Trimethoprim or 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine was synthesized in 1956 by Hitchings at the Wellcome Laboratories in the USA. It has both antibacterial and antimalarial activity, while another diaminopyrimidine, pyrimethamine, which was synthesized in 1951, is mainly active against malaria and Toxoplasma gondii. Trimethoprim interrupts bacterial purine synthesis and acts in the same metabolic pathway as the sulfonamides. The combination of these two drugs, therefore, has a synergistic effect against certain bacteria.

In the period 1968–78, trimethoprim was available for general clinical use only as a mixture with the medium-acting sulfonamide sulfamethoxazole. Sulfamethoxazole was selected for commercial formulations because its rate of absorption and excretion closely parallels that of trimethoprim. Commercial preparations contain a mixture of sulfamethoxazole and trimethoprim in a fixed ratio of 5:1. The generic name of co-trimoxazole (Co-T) is used to describe this drug combination, although the term trimethoprim–sulfamethoxazole (TMP-SMX) is more widely used in the USA and some other countries.

Clinical Uses

Trimethoprim alone is mainly used for the treatment and prophylaxis of urinary tract infection. Co-T, on the other hand, has both these indications and a very broad range of other uses. A number of other trimethoprim–sulfonamide combinations have been marketed over the years, including trimethoprim–sulfadiazine and trimethoprim–sulfamoxazole, but these are no longer available. At one time, other diaminopyrimidines such as tetroxoprim, which was marketed in combination with sulfadiazine, and brodimoprim as a single ingredient preparation, were marketed, but these have subsequently been withdrawn. Two other diaminopyrimidines, ormetoprim and baquiloprim, are available exclusively for veterinary use. At least one new diaminopyrimidine is under development, iclaprim, which appears to retain activity against trimethoprim-resistant Gram-positive bacteria.