|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Excretion||Urine (50–60%), faeces (4%)|
|ATC code||J01 QJ51|
|PDB ligand ID||TOP (, )|
|Mol. mass||290.32 g/mol|
|(what is this?)|
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.
Trimethoprim is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
Trimethoprim and sulfamethoxazole are commonly used in combination.
The abbreviations TRI and TMP (in clinical use) or W (in laboratory use) are common for referring to trimethoprim, but abbreviating drug names is not best practice in medicine.
It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species (see table). It may also be used to treat and prevent Pneumocystis jiroveci pneumonia. It is generally not recommended for the treatment of anaerobic infections like pseudomembranous colitis (the leading cause for antibiotic-induced diarrhoea).
|Micro-organism name||Susceptible to trimethoprim?|
|Escherichia coli sp.||Yes|
|Streptococcus - group A, B, C, G||Yes|
|Streptococcus viridans group||No|
Mechanism of action
Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis. Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase. Sulfamethoxazole inhibits dihydropteroate synthetase, an enzyme involved further upstream in the same pathway. Trimethoprim and sulfamethoxazole are commonly used in combination due to their synergistic effects. This drug combination also reduces the development of resistance that is seen when either drug is used alone.
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 combination's 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.
Contraindications and reactions
Trimethoprim can cause thrombocytopenia (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, in particular when used in combination with sulfamethoxazole. The trophoblasts in the early fetus are sensitive to changes in the folate cycle. A recent study has found a doubling in the risk of miscarriage in women exposed to trimethoprim in the early pregnancy.
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