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Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travellers' diarrhoea. It is taken orally (swallowed by mouth). It works by blocking folate metabolism via dihydrofolate reductase in some bacteria, preventing creation of bacterial DNA and RNA and leading to bacterial cell death. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

Medical uses

It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species. It may also be used to treat and prevent Pneumocystis jirovecii pneumonia.

Resistance to trimethoprim is increasing, but it is still a first-line antibiotic in many countries.

Spectrum of susceptibility

Cultures and susceptibility tests should be done to make sure bacteria are treated by trimethoprim.

  • Escherichia coli
  • Proteus mirabilis
  • Klebsiella pneumoniae
  • Enterobacter species
  • Coagulase-negative Staphylococcus species, including S. saprophyticus
  • Streptococcus pneumoniae
  • Haemophilus influenzae

Side effects

Common

  • Nauseas
  • Change in taste
  • Vomiting
  • Diarrhoea
  • Rashes
  • Sun sensitivity
  • Itchiness

Rare

  • Can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia.
  • Trimethoprim antagonizes the epithelial sodium channel <!-- (ENaC) --> in the distal tubule, thus acting like amiloride. This can cause increased potassium levels in the body (hyperkalemia).
  • Can compete with creatinine for secretion into the renal tubule. This can cause an artificial rise in the serum creatinine.
  • Use in EHEC infections may lead to an increase in expression of Shiga toxin.

Contraindications

  • Known hypersensitivity to trimethoprim
  • History of megaloblastic anemia due to folate deficiency<!-- supports all -->

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.

Pregnancy

Based on the studies that show that trimethoprim crosses the placenta and can affect folate metabolism, there has been growing evidence of the risk of structural birth defects associated with trimethoprim, especially during the first trimester of pregnancy.

The trophoblasts in the early fetus are sensitive to changes in the folate cycle. A 2013 study found a doubling in the risk of miscarriage in women exposed to trimethoprim in the early pregnancy.

Mechanism of action

thumb|upright=1.25|Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). Sulfamethoxazole inhibits dihydropteroate synthase, an enzyme involved further upstream in the same pathway. This benefit has been questioned.

class=skin-invert-image|[[Tetrahydrofolate synthesis pathway|thumb|none|upright=1.25]]

History

Trimethoprim was first used in 1962.