Review of the Sulfonamides and Trimethoprim

Abstract

1. Connie L. Smith, MD, RPh* 2. Keith R. Powell, MD† 1. 2. *Senior Chief Resident in Pediatrics. 3. 4. †Dr Noah Miller Chair of Pediatric Medicine, Children’s Hospital and Medical Center of Akron; Professor and Chair, Department of Pediatrics, Northeastern Ohio Universities College of Medicine, Akron, OH. After completing this article, readers should be able to: 1. Identify the most frequently prescribed sulfonamide-containing anti-microbial and its primary indications. 2. Describe the noninfectious uses of the sulfonamides. 3. Identify the supplementation that generally is recommended with the use of sulfasalazine. 4. Describe the adverse reactions associated with sulfonamide use. In the 1930s it was observed that the industrial dye sulfachrysoidine had antimicrobial activity. Sulfanilamide (para-aminobenzenesulfonamide), a metabolite of this dye, was found to be the active compound, and over the years sulfanilamide was chemically modified to form new compounds that had broader antimicrobial activity and less toxicity. The sulfonamides are structural analogues of paraaminobenzoic acid (PABA) that have different solubility, absorption, and excretion characteristics. The combination of trimethoprim, a diaminopyrimidine antimicrobial, with a sulfonamide was shown to be synergistic in the late 1960s, and this combination is now used widely in clinical practice. Folic acid is essential for bacterial growth. The combination of trimethoprim and a sulfonamide results in the sequential blockade of folic acid synthesis. Sulfonamides competitively inhibit the incorporation of PABA into folic acid, thereby preventing the synthesis of folic acid. Trimethoprim binds reversibly to and inhibits dihyrofolate reductase, an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, decreasing folic acid synthesis. Humans do not synthesize folic acid, but obtain it in their diet. Sulfonamides are classified as short-, medium-, or long-acting, based on increasing serum half-lives. All classes generally are well absorbed from the gastrointestinal tract. When sulfonamides are used topically, systemic absorption results in measurable serum concentrations. The emergence of sulfonamide resistance and the demonstration of synergy when sulfonamides are used in combination with trimethoprim have resulted in the widespread use of trimethoprim/sulfamethoxazole (TMP/SMX). Synergistic activity is optimal when serum concentrations of TMP and SMX are at a ratio of 1:20, which can be achieved when TMP and …