A group of diaminopyrimidines (trimethoprim, methoprim, ormetoprim, aditoprim, pyrimethamine) inhibit dihydrofolate reductase in bacteria and protozoa far more efficiently than in mammalian cells. Used alone, these agents are not particularly effective against bacteria, and resistance develops rapidly. However, when combined with sulfonamides, a sequential blockade of microbial enzyme systems occurs with bactericidal consequences.

 

Examples of such potentiated sulfonamide preparations include trimethoprim/sulfadiazine (co-trimazine), trimethoprim/sulfamethoxazole (co-trimoxazole), tri-methopriim/sulfadoxine (co-trimoxine), and ormetoprim/sulfadimethoxine.

 

Antimicrobial Features

In susceptible bacteria, the sulfonamide component blocks the synthesis of dihydrofolic acid, and the particular diaminopyrimidine used in combination inhibits the next enzyme in the

 

sequence (dihydrofolate reductase) to prevent the formation of tetrahydrofolic acSd (folTnic acid). Folinic acid is required for the synthesis of DNA. This sequential blockade produces a bactericidal rather than bacteriostatic effect under usual conditions, but in the presence of thymidine, only bacteriostasis is evident because the block is circumvented.

 

The optimal ratio in vitro for the combination of trimethoprim or ormetoprim and a sulfonamide depends on the type of microorganism but is usually ~1:20. However, the commercially available preparations use a ratio of 1:5.