Antibacterial Agents, Sulfonamides (2003)

Abstract Sulfonamides derived from sulfanilamide ( p ‐aminobenzenesulfonamide) are commonly referred to as sulfa drugs. The sulfa drugs are still important as antimicrobial agents, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in developing countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. Sulfamethoxazole with trimethoprim is currently utilized as first‐line therapy and for prophylaxis of pneumonia caused by the fungus Pneumocystis carinii , a common infection in AIDS patients. The sulfonamides also remain clinically useful in the treatment of chancroid, lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and the fungus‐related nocardiosis. The sulfone, dapsone, remains an accepted treatment for all forms of leprosy. Currently used sulfonamides vary widely in their absorption, distribution, and excretion patterns. Some of those in clinical practice, past or present, are sulfanilamide, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfaguanidine, sulfisomidine, sulfisoxazole, sulfamethazine, sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, sulfamoxole, sulfaphenazole, sulfapyridine, sulfapyrazine, and sulfathiazole. The action of the sulfonamides and related sulfones is bacteriostatic rather than bactericidal. Numerous studies have been made to find a correlation between the physicochemical properties of the sulfonamides and their bacteriostatic activity. Relationships to the degree of ionization, lipid–water solubility, electron distribution values, and protein binding have all been observed. One of the principal disadvantages of sulfonamide therapy is the emergence of drug‐resistant strains of bacteria. Mutations and/or amino acid duplications near the active site of the dihydropteroate synthase (DHPS) enzyme result in an inability to bind the sulfonamides resulting in resistance. The most common method for the preparation of sulfonamides is by the action of N ‐acetylsulfanilyl chloride with the appropriate amine. A small percentage of patients treated with sulfonamides have shown toxic effects, such as drug fever, rashes, mild peripheral neuritis, and mental disturbance. In 1966 the FDA required that two long‐acting sulfonamides, sulfamethoxypyridazine and sulfadimethoxine carry a label warning of the possibility of death due to Stevens‐Johnson syndrome, an extremely severe dermatologic reaction. Blood dyscrasias are quite uncommon, but if they occur may be serious enough to cause discontinuance of the therapy. Administration of sulfonamides can cause hypersensitivity reactions, but in general, use of sulfonamide therapy is considered relatively safe.