Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Trimethoprim: Difference between pages

{{Short description|Antibiotic}}

{{Distinguish|Thymidine monophosphate}}

{{Use dmy dates|date=March 2024}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{infobox drug

| Watchedfields = changed

| verifiedrevid = 470615131

| width = 240

| alt = Structural formula of trimethoprim

| width2 = 250

| alt2 = Ball-and-stick model of the trimethoprim molecule

<!-- Clinical data -->

| pronounce = {{IPAc-en|t|r|aɪ|ˈ|m|ɛ|θ|ə|p|r|ɪ|m}}

| tradename = Proloprim, Monotrim, Triprim, others

| DailyMedID = Trimethoprim

| routes_of_administration = [[By mouth]]

| class = [[Diaminopyrimidine]]s

| ATC_prefix = J01

| ATC_suffix = EA01

| ATC_supplemental = {{ATCvet|J51|EA01}}

| legal_CA = Rx-only

| legal_US = Rx-only

<!-- Pharmacokinetic data -->

| protein_bound = 44%

| metabolism = [[Liver]]

| elimination_half-life = 8–12 hours

| excretion = [[Kidney]] (50–60%), faeces (4%)

<!-- Identifiers -->

| UNII_Ref = {{fdacite|correct|FDA}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| PDB_ligand = TOP

<!-- Chemical data -->

| 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

<!-- Definition and uses -->

'''Trimethoprim''' ('''TMP''') is an [[antibiotic]] used mainly in the treatment of [[urinary tract infection|bladder infections]].<ref name=AHFS2015>{{cite web|title=Trimethoprim|url=https://www.drugs.com/monograph/trimethoprim.html|publisher=The American Society of Health-System Pharmacists|access-date=1 August 2015|url-status=live|archive-url=https://web.archive.org/web/20150924014936/http://www.drugs.com/monograph/trimethoprim.html|archive-date=24 September 2015}}</ref> Other uses include for [[acute otitis media|middle ear infections]] and [[travelers' diarrhea]].<ref name=AHFS2015/> With [[Trimethoprim/sulfamethoxazole|sulfamethoxazole]] or [[dapsone]] it may be used for [[Pneumocystis pneumonia|''Pneumocystis'' pneumonia]] in people with [[HIV/AIDS]].<ref name=AHFS2015/><ref>{{cite journal | vauthors = Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE | title = 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 | journal = Clinical Infectious Diseases | volume = 58 | issue = 9 | pages = 1308–1311 | date = May 2014 | pmid = 24585567 | pmc = 3982842 | doi = 10.1093/cid/ciu094 }}</ref> It is taken [[oral administration|orally]] (swallowed by mouth).<ref name=AHFS2015/>

<!-- Side effects -->

Common side effects include nausea, changes in taste, and rash.<ref name=AHFS2015/> Rarely it may result in blood problems such as not enough [[platelets]] or [[white blood cells]].<ref name=AHFS2015/> Trimethoprim may cause sun sensitivity.<ref name=AHFS2015/> There is evidence of potential [[tetragenic|harm during pregnancy]] in some animals but not humans.<ref name=TGA2014>{{cite web|title=Prescribing medicines in pregnancy database|url=http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw|work=Australian Government|access-date=22 April 2014|date=3 March 2014|url-status=live|archive-url=https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm#.U1Yw8Bc3tqw|archive-date=8 April 2014}}</ref> 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.<ref name=AHFS2015/>

<!-- History, society and culture -->

Trimethoprim was first used in 1962.<ref name=Huo2001>{{cite journal | vauthors = Huovinen P | title = Resistance to trimethoprim-sulfamethoxazole | journal = Clinical Infectious Diseases | volume = 32 | issue = 11 | pages = 1608–1614 | date = June 2001 | pmid = 11340533 | doi = 10.1086/320532 | doi-access = free }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a generic medication.<ref name=Ric2015>{{cite book| vauthors = Hamilton R |title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=978-1-284-05756-0|page=113}}</ref>

==Medical uses==

It is primarily used in the treatment of [[urinary tract infections]], although it may be used against any susceptible [[Aerobic organism|aerobic bacterial species]].<ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref> It may also be used to treat and prevent ''[[Pneumocystis jirovecii]]'' pneumonia.<ref name = AMH/> It is generally not recommended for the treatment of [[Anaerobic organism|anaerobic infections]] such as [[Clostridioides difficile infection|''Clostridioides difficile'' colitis]] (the leading cause of antibiotic-induced diarrhea).<ref name = AMH/> Trimethoprim has been used in trials to treat [[toxoplasmic chorioretinitis|retinitis]].<ref name="Pradhan">{{cite journal | vauthors = Pradhan E, Bhandari S, Gilbert RE, Stanford M | title = Antibiotics versus no treatment for toxoplasma retinochoroiditis | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 5 | pages = CD002218 | date = May 2016 | pmid = 27198629 | pmc = 7100541 | doi = 10.1002/14651858.CD002218.pub2 }}</ref>

Resistance to trimethoprim is increasing, but it is still a first-line antibiotic in many countries.<ref>{{cite web |url=https://www.nice.org.uk/advice/ktt10/chapter/evidence-context |title=Three-day courses of antibiotics for uncomplicated urinary tract infection &#124; Guidance and guidelines &#124; NICE |date=15 January 2015 |access-date=30 December 2015 |url-status=live |archive-url=https://web.archive.org/web/20151208004951/http://www.nice.org.uk/advice/ktt10/chapter/Evidence-context |archive-date=8 December 2015 }}</ref>

===Spectrum of susceptibility===

Cultures and susceptibility tests should be done to make sure bacteria are treated by trimethoprim.<ref name="dailymed.nlm.nih.gov">{{Cite web| work = DailyMed | title = TRIMETHOPRIM- trimethoprim tablet|url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4e9183f-d0eb-4ba7-9204-760b1fd62010| publisher = U.S. National Library of Medicine |access-date = 4 November 2015|url-status = live|archive-url = https://web.archive.org/web/20150930162821/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4e9183f-d0eb-4ba7-9204-760b1fd62010|archive-date = 30 September 2015}}</ref><ref>{{Cite web| work = DailyMed | title = PRIMSOL- trimethoprim hydrochloride solution|url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a06ea7d8-a884-4b62-a87f-c36d824f2aa4| publisher = U.S. National Library of Medicine |access-date = 4 November 2015|url-status = live|archive-url = https://web.archive.org/web/20151117024132/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a06ea7d8-a884-4b62-a87f-c36d824f2aa4|archive-date = 17 November 2015}}</ref>

* ''[[Escherichia coli]]''

* ''[[Proteus mirabilis]]''

* ''[[Klebsiella pneumoniae]]''

* ''[[Enterobacter]]'' species

* [[Coagulase|Coagulase-negative]] ''[[Staphylococcus]]'' species, including [[Staphylococcus saprophyticus|''S. saprophyticus'']]

* ''[[Streptococcus pneumoniae]]''

* ''[[Haemophilus influenzae]]''

==Side effects==

=== Common ===

* Nauseas

* Change in taste

* Vomiting

* Diarrhea

* Rashes

* Sun sensitivity

* Itchiness<ref name=":1">{{Cite web| work = DailyMed | title = PROLOPRIM® (trimethoprim)100-mg and 200-mg Scored Tablets|url = http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=3220| publisher = U.S. National Library of Medicine |access-date = 4 November 2015|url-status = live|archive-url = https://web.archive.org/web/20151117015344/http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=3220|archive-date = 17 November 2015}}</ref><ref>{{Cite book|title = American Hospital Formulary Service- Drug Information 2002.| vauthors = Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J |publisher = Williams and Wilkins|location = Baltimore, MD|pages = 236}}</ref>

=== Rare ===

* Can cause [[thrombocytopenia]] (low levels of [[platelets]]) by lowering [[folic acid]] levels; this may also cause [[megaloblastic anemia]].<ref name=":2">{{Cite book|title = Drug Information for the Health Care Professional | edition = 22nd | volume = 1 |last = MICROMEDEX Thomson Health Care. USPDI | publisher = Thomson Health Care |location = Greenwood Village, CO. | date = 2002 | page = 2849 }}</ref>

* 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]]).<ref>{{cite journal | vauthors = Choi MJ, Fernandez PC, Patnaik A, Coupaye-Gerard B, D'Andrea D, Szerlip H, Kleyman TR | title = Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS | journal = The New England Journal of Medicine | volume = 328 | issue = 10 | pages = 703–706 | date = March 1993 | pmid = 8433730 | doi = 10.1056/NEJM199303113281006 | doi-access = free }}</ref>

* Can compete with [[creatinine]] for secretion into the renal tubule. This can cause an artificial rise in the serum creatinine.<ref>{{cite journal | vauthors = Naderer O, Nafziger AN, Bertino JS | title = Effects of moderate-dose versus high-dose trimethoprim on serum creatinine and creatinine clearance and adverse reactions | journal = Antimicrobial Agents and Chemotherapy | volume = 41 | issue = 11 | pages = 2466–2470 | date = November 1997 | pmid = 9371351 | pmc = 164146 | doi = 10.1128/AAC.41.11.2466 }}</ref>

* Use in [[Enterohemorrhagic Escherichia coli|EHEC]] infections may lead to an increase in expression of [[Shiga toxin]].<ref>{{cite journal | vauthors = Kimmitt PT, Harwood CR, Barer MR | title = Toxin gene expression by shiga toxin-producing Escherichia coli: the role of antibiotics and the bacterial SOS response | journal = Emerging Infectious Diseases | volume = 6 | issue = 5 | pages = 458–465 | year = 2000 | pmid = 10998375 | pmc = 2627954 | doi = 10.3201/eid0605.000503 }}</ref>

=== Contraindications ===

* Known [[hypersensitivity]] to trimethoprim

* History of [[megaloblastic anemia]] due to folate deficiency<ref name=":0">{{Cite web| work = DailyMed | title = PRIMSOL- trimethoprim hydrochloride solution|url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a06ea7d8-a884-4b62-a87f-c36d824f2aa4| publisher = U.S. National Library of Medicine |access-date = 4 November 2015|url-status = live|archive-url = https://web.archive.org/web/20151117024132/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a06ea7d8-a884-4b62-a87f-c36d824f2aa4|archive-date = 17 November 2015}}</ref><!-- 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]].<ref>{{cite journal | vauthors = Edwards DL, Fink PC, Van Dyke PO | title = Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole | journal = Clinical Pharmacy | volume = 5 | issue = 12 | pages = 999–1000 | date = December 1986 | pmid = 3492326 | url = http://cat.inist.fr/?aModele=afficheN&cpsidt=8287529 | url-status = live | archive-url = https://web.archive.org/web/20090124113327/http://cat.inist.fr/?aModele=afficheN&cpsidt=8287529 | archive-date = 24 January 2009 }}</ref><ref>{{cite journal | vauthors = Heelon MW, White M | title = Disulfiram-cotrimoxazole reaction | journal = Pharmacotherapy | volume = 18 | issue = 4 | pages = 869–870 | year = 1998 | pmid = 9692665 | doi = 10.1002/j.1875-9114.1998.tb03913.x | url = http://cat.inist.fr/?aModele=afficheN&cpsidt=2340043 | url-status = live | s2cid = 23968977 | archive-url = https://web.archive.org/web/20090124113456/http://cat.inist.fr/?aModele=afficheN&cpsidt=2340043 | archive-date = 24 January 2009 }}</ref>

=== 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 [[Pregnancy|trimester]] of pregnancy.<ref name="Sivojelezova 1085–1086">{{cite journal | vauthors = Sivojelezova A, Einarson A, Shuhaiber S, Koren G | title = Trimethoprim-sulfonamide combination therapy in early pregnancy | journal = Canadian Family Physician | volume = 49 | pages = 1085–1086 | date = September 2003 | pmid = 14526858 | pmc = 2214286 }}</ref>

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.<ref>{{cite journal | vauthors = Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen EW, Andersen NL, Afzal S, Torp-Pedersen C, Keiding N, Poulsen HE | title = Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study | journal = Epidemiology and Infection | volume = 141 | issue = 8 | pages = 1749–1755 | date = August 2013 | pmid = 23010291 | pmc = 9151599 | doi = 10.1017/S0950268812002178 | s2cid = 19917493 }}</ref>

==Mechanism of action==

[[File:Wild-type staphylococcus aureus DHFR in complex with NADPH and trimethoprim.gif|thumb|upright=1.25|''Staphylococcus aureus'' DHFR in complex with NADPH and trimethoprim PDB entry {{PDBe|2W9G}}<ref>{{cite journal | vauthors = Heaslet H, Harris M, Fahnoe K, Sarver R, Putz H, Chang J, Subramanyam C, Barreiro G, Miller JR | title = Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim | journal = Proteins | volume = 76 | issue = 3 | pages = 706–717 | date = August 2009 | pmid = 19280600 | doi = 10.1002/prot.22383 | s2cid = 1373618 }}</ref>]]

Trimethoprim binds to [[dihydrofolate reductase]] and inhibits the reduction of [[dihydrofolic acid]] (DHF) to [[tetrahydrofolic acid]] (THF).<ref name = drugs82/> THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.<ref name = drugs82/> Trimethoprim's inhibitory activity for bacterial dihydrofolate reductase is sixty thousand times greater than for human dihydrofolate reductase.<ref>{{cite journal | vauthors = Burchall JJ | title = Mechanism of action of trimethoprim-sulfamethoxazole. II | journal = The Journal of Infectious Diseases | volume = 128 | pages = Suppl: 437-Suppl: 441 | date = November 1973 | pmid = 4585969 | doi = 10.1093/infdis/128.Supplement_3.S437 | ref = TMP1 | jstor = 30105875 }}</ref> [[Sulfamethoxazole]] inhibits [[dihydropteroate synthase]], an enzyme involved further upstream in the same pathway.<ref name = drugs82/> [[Trimethoprim/sulfamethoxazole|Trimethoprim and sulfamethoxazole]] are commonly used in combination due to possible synergistic effects, and reduced development of resistance.<ref name = drugs82>{{cite journal | vauthors = Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS | title = Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections | journal = Drugs | volume = 23 | issue = 6 | pages = 405–430 | date = June 1982 | pmid = 7049657 | doi = 10.2165/00003495-198223060-00001 | s2cid = 21806926 }}</ref> This benefit has been questioned.<ref name=Brumfitt1993>{{cite journal | vauthors = Brumfitt W, Hamilton-Miller JM | title = Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines | journal = Journal of Chemotherapy | volume = 5 | issue = 6 | pages = 465–469 | date = December 1993 | pmid = 8195839 | doi = 10.1080/1120009X.1993.11741097 }}</ref>

[[Image:THFsynthesispathway.png|[[Tetrahydrofolate]] synthesis pathway|thumb|none|upright=1.25]]

==History==

Trimethoprim was first used in 1962.<ref name=Huo2001/> In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland.<ref name="Huo2001"/>

Its name is derived from ''trimeth''yl''o''xy-[[pyrimidine|''p''y''rim''idine]].

{{Clear right}}

== References ==

{{reflist}}

{{Sulfonamides and trimethoprim}}

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