Trimethoprim Explained

Watchedfields:changed
Verifiedrevid:470615131
Width:240
Width2:250
Alt2:Ball-and-stick model of the trimethoprim molecule
Tradename:Proloprim, Monotrim, Triprim, others
Dailymedid:Trimethoprim
Pregnancy Au:B3
Routes Of Administration:By mouth
Class:Diaminopyrimidines
Atc Prefix:J01
Atc Suffix:EA01
Legal Au:S4
Legal Ca:Rx-only
Legal Uk:POM
Legal Us:Rx-only
Bioavailability:90–100%
Protein Bound:44%
Metabolism:Liver
Elimination Half-Life:8–12 hours
Excretion:Kidney (50–60%), faeces (4%)
Cas Number:738-70-5
Pubchem:5578
Drugbank:DB00440
Chemspiderid:5376
Unii:AN164J8Y0X
Kegg:D00145
Chebi:45924
Chembl:22
Pdb Ligand:TOP
Iupac Name:5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
C:14
H:18
N:4
O:3
Smiles:Nc1nc(N)ncc1Cc(cc2OC)cc(OC)c2OC
Stdinchi: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)
Stdinchikey:IEDVJHCEMCRBQM-UHFFFAOYSA-N

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections.[1] Other uses include for middle ear infections and travelers' diarrhea.[1] With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS.[1] [2] It is taken orally (swallowed by mouth).[1]

Common side effects include nausea, changes in taste, and rash.[1] Rarely it may result in blood problems such as not enough platelets or white blood cells.[1] Trimethoprim 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 via dihydrofolate reductase in some bacteria, preventing creation of bacterial DNA and RNA and leading to bacterial cell death.[1]

Trimethoprim was first used in 1962.[4] It is on the World Health Organization's List of Essential Medicines.[5] It is available as a generic medication.[6]

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 jirovecii 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] Trimethoprim has been used in trials to treat retinitis.[8]

Resistance to trimethoprim is increasing, but it is still a first line antibiotic in many countries.[9]

Spectrum of susceptibility

Cultures and susceptibility tests should be done to make sure bacteria are treated by trimethoprim.[10] [11]

Side effects

Common

Rare

Contraindications

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.[19] [20]

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.[21]

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.[22]

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 inhibitory activity for bacterial dihydrofolate reductase is sixty thousand times greater than for human dihydrofolate reductase.[23] 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.[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]

Its name is derived from trimethyloxy-pyrimidine.

Notes and References

  1. Web site: Trimethoprim. The American Society of Health-System Pharmacists. 1 August 2015. live. https://web.archive.org/web/20150924014936/http://www.drugs.com/monograph/trimethoprim.html. 24 September 2015.
  2. Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE . 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 . 58 . 9 . 1308–1311 . May 2014 . 24585567 . 3982842 . 10.1093/cid/ciu094 .
  3. Web site: Prescribing medicines in pregnancy database. Australian Government. 22 April 2014. 3 March 2014. live. https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw. 8 April 2014.
  4. Huovinen P . Resistance to trimethoprim-sulfamethoxazole . Clinical Infectious Diseases . 32 . 11 . 1608–1614 . June 2001 . 11340533 . 10.1086/320532 . free .
  5. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  6. Book: Hamilton R . Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. 2015. Jones & Bartlett Learning. 978-1-284-05756-0. 113.
  7. Book: Rossi S . 978-0-9805790-9-3 . Australian Medicines Handbook . Adelaide . The Australian Medicines Handbook Unit Trust . 2013 . 2013 .
  8. Pradhan E, Bhandari S, Gilbert RE, Stanford M . Antibiotics versus no treatment for toxoplasma retinochoroiditis . The Cochrane Database of Systematic Reviews . 2016 . 5 . CD002218 . May 2016 . 27198629 . 7100541 . 10.1002/14651858.CD002218.pub2 .
  9. Web site: Three-day courses of antibiotics for uncomplicated urinary tract infection | Guidance and guidelines | NICE . 15 January 2015 . 30 December 2015 . live . https://web.archive.org/web/20151208004951/http://www.nice.org.uk/advice/ktt10/chapter/Evidence-context . 8 December 2015 .
  10. Web site: DailyMed . TRIMETHOPRIM- trimethoprim tablet. U.S. National Library of Medicine . 4 November 2015. live. https://web.archive.org/web/20150930162821/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4e9183f-d0eb-4ba7-9204-760b1fd62010. 30 September 2015.
  11. Web site: DailyMed . PRIMSOL- trimethoprim hydrochloride solution. U.S. National Library of Medicine . 4 November 2015. live. https://web.archive.org/web/20151117024132/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a06ea7d8-a884-4b62-a87f-c36d824f2aa4. 17 November 2015.
  12. Web site: DailyMed . PROLOPRIM® (trimethoprim)100-mg and 200-mg Scored Tablets. U.S. National Library of Medicine . 4 November 2015. live. https://web.archive.org/web/20151117015344/http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=3220. 17 November 2015.
  13. Book: American Hospital Formulary Service- Drug Information 2002.. Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J . Williams and Wilkins. Baltimore, MD. 236.
  14. Book: MICROMEDEX Thomson Health Care. USPDI . Drug Information for the Health Care Professional . 22nd . 1 . Thomson Health Care . Greenwood Village, CO. . 2002 . 2849 .
  15. Choi MJ, Fernandez PC, Patnaik A, Coupaye-Gerard B, D'Andrea D, Szerlip H, Kleyman TR . Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS . The New England Journal of Medicine . 328 . 10 . 703–706 . March 1993 . 8433730 . 10.1056/NEJM199303113281006 . free .
  16. Naderer O, Nafziger AN, Bertino JS . 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 . November 1997 . 9371351 . 164146 . 10.1128/AAC.41.11.2466 .
  17. Kimmitt PT, Harwood CR, Barer MR . Toxin gene expression by shiga toxin-producing Escherichia coli: the role of antibiotics and the bacterial SOS response . Emerging Infectious Diseases . 6 . 5 . 458–465 . 2000 . 10998375 . 2627954 . 10.3201/eid0605.000503 .
  18. Web site: DailyMed . PRIMSOL- trimethoprim hydrochloride solution. U.S. National Library of Medicine . 4 November 2015. live. https://web.archive.org/web/20151117024132/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a06ea7d8-a884-4b62-a87f-c36d824f2aa4. 17 November 2015.
  19. Edwards DL, Fink PC, Van Dyke PO . Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole . Clinical Pharmacy . 5 . 12 . 999–1000 . December 1986 . 3492326 . live . https://web.archive.org/web/20090124113327/http://cat.inist.fr/?aModele=afficheN&cpsidt=8287529 . 24 January 2009 .
  20. Heelon MW, White M . Disulfiram-cotrimoxazole reaction . Pharmacotherapy . 18 . 4 . 869–870 . 1998 . 9692665 . 10.1002/j.1875-9114.1998.tb03913.x . live . 23968977 . https://web.archive.org/web/20090124113456/http://cat.inist.fr/?aModele=afficheN&cpsidt=2340043 . 24 January 2009 .
  21. Sivojelezova A, Einarson A, Shuhaiber S, Koren G . Trimethoprim-sulfonamide combination therapy in early pregnancy . Canadian Family Physician . 49 . 1085–1086 . September 2003 . 14526858 . 2214286 .
  22. Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen EW, Andersen NL, Afzal S, Torp-Pedersen C, Keiding N, Poulsen HE . Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study . Epidemiology and Infection . 141 . 8 . 1749–1755 . August 2013 . 23010291 . 9151599 . 10.1017/S0950268812002178 . 19917493 .
  23. Burchall JJ . Mechanism of action of trimethoprim-sulfamethoxazole. II . The Journal of Infectious Diseases . 128 . Suppl: 437-Suppl: 441 . November 1973 . 4585969 . 10.1093/infdis/128.Supplement_3.S437 . TMP1 . 30105875 .
  24. Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS . Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections . Drugs . 23 . 6 . 405–430 . June 1982 . 7049657 . 10.2165/00003495-198223060-00001 . 21806926 .
  25. Brumfitt W, Hamilton-Miller JM . Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines . Journal of Chemotherapy . 5 . 6 . 465–469 . December 1993 . 8195839 . 10.1080/1120009X.1993.11741097 .

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