Trimethoprim

Trimethoprim (INN) is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.

It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoSmithKline under trade names including Proloprim, Monotrim and Triprim; but these trade names have been licensed to various generic pharmaceutical manufacturers. In clinical use it is often abbreviated TRI or TMP; its common laboratory abbreviation is W.

Mechanism of action
Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid. Tetrahydrofolic acid is an essential precursor in the de novo synthesis of the intermediate Thymidine monophosphate (dTMP), precursor of DNA metabolite Thymidine triphosphate. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) and are thus dependent on their own de novo synthesis. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication causing, in certain circumstances, cell lethality due to thymineless death. This drug was developed by George H Hitchings and collaborators, who shared the Nobel Prize for Physiology or Medicine in 1988 for the discovery of antifolates.

Co-trimoxazole
Trimethoprim was commonly (from 1969 to 1980 in the UK) used in a 1:5 combination with sulfamethoxazole, a sulfonamide antibiotic, which inhibits an earlier step in the folate synthesis pathway (see diagram below). This combination, also known as co-trimoxazole, TMP-sulfa, or TMP-SMX, results in an in vitro synergistic antibacterial effect by inhibiting successive steps in folate synthesis. This claimed benefit was not seen in general clinical use.

The combinations use has been declining due to reports of sulfamethoxazole bone marrow toxicity, resistance and lack of greater efficacy in treating common urine and chest infections,   and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 following the availability of trimethoprim (not in combination) in 1980.

With its greater efficacy against a limited number of bacteria, Co-trimoxazole remains indicated for some infections; for example, it is used as prophylaxis in patients at risk for Pneumocystis jirovecii pneumonia (e.g. AIDS patients and those with some hematological malignancies) and as therapy in Whipple's disease. Gram positive bacteria are generally or moderately susceptible.

Clinical indications
Trimethoprim, used as monotherapy (since 1980 in the UK), is indicated for the prophylaxis and treatment of urinary tract infections. (Co-trimoxazole, with its greater efficacy against a limited number of bacteria, and parasites remains indicated for some infections, see above.)

Contraindications and reactions
Trimethoprim can cause thromocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia. Trimethoprim antagonises the epithelial sodium channel (ENaC) in the distal tubule, thus acting like amiloride, this can cause hyperkalemia. Trimethoprim also competes with creatinine for secretion into the renal tubule, this can cause an artefactual rise in the serum creatinine. Use in EHEC infections may lead to an increase in expression of Shiga toxin. Due to the fact that it crosses the placenta and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester. It may be involved in a reaction similar to disulfiram when alcohol is consumed after it is used, particularly when used in combination with sulfamethoxazole.

Chemistry


Stenbuck, P.; Hood, H. M.; 1962,.