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TrimethoprimWikipedia,thefreeencyclopedia

Trimethoprim
FromWikipedia,thefreeencyclopedia

Trimethoprim(TMP)isanantibioticusedmainlyinthe
treatmentofbladderinfections.[1]Otherusesincludefor
middleearinfectionsandtravelers'diarrhea.With
sulfamethoxazoleordapsoneitmaybeusedfor
PneumocystispneumoniainpeoplewithHIV/AIDS.[1][2]Itis
takenbymouth.[1]

Trimethoprim

Commonsideeffectsincludenausea,changesintaste,and
rash.Rarelyitmayresultinbloodproblemssuchasnot
enoughplateletsorwhitebloodcells.Maycausesun
sensitivity.[1]Thereisevidenceofpotentialharmduring
pregnancyinsomeanimalsbutnothumans.[3]Itworksby
blockingfolatemetabolismviadihydrofolatereductasein
somebacteriawhichresultsintheirdeath.[1]
Trimethoprimwasfirstusedin1962.[4]ItisontheWorld
HealthOrganization'sListofEssentialMedicines,themost
importantmedicationsneededinabasichealthsystem.[5]It
isavailableasagenericmedicationandisnotvery
expensive.[6]IntheUnitedStates10daysoftreatmentis
about21USD.[1]

Contents
1 Medicaluses
1.1 Spectrumofsusceptibility
2 Sideeffects
2.1 Common
2.2 Rare
2.3 Contraindications
2.4 Liverandkidneyproblems
2.5 Pregnancy
3 Mechanismofaction
4 History
5 Seealso
6 References
7 Externallinks

Medicaluses
Itisprimarilyusedinthetreatmentofurinarytract
infections,althoughitmaybeusedagainstanysusceptible
aerobicbacterialspecies.[7]Itmayalsobeusedtotreatand
preventPneumocystisjirovecipneumonia.[7]Itisgenerally

https://en.wikipedia.org/wiki/Trimethoprim

Systematic(IUPAC)name
5(3,4,5Trimethoxybenzyl)pyrimidine2,4diamine

Clinicaldata
Pronunciation

/tramprm/

Tradenames

Proloprim,Monotrim,Triprim,
others

AHFS/Drugs.com Monograph(https://www.drugs.
com/monograph/trimethoprim.ht
ml)
MedlinePlus

a684025(http://www.nlm.nih.go
v/medlineplus/druginfo/meds/a6
84025.html)

Licensedata

USFDA:Trimethoprim

(http://www.accessdata.fd
a.gov/scripts/cder/drugsat
fda/index.cfm?fuseaction
=Search.SearchAction&S
earchTerm=Trimethoprim
&SearchType=BasicSearc
h)
Pregnancy
category
Routesof
administration

AU:B3
US:C(Risknotruledout)

Oral
Legalstatus

Legalstatus

AU:S4(Prescription

only)
CA :only
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notrecommendedforthetreatmentofanaerobicinfections
suchasClostridiumdifficilecolitis(theleadingcauseof
antibioticinduceddiarrhea).[7]
Resistancetotrimethoprimisincreasing,butitisstillafirst
lineantibioticinmanycountries.[8]

UK:POM(Prescription

only)
US:only
Pharmacokineticdata
Bioavailability

90100%

Proteinbinding

44%

Spectrumofsusceptibility

Metabolism

hepatic

Culturesandsusceptibilitytestsshouldbedonetomakesure
bacteriaistreatedbytrimethoprim.[9][10]

Biologicalhalf
life
Excretion

812hours

Escherichiacoli
Proteusmirabilis
Klebsiellapneumoniae
Enterobacterspecies
CoagulasenegativeStaphylococcusspecies,including
S.saprophyticus
Streptococcuspneumoniae
Haemophilusinfluenzae

Identifiers
CASNumber

Nausea
Changeintaste
Vomiting
Diarrhea
Rash
Sunsensitivity
Itchiness[11][12]

ATCcode

J01EA01(WHO(http://www.wh
occ.no/atc_ddd_index/?code=J01
EA01))QJ51EA01(WHO(htt
p://www.whocc.no/atcvet/atcvet_
index/?code=QJ51EA01))

PubChem

CID5578(https://pubchem.ncbi.
nlm.nih.gov/summary/summary.
cgi?cid=5578)

DrugBank

DB00440(http://www.drugbank.
ca/drugs/DB00440)

ChemSpider

Cancausethrombocytopenia(lowlevelsofplatelets)
byloweringfolicacidlevelsthismayalsocause
megaloblasticanemia.[13]
Trimethoprimantagonizestheepithelialsodium
channelinthedistaltubule,thusactinglikeamiloride.
Thiscancauseincreasedpotassiumlevelsinthebody
(hyperkalemia).[14]
Cancompetewithcreatinineforsecretionintothe
renaltubule.Thiscancauseanartificialriseinthe
serumcreatinine.[15]
UseinEHECinfectionsmayleadtoanincreasein
expressionofShigatoxin.[16]

Contraindications
Knownhypersensitivitytotrimethoprim
Historyofmegaloblasticanemiaduetofolate
deficiency[17]
https://en.wikipedia.org/wiki/Trimethoprim

5376(http://www.chemspider.co
m/ChemicalStructure.5376.htm
l)

UNII

Rare

738705(http://www.commonc
hemistry.org/ChemicalDetail.asp
x?ref=738705)

Sideeffects
Common

Urine(5060%),faeces(4%)

AN164J8Y0X(http://fdasis.nlm.
nih.gov/srs/srsdirect.jsp?regno=
AN164J8Y0X)

KEGG

D00145(http://www.kegg.jp/ent
ry/D00145)

ChEBI

CHEBI:45924(https://www.ebi.
ac.uk/chebi/searchId.do?chebiId
=CHEBI:45924)

ChEMBL

CHEMBL22(https://www.ebi.a
c.uk/chembldb/index.php/compo
und/inspect/CHEMBL22)

PDBligandID

TOP(PDBe(http://www.ebi.ac.
uk/pdbesrv/PDBeXplore/ligan
d/?ligand=TOP),RCSBPDB(ht
tp://www.rcsb.org/pdb/search/sm
artSubquery.do?smartSearchSubt
ype=ChemCompIdQuery&chem

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Liverandkidneyproblems

CompId=TOP&polymericType=
Any))

1020%oftrimethoprimismetabolizedbytheliverandthe
restisexcretedintheurine.Therefore,trimethoprimshould
beusedwithcautioninindividualswithkidneyandliver
impairments.Dosageadjustmentisnotneededforliver
impairmentbutshouldbeadjustedforkidneyimpairment.[18]

Chemicaldata
Formula

C14H18N4O3

Molarmass

290.32g/mol

SMILES
InChI

Pregnancy

(verify)

Basedonstudiesthatshowthattrimethoprimcrossesthe
placentaandcanaffectfolatemetabolism,therehasbeengrowingevidenceoftheriskofstructuralbirthdefects
associatedwithtrimethoprim,especiallyduringthefirsttrimesterofpregnancy.[19]Itmaybeinvolvedina
reactionsimilartodisulfiramwhenalcoholisconsumedafteritisused,inparticularwhenusedincombination
withsulfamethoxazole.[20][21]Thetrophoblastsintheearlyfetusaresensitivetochangesinthefolatecycle.A
recentstudyhasfoundadoublingintheriskofmiscarriageinwomenexposedtotrimethoprimintheearly
pregnancy.[22]

Mechanismofaction
Trimethoprimbindstodihydrofolatereductaseandinhibitsthe
reductionofdihydrofolicacid(DHF)totetrahydrofolicacid(THF).[24]
THFisanessentialprecursorinthethymidinesynthesispathwayand
interferencewiththispathwayinhibitsbacterialDNAsynthesis.[24]
Trimethoprim'saffinityforbacterialdihydrofolatereductaseisseveral
thousandtimesgreaterthanitsaffinityforhumandihydrofolate
reductase.[24]Sulfamethoxazoleinhibitsdihydropteroatesynthase,an
enzymeinvolvedfurtherupstreaminthesamepathway.[24]
Trimethoprimandsulfamethoxazolearecommonlyusedincombination
duetopossiblesynergisticeffects,andreduceddevelopmentof
resistance.[24]Thisbenefithasbeenquestioned.[25]

Tetrahydrofolatesynthesispathway

>

History
Trimethoprimwasfirstusedin1962.[4]In1972,itwasusedasa
prophylactictreatmentforurinarytractinfectionsinFinland.[4]

Seealso

StaphylococcusaureusDHFRin
complexwithNADPHand
trimethoprimPDBentry2W9G(htt
p://www.pdbe.org/2W9G) [23]

Tetroxoprim
Iclaprim

References
1."Trimethoprim".TheAmericanSocietyofHealth
SystemPharmacists.RetrievedAug1,2015.
2.Masur,HBrooks,JTBenson,CAHolmes,KK
Pau,AKKaplan,JENationalInstitutesof,Health
CentersforDiseaseControland,PreventionHIV
MedicineAssociationoftheInfectiousDiseases
https://en.wikipedia.org/wiki/Trimethoprim

MedicineAssociationoftheInfectiousDiseases
Societyof,America(May2014)."Preventionand
treatmentofopportunisticinfectionsinHIVinfected
adultsandadolescents:UpdatedGuidelinesfromthe
CentersforDiseaseControlandPrevention,National
InstitutesofHealth,andHIVMedicineAssociationof

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InstitutesofHealth,andHIVMedicineAssociationof
theInfectiousDiseasesSocietyofAmerica.".Clinical
InfectiousDiseases.58(9):130811.
doi:10.1093/cid/ciu094.PMID24585567.
3."Prescribingmedicinesinpregnancydatabase".
AustralianGovernment.3March2014.Retrieved
22April2014.
4.Huovinen,P(1June2001)."Resistanceto
trimethoprimsulfamethoxazole.".ClinicalInfectious
Diseases.32(11):160814.doi:10.1086/320532.
PMID11340533.
5."WHOModelListofEssentialMedicines"(PDF).
WorldHealthOrganization.October2013.Retrieved
22April2014.
6.Hamilton,Richart(2015).TarasconPocket
Pharmacopoeia2015DeluxeLabCoatEdition.Jones
&BartlettLearning.p.113.ISBN9781284057560.
7.Rossi,S,ed.(2013).AustralianMedicinesHandbook
(2013ed.).Adelaide:TheAustralianMedicines
HandbookUnitTrust.ISBN9780980579093.
8.https://www.nice.org.uk/advice/ktt10/chapter/evidence
context
9."DailyMedTRIMETHOPRIMtrimethoprim
tablet".dailymed.nlm.nih.gov.Retrieved20151104.
10."DailyMedPRIMSOLtrimethoprimhydrochloride
solution".dailymed.nlm.nih.gov.Retrieved
20151104.
11."PROLOPRIM(trimethoprim)100mgand200mg
ScoredTablets".dailymed.nlm.nih.gov.Retrieved
20151104.
12.Ellenhorn,M.J.S.SchonwaldG.OrdogJ.
Wasserberger.AmericanHospitalFormularyService
DrugInformation2002.Baltimore,MD:Williams
andWilkins.p.236.
13.MICROMEDEXThomsonHealthCare.
USPDIpublisher=ThomsonHealth.Drug
InformationfortheHealthCareProfessional.22nd
ed.Volume1.CareGreenwoodVillage,CO.2002p.
2849.
14.Choi,MichaelJ.Fernandez,PedroC.Patnaik,Asit
CoupayeGerard,BrigitteD'Andrea,DeniseSzerlip,
HaroldKleyman,ThomasR.(19930311).
"TrimethoprimInducedHyperkalemiainaPatient
withAIDS".NewEnglandJournalofMedicine.328
(10):703706.doi:10.1056/NEJM199303113281006.
ISSN00284793.PMID8433730.
15.Naderer,O.Nafziger,A.N.Bertino,J.S.(199711
01)."Effectsofmoderatedoseversushighdose
trimethoprimonserumcreatinineandcreatinine
clearanceandadversereactions".Antimicrobial
AgentsandChemotherapy.41(11):24662470.
ISSN00664804.PMC164146 .PMID9371351.
16.KimmittPT,HarwoodCR,BarerMR(2000)."Toxin
GeneExpressionbyShigaToxinproducing
Escherichiacoli:TheRoleofAntibioticsandthe
BacterialSOSResponse"(pdf).EmergInfectDis.6
(5):458465.doi:10.3201/eid0605.000503.
PMC2627954 .PMID10998375.
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18."DailyMedTRIMETHOPRIMtrimethoprim
tablet".dailymed.nlm.nih.gov.Retrieved20151104.
19.Sivojelezova,AnnaEinarson,AdrienneShuhaiber,
SamarKoren,Gideon(20030901)."Trimethoprim
sulfonamidecombinationtherapyinearly
pregnancy.".CanadianFamilyPhysician.49:1085
1086.ISSN0008350X.PMC2214286 .
PMID14526858.
20.EdwardsDL,FinkPC,vanDykePO(1986).
"Disulfiramlikereactionassociatedwithintravenous
trimethoprimsulfamethoxazoleandmetronidazole".J
Clinicalpharmacy.5(12):9991000.
PMID3492326.
21.HeelonMW,WhiteM(1998)."Disulfiram
cotrimoxazolereaction".JPharmacotherapy.18(4):
869870.PMID9692665.
22.AndersenJT,PetersenM,JimenezSolemE,
BroedbaekK,AndersenEW,AndersenNL,AfzalS,
TorpPedersenC,KeidingN,PoulsenHE(2013).
"Trimethoprimuseinearlypregnancyandtheriskof
miscarriage:aregisterbasednationwidecohort
study".EpidemiologyandInfection.141(8):1749
1755.doi:10.1017/S0950268812002178.
PMID23010291.
23.Heaslet,H.Harris,M.Fahnoe,K.Sarver,R.Putz,
H.Chang,J.Subramanyam,C.Barreiro,G.
Miller,J.R.(2009)."Structuralcomparisonof
chromosomalandexogenousdihydrofolatereductase
fromStaphylococcusaureusincomplexwiththepotent
inhibitortrimethoprim".Proteins:Structure,
Function,andBioinformatics.76(3):706717.
doi:10.1002/prot.22383.PMID19280600.
24.Brogden,RNCarmine,AAHeel,RCSpeight,TM
Avery,GS(June1982)."Trimethoprim:areviewof
itsantibacterialactivity,pharmacokineticsand
therapeuticuseinurinarytractinfections.".Drugs.23
(6):40530.doi:10.2165/00003495198223060
00001.PMID7049657.
25.Brumfitt,WHamiltonMiller,JM(December1993).
"Reassessmentoftherationaleforthecombinations
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ofChemotherapy.5(6):4659.PMID8195839.

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Externallinks
Nucleicacidinhibitors(http://www.med.sc.edu:96/Biopharm/PDFs/NucleicAcidInhibitors.pdf)(PDF
file).
Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Trimethoprim&oldid=730514769"
Categories: Antibiotics Bacterialdihydrofolatereductaseinhibitors
Protozoaldihydrofolatereductaseinhibitors Pyrimidines WorldHealthOrganizationessentialmedicines
Phenolethers Aromaticamines
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