liver injury. Hepatotoxicity appears to be a class effect, in that virtually all sulfonamides used today have been linked to rare, but convincing cases of drug induced liver injury. The pattern of injury is variable, often mixed but it can be either hepatocellular or cholestatic. Most typically, the injury appears precipitously within one to three weeks of starting therapy, often preceded or accompanied by signs of hypersensitivity such as fever, rash, facial edema, lymphadenopathy, arthralgias, and eosinophilia or atypical lymphocytosis (or both). Hepatotoxicity from sulfonamides may represent a part of a spectrum of hypersensitivity due to sulfa-derived medications and have been linked to many cases of DRESS (drug rash with eosinophilia and systemic symptoms) as well as Stevens Johnson syndrome and toxic epidermal necrosis. The severity of injury varies widely. Most instances of sulfonamide related liver injury are mild-to-moderate in severity and self-limited in course. Cases with severe cholestasis may be prolonged and can lead to vanishing bile duct syndrome. Importantly, sulfonamides can cause acute liver failure, particularly in instances with a precipitious onset and hepatocellular pattern of serum enzyme elevations. Indeed, the sulfonamides remain one of the most common causes of drug induced acute liver failure and account for 5% to 10% of instances in many case series. Formulations of sulfonamides currently in general use in the United States include sulfadiazine, sulfadoxine, and sulfisoxazole as well as the combination formulations including sulfasalazine and trimethoprim-sulfamethazole (TMP-SMZ, also referred to as co-trimoxazole). The term sulfonamide applies to derivatives of para-aminobenzene sulfonamide (sulfanilamide), which is composed of a benzene ring with a sulfate and amide group at one end and an amide group at the other (para-position). These agents will be discussed as groups, rather than individual medications, and cases and references are combined.