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Trimethoprim (INN)
Structural formula of trimethoprim
Ball-and-stick model of the trimethoprim molecule
Clinical data
Pronunciation/traɪˈmɛθəprɪm/
Trade namesProloprim, Monotrim, Triprim, others
AHFS/Drugs.comMonograph
MedlinePlusa684025
License data
Pregnancy
category
  • AU: B3
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability90–100%
Protein binding44%
Metabolismhepatic
Elimination half-life8-12 hours
ExcretionUrine (50–60%), faeces (4%)
Identifiers
  • 5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC14H18N4O3
Molar mass290.32 g/mol g·mol−1
3D model (JSmol)
  • COc1cc(cc(c1OC)OC)Cc2cnc(nc2N)N
  • 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) checkY
  • Key:IEDVJHCEMCRBQM-UHFFFAOYSA-N checkY
  (verify)

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of uncomplicated urinary tract infections. [1] Trimethoprim is also used in the treatment of travelers' diarrhea and pediatric patient middle ear infections.[2][3] With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS.[4] It works to selectively inhibit the bacterial dihydrofolate reductase used in folate synthesis, which leads to folate depletion and bacterial death.[5] Trimethoprim is available both as an oral tablet and oral solution. The tablet form is available as a generic medication.[6] Primsol, the oral solution, is currently the only FDA-approved liquid solution of trimethoprim[7].

Common side effects include nausea, changes in taste, and rash.[8] Rarely it may result in blood problems such as not enough platelets or white blood cells.[9] May cause sun sensitivity.[10][11] There is evidence of potential harm during pregnancy.[12]

Trimethoprim began to be used in a clinical setting to treat bacterial infections in 1962.[13] In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland.[14] Trimethoprim is on the World Health Organization's List of Essential Medicines, the important medications needed in a basic health system.[15]

Medical uses

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It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species.[16] It may also be used to treat and prevent Pneumocystis jiroveci pneumonia.[16] It is generally not recommended for the treatment of anaerobic infections such as Clostridium difficile colitis (the leading cause of antibiotic-induced diarrhea).[16]

When trimethoprim used alone for urinary tract infections, resistance quickly developed. Therefore, it's rarely used alone.[17]

Spectrum of susceptibility

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Cultures and susceptibility tests should be carried out to determine the susceptibility of the bacteria causing the infection to trimethoprim. The MIC range for susceptible bacteria strains are, [18][19]

Side effects

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Common

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Common side effects include:[20][8]

  • Nausea
  • Change in Taste
  • Vomiting
  • Diarrhea
  • Rash
  • Itchiness

Rare

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Contraindications

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Contraindications include the following:[2]

  • known hypersensitivity to trimethoprim
  • history of megaloblastic anemia due to folate deficiency

Precautions

[edit]
Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry 2W9G [24]

Renal and Hepatic Impairment

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The metabolism of trimethoprim consists of 10-20% mainly by the liver whereas the remainder is excreted unchanged in the urine. Therefore, trimethoprim should be used with caution in patients with renal and hepatic impairment. Hepatic dosage adjustment is not provided. However for patients with a creatinine clearance 15 to 30 mL/min, the dose should be decreased. Trimethoprim is not recommended for patients with creatinine clearance less than 15 mL/min. [25]

Pregnancy

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Based on recent studies, since 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.[26] 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.[27][28] 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.[29]

Mechanism of action

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Tetrahydrofolate synthesis pathway

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 claimed synergistic effects, and reduced development of resistance.[30] This benefit has been questioned.[31]

See also

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References

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  1. ^ "DailyMed - TRIMETHOPRIM- trimethoprim tablet". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  2. ^ a b "DailyMed - PRIMSOL- trimethoprim hydrochloride solution". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  3. ^ DuPont, Herbert L.; Reves, Randall R.; Galindo, Emma; Sullivan, Peggy S.; Wood, Lindsey V.; Mendiola, Jaime G. (1982-09-30). "Treatment of Travelers' Diarrhea with Trimethoprim/Sulfamethoxazole and with Trimethoprim Alone". New England Journal of Medicine. 307 (14): 841–844. doi:10.1056/NEJM198209303071401. ISSN 0028-4793. PMID 7050714.
  4. ^ Masur, Henry; Brooks, John T.; Benson, Constance A.; Holmes, King K.; Pau, Alice K.; Kaplan, Jonathan E. (2014-05-01). "Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America". Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 58 (9): 1308–1311. doi:10.1093/cid/ciu094. ISSN 1537-6591. PMC 3982842. PMID 24585567.
  5. ^ "Trimethoprim Tablets, USP". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  6. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 113. ISBN 9781284057560.
  7. ^ "Primsol Solution". Primsol Solution. Retrieved 2015-11-04.
  8. ^ a b "PROLOPRIM® (trimethoprim)100-mg and 200-mg Scored Tablets". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  9. ^ a b MICROMEDEX Thomson Health Care. USPDIpublisher = Thomson Health. Drug Information for the Health Care Professional. 22nd ed. Volume 1. CareGreenwood Village, CO. 2002 p. 2849.{{cite book}}: CS1 maint: location (link)
  10. ^ "Trimethoprim". The American Society of Health-System Pharmacists. Retrieved Aug 1, 2015.
  11. ^ "Trimethoprim (Oral Route) Precautions - Mayo Clinic". www.mayoclinic.org. Retrieved 2015-11-04.
  12. ^ Sivojelezova, Anna; Einarson, Adrienne; Shuhaiber, Samar; Koren, Gideon (2003-09-01). "Trimethoprim-sulfonamide combination therapy in early pregnancy". Canadian Family Physician. 49: 1085–1086. ISSN 0008-350X. PMC 2214286. PMID 14526858.
  13. ^ Huovinen, P.; Sundström, L.; Swedberg, G.; Sköld, O. (1995-02-01). "Trimethoprim and sulfonamide resistance". Antimicrobial Agents and Chemotherapy. 39 (2): 279–289. doi:10.1128/AAC.39.2.279. ISSN 0066-4804. PMC 162528. PMID 7726483.
  14. ^ Huovinen, P (1 June 2001). "Resistance to trimethoprim-sulfamethoxazole". Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 32 (11): 1608–14. doi:10.1086/320532. PMID 11340533.
  15. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  16. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  17. ^ [Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 1056
  18. ^ "DailyMed - TRIMETHOPRIM- trimethoprim tablet". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  19. ^ "DailyMed - PRIMSOL- trimethoprim hydrochloride solution". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  20. ^ Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. American Hospital Formulary Service- Drug Information 2002. Baltimore, MD: Williams and Wilkins. p. 236.{{cite book}}: CS1 maint: multiple names: authors list (link)
  21. ^ Choi, Michael J.; Fernandez, Pedro C.; Patnaik, Asit; Coupaye-Gerard, Brigitte; D'Andrea, Denise; Szerlip, Harold; Kleyman, Thomas R. (1993-03-11). "Trimethoprim-Induced Hyperkalemia in a Patient with AIDS". New England Journal of Medicine. 328 (10): 703–706. doi:10.1056/NEJM199303113281006. ISSN 0028-4793. PMID 8433730.
  22. ^ Naderer, O.; Nafziger, A. N.; Bertino, J. S. (1997-11-01). "Effects of moderate-dose versus high-dose trimethoprim on serum creatinine and creatinine clearance and adverse reactions". Antimicrobial Agents and Chemotherapy. 41 (11): 2466–2470. doi:10.1128/AAC.41.11.2466. ISSN 0066-4804. PMC 164146. PMID 9371351.
  23. ^ Kimmitt PT, Harwood CR, Barer MR (2000). "Toxin Gene Expression by Shiga Toxin-producing Escherichia coli: The Role of Antibiotics and the Bacterial SOS Response". Emerg Infect Dis. 6 (5): 458–465. doi:10.3201/eid0605.000503. PMC 2627954. PMID 10998375.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Heaslet, H.; Harris, M.; Fahnoe, K.; Sarver, R.; Putz, H.; Chang, J.; Subramanyam, C.; Barreiro, G.; Miller, J. R. (2009). "Structural comparison of chromosomal and exogenous dihydrofolate reductase fromStaphylococcus aureusin complex with the potent inhibitor trimethoprim". Proteins: Structure, Function, and Bioinformatics. 76 (3): 706–717. doi:10.1002/prot.22383. PMID 19280600. S2CID 1373618.
  25. ^ "DailyMed - TRIMETHOPRIM- trimethoprim tablet". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  26. ^ Sivojelezova, Anna; Einarson, Adrienne; Shuhaiber, Samar; Koren, Gideon (2003-09-01). "Trimethoprim-sulfonamide combination therapy in early pregnancy". Canadian Family Physician. 49: 1085–1086. ISSN 0008-350X. PMC 2214286. PMID 14526858.
  27. ^ Edwards DL, Fink PC, van Dyke PO (1986). "Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole". J Clinical Pharmacy. 5 (12): 999–1000. PMID 3492326.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Heelon MW; White M (1998). "Disulfiram cotrimoxazole reaction". J Pharmacotherapy. 18 (4): 869–870. doi:10.1002/j.1875-9114.1998.tb03913.x. PMID 9692665. S2CID 23968977.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen EW, Andersen NL, Afzal S, Torp-Pedersen C, Keiding N, Poulsen HE (2013). "Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study". Epidemiology and Infection. 141 (8): 1749–1755. doi:10.1017/S0950268812002178. PMID 23010291.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ Brogden, RN; Carmine, AA; Heel, RC; Speight, TM; Avery, GS (June 1982). "Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections". Drugs. 23 (6): 405–30. doi:10.2165/00003495-198223060-00001. PMID 7049657. S2CID 21806926.
  31. ^ Brumfitt, W; Hamilton-Miller, JM (December 1993). "Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines". Journal of Chemotherapy. 5 (6): 465–9. doi:10.1080/1120009X.1993.11741097. PMID 8195839.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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Category:Antibiotics Category:Bacterial dihydrofolate reductase inhibitors Category:Protozoal dihydrofolate reductase inhibitors Category:Pyrimidines Category:World Health Organization essential medicines Category:Phenol ethers Category:Aromatic amines

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