Trimethoprim

Trimethoprim (INN)

Systematic (IUPAC) name
5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
Clinical data
Pronunciation	/traɪˈmɛθəprɪm/
Trade names	Proloprim, Monotrim, Triprim, others
AHFS/Drugs.com	monograph
MedlinePlus	a684025
Licence data	US FDA:link
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	90–100%
Protein binding	44%
Metabolism	hepatic
Biological half-life	8-12 hours
Excretion	Urine (50–60%), faeces (4%)
Identifiers
CAS Number	738-70-5 Y
ATC code	J01EA01 QJ51EA01
PubChem	CID 5578
DrugBank	DB00440 Y
ChemSpider	5376 Y
UNII	AN164J8Y0X Y
KEGG	D00145 Y
ChEBI	CHEBI:45924 Y
ChEMBL	CHEMBL22 Y
PDB ligand ID	TOP (PDBe, RCSB PDB)
Chemical data
Formula	C14H18N4O3
Molar mass	290.32 g/mol
SMILES COc1cc(cc(c1OC)OC)Cc2cnc(nc2N)N
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) Y Key:IEDVJHCEMCRBQM-UHFFFAOYSA-N Y
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Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections.^[1] 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.^[1][2] It is taken by mouth.^[1]

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.^[1] There is evidence of potential harm during pregnancy in some animals but not humans.^[3] It works by blocking folate metabolism in some bacteria which results in their death.^[1]

Trimethoprim was first used in 1962.^[4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.^[5] It is available as a generic medication and is not very expensive.^[6] In the United States 10 days of treatment is about 21 USD.^[1]

Medical uses

It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species.^[7] It may also be used to treat and prevent Pneumocystis jiroveci pneumonia.^[7] It is generally not recommended for the treatment of anaerobic infections such as Clostridium difficile colitis (the leading cause of antibiotic-induced diarrhea).^[7]

Resistance to trimethoprim is increasing, but it is still a first line antibiotic in many countries.^[8]

Spectrum of susceptibility

Cultures and susceptibility tests should be done to make sure bacteria is treated by trimethoprim.^[9][10]

• 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^[11][12]

Rare

• Can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia.^[13]
• Trimethoprim antagonizes the epithelial sodium channel in the distal tubule, thus acting like amiloride. This can cause increased potassium levels in the body (hyperkalemia).^[14]
• Can compete with creatinine for secretion into the renal tubule. This can cause an artificial rise in the serum creatinine.^[15]
• Use in EHEC infections may lead to an increase in expression of Shiga toxin.^[16]

Contraindications

• Known hypersensitivity to trimethoprim
• History of megaloblastic anemia due to folate deficiency^[17]

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.^[18]

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.^[19] 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.^[20][21] 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.^[22]

Mechanism of action

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF).^[24] THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.^[24] Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase.^[24] Sulfamethoxazole inhibits dihydropteroate synthetase, an enzyme involved further upstream in the same pathway.^[24] Trimethoprim and sulfamethoxazole are commonly used in combination due to possible synergistic effects, and reduced development of resistance.^[24] This benefit has been questioned.^[25]

History

Trimethoprim was first used in 1962.^[4] In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland.^[4]

See also

• Tetroxoprim
• Iclaprim

References

External links

• Nucleic acid inhibitors (PDF file).

Antibacterials: nucleic acid inhibitors (J01E, J01M) Antifolates (inhibits purine metabolism, thereby inhibiting DNA and RNA synthesis) DHFR inhibitor 2,4-Diaminopyrimidine Trimethoprim# Brodimoprim Tetroxoprim Iclaprim† Sulfonamides (DHPS inhibitor) Short- acting Sulfaisodimidine Sulfamethizole Sulfadimidine Sulfapyridine Sulfafurazole Sulfanilamide Prontosil Sulfathiazole Sulfathiourea Intermediate- acting Sulfamethoxazole Sulfadiazine# Sulfamoxole Long- acting Sulfadimethoxine Sulfadoxine Sulfalene Sulfametomidine Sulfametoxydiazine Sulfamethoxypyridazine Sulfaperin Sulfamerazine Sulfaphenazole Sulfamazone Other/ungrouped Sulfacetamide Sulfadicramide Sulfametrole Combinations Trimethoprim/sulfamethoxazole# Topoisomerase inhibitors/ quinolones/ (inhibits DNA replication) 1st g. Cinoxacin‡ Flumequine‡ Nalidixic acid‡ Oxolinic acid‡ Pipemidic acid‡ Piromidic acid‡ Rosoxacin‡ Fluoro- quinolones 2nd g. Ciprofloxacin# Ofloxacin Enoxacin‡ Fleroxacin‡ Lomefloxacin‡ Nadifloxacin‡ Norfloxacin‡ Pefloxacin‡ Rufloxacin‡ 3rd g. Levofloxacin Balofloxacin‡ Grepafloxacin‡ Pazufloxacin‡ Sparfloxacin‡ Temafloxacin‡ Tosufloxacin‡ 4th g. Besifloxacin Gatifloxacin Finafloxacin Gemifloxacin Moxifloxacin Clinafloxacin† Garenoxacin‡ Prulifloxacin‡ Sitafloxacin‡ Trovafloxacin‡/Alatrofloxacin‡ Vet. Danofloxacin Difloxacin Enrofloxacin Ibafloxacin Marbofloxacin Orbifloxacin Pradofloxacin Sarafloxacin Newer non-fluorinated Nemonoxacin Related (DG) Aminocoumarins: Novobiocin Anaerobic DNA inhibitors Nitro- imidazole derivatives Metronidazole# Tinidazole Ornidazole Nitrofuran derivatives Nitrofurantoin# Furazolidone‡ Nifurtoinol RNA synthesis Rifamycins/ RNA polymerase Rifampicin# Rifabutin Rifapentine Rifaximin Rifalazil§ #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III