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Trimethoprim

Clinical data
Pronunciation	/traɪˈmɛθəprɪm/
Trade names	Proloprim, Monotrim, Triprim, others
AHFS/Drugs.com	Monograph
MedlinePlus	a684025
License data	US FDA: Trimethoprim
Pregnancy category	AU: B3
Routes of administration	Oral
ATC code	J01EA01 (WHO) QJ51EA01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	90–100%
Protein binding	44%
Metabolism	hepatic
Elimination half-life	8-12 hours
Excretion	Urine (50–60%), faeces (4%)
Identifiers
IUPAC name 5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
CAS Number	738-70-5
PubChem CID	5578
DrugBank	DB00440
ChemSpider	5376
UNII	AN164J8Y0X
KEGG	D00145
ChEBI	CHEBI:45924
ChEMBL	ChEMBL22
PDB ligand	TOP (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID3023712
ECHA InfoCard	100.010.915
Chemical and physical data
Formula	C14H18N4O3
Molar mass	290.32 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES Nc1nc(N)ncc1Cc(cc2OC)cc(OC)c2OC
InChI InChI=1S/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18) Key:IEDVJHCEMCRBQM-UHFFFAOYSA-N
(verify)

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS. It is taken by mouth.

Common side effects include nausea, changes in taste, and rash. Rarely it may result in blood problems such as not enough platelets or white blood cells. May cause sun sensitivity. There is evidence of potential harm during pregnancy in some animals but not humans. It works by blocking folate metabolism via dihydrofolate reductase in some bacteria which results in their death.

Trimethoprim was first used in 1962. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication and is not very expensive. In the United States 10 days of treatment is about 21 USD.

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 jiroveci pneumonia. It is generally not recommended for the treatment of anaerobic infections such as Clostridium difficile colitis (the leading cause of antibiotic-induced diarrhea). Trimethoprim has been used in trials to treat retinitis.

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 is 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

• Nausea
• Change in taste
• Vomiting
• Diarrhea
• Rash
• 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 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

Liver and kidney problems

10-20% of trimethoprim is metabolized by the liver and the rest is excreted in the urine. Therefore, trimethoprim should be used with caution in individuals with kidney and liver impairments. Dosage adjustment is not needed for liver impairment but should be adjusted for kidney impairment.

Pregnancy

Based on 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. 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.

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 synthase, an enzyme involved further upstream in the same pathway. Trimethoprim and sulfamethoxazole are commonly used in combination due to possible synergistic effects, and reduced development of resistance. This benefit has been questioned.

History

Trimethoprim was first used in 1962. In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland.

See also

• Tetroxoprim
• Iclaprim

References

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External links

• Nucleic acid inhibitors (PDF file).

• Antibiotics
• Bacterial dihydrofolate reductase inhibitors
• Protozoal dihydrofolate reductase inhibitors
• Pyrimidines
• World Health Organization essential medicines
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• Aromatic amines
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• Antimetabolites