Trimethoprim

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| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields= |Watchedfields=changed |verifiedrevid=470615131}} Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections.<ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Other uses include for middle ear infections and travelers' diarrhea.<ref name=AHFS2015/> With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS.<ref name=AHFS2015/><ref>Template:Cite journal</ref> It is taken orally (swallowed by mouth).<ref name=AHFS2015/>

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 harm during pregnancy in some animals but not humans.<ref name=TGA2014>{{#invoke:citation/CS1|citation |CitationClass=web }}</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/>

Trimethoprim was first used in 1962.<ref name=Huo2001>Template:Cite journal</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO22nd">Template:Cite book</ref> It is available as a generic medication.<ref name=Ric2015>Template:Cite book</ref>

Medical uses

It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species.<ref name="AMH">Template:Cite book</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 infections such as Clostridioides difficile colitis (the leading cause of antibiotic-induced diarrhea).<ref name = AMH/> Trimethoprim has been used in trials to treat retinitis.<ref name="Pradhan">Template:Cite journal</ref>

Resistance to trimethoprim is increasing, but it is still a first-line antibiotic in many countries.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• Escherichia coli
• Proteus mirabilis
• Klebsiella pneumoniae
• Enterobacter species
• Coagulase-negative Staphylococcus species, including S. saprophyticus
• Streptococcus pneumoniae
• Haemophilus influenzae

Side effects

Common

• Nauseas
• Change in taste
• Vomiting
• Diarrhea
• Rashes
• Sun sensitivity
• Itchiness<ref name=":1">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>Template:Cite book</ref>

Rare

• Can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia.<ref name=":2">Template:Cite book</ref>
• Trimethoprim antagonizes the epithelial sodium channel in the distal tubule, thus acting like amiloride. This can cause increased potassium levels in the body (hyperkalemia).<ref>Template:Cite journal</ref>
• Can compete with creatinine for secretion into the renal tubule. This can cause an artificial rise in the serum creatinine.<ref>Template:Cite journal</ref>
• Use in EHEC infections may lead to an increase in expression of Shiga toxin.<ref>Template:Cite journal</ref>

Contraindications

• Known hypersensitivity to trimethoprim
• History of megaloblastic anemia due to folate deficiency<ref name=":0">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

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>Template:Cite journal</ref><ref>Template:Cite journal</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 trimester of pregnancy.<ref name="Sivojelezova 1085–1086">Template:Cite journal</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>Template:Cite journal</ref>

Mechanism of action

File:Wild-type staphylococcus aureus DHFR in complex with NADPH and trimethoprim.gif

Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry Template:PDBe<ref>Template:Cite journal</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>Template:Cite journal</ref> Sulfamethoxazole inhibits dihydropteroate synthase, an enzyme involved further upstream in the same pathway.<ref name = drugs82/> Trimethoprim and sulfamethoxazole are commonly used in combination due to possible synergistic effects, and reduced development of resistance.<ref name = drugs82>Template:Cite journal</ref> This benefit has been questioned.<ref name=Brumfitt1993>Template:Cite journal</ref>

File:THFsynthesispathway.png

Tetrahydrofolate synthesis pathway

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 trimethyloxy-pyrimidine.