Trimethoprim

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Trimethoprim
Trimethoprim2DACS.svg
Trimethoprim3Dan.gif
Systematic (IUPAC) name
5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a684025
Licence data US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 90–100%
Protein binding 44%
Metabolism hepatic
Half-life 8-12 hours
Excretion Urine (50–60%), faeces (4%)
Identifiers
CAS number 738-70-5 YesY
ATC code J01EA01 QJ51EA01
PubChem CID 5578
DrugBank DB00440
ChemSpider 5376 YesY
UNII AN164J8Y0X YesY
KEGG D00145 YesY
ChEBI CHEBI:45924 YesY
ChEMBL CHEMBL22 YesY
PDB ligand ID TOP (PDBe, RCSB PDB)
Chemical data
Formula C14H18N4O3 
Mol. mass 290.32 g/mol
 YesY (what is this?)  (verify)

Trimethoprim (INN) /trˈmɛθəprɪm/ is a bacteriostatic antibiotic used mainly in the prophylaxis and treatment of urinary tract infections.

It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoSmithKline under trade names including Proloprim, Monotrim, and Triprim; but these trade names have been licensed to various generic pharmaceutical manufacturers. In clinical use it is often abbreviated TRI or TMP; its common laboratory abbreviation is W.

Medical uses[edit]

It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species (see table).[1] It may also be used to treat and prevent pneumocystis jiroveci pneumonia.[1] It is generally not recommended for the treatment of anaerobic infections like pseudomembranous colitis (the leading cause for antibiotic-induced diarrhoea).[1]

Micro-organism name Susceptible to trimethoprim?[1]
Aerobic bacteria
Acinetobacter sp. No
Aeromonas sp. Yes
Burkholderia cepacia Yes
Burkholderia pseudomallei No
Campylobacter coli No
Campylobacter jejuni No
Citrobacter freundii Yes
Corynebacterium jeikeium No
Enterobacter sp. Yes
Enterococcus sp. No
Escherichia coli sp. Yes
Haemophilus influenzae Yes
Klebsiella sp. Yes
Moraxella catarrhalis No
Morganella sp. Yes
Neisseria meningitidis No
Proteus mirabilis Yes
Proteus vulgaris Yes
Providencia sp. Yes
Pseudomonas aeruginosa No
Salmonella sp. Yes
Serratia sp. Yes
Shigella sp. No
Staphylococcus aureus Yes
Staphylococcus saprophyticus Yes
Stenotrophomonas maltophilia No
Streptococcus - group A, B, C, G Yes
Streptococcus pneumoniae No
Streptococcus viridans group No
Yersinia sp. Yes


Mechanism of action[edit]

Tetrahydrofolate synthesis pathway

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF).[2] THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.[2] Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase.[2] Sulfamethoxazole inhibits dihydropteroate synthetase, an enzyme involved further upstream in the same pathway.[2] Trimethoprim and sulfamethoxazole are commonly used in combination due to their synergistic effects.[2] This drug combination also reduces the development of resistance that is seen when either drug is used alone.[2]

Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry 2W9G [3]

Co-trimoxazole[edit]

Trimethoprim was commonly (from 1969 to 1980 in the UK) used in a 1:5 combination with sulfamethoxazole, a sulfonamide antibiotic, which inhibits an earlier step in the folate synthesis pathway (see diagram below). This combination, also known as co-trimoxazole, TMP-sulfa, or TMP-SMX, results in an in vitro synergistic antibacterial effect by inhibiting successive steps in folate synthesis. This claimed benefit was not seen in general clinical use.[4][5]

The combination's use has been declining due to reports of sulfamethoxazole bone marrow toxicity, resistance and lack of greater efficacy in treating common urine and chest infections,[6][7][8][9] and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 [10] following the availability of trimethoprim (not in combination) in 1980.

With its greater efficacy against a limited number of bacteria, Co-trimoxazole remains indicated for some infections; for example, it is used as prophylaxis in patients at risk for Pneumocystis jirovecii pneumonia (e.g. AIDS patients and those with some hematological malignancies) and as therapy in Whipple's disease. Gram-positive bacteria are generally or moderately susceptible.

Clinical indications[edit]

Trimethoprim, used as monotherapy (since 1980 in the UK), is indicated for the prophylaxis and treatment of urinary tract infections. (Co-trimoxazole, with its greater efficacy against a limited number of bacteria and parasites, remains indicated for some infections; see above.)

Contraindications and reactions[edit]

Trimethoprim can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia. Trimethoprim antagonises the epithelial sodium channel (ENaC) in the distal tubule, thus acting like amiloride. This can cause hyperkalemia. Trimethoprim also competes with creatinine for secretion into the renal tubule. This can cause an artefactual rise in the serum creatinine. Use in EHEC infections may lead to an increase in expression of Shiga toxin.[11] Due to the fact that it crosses the placenta and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester.[12] 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.[13][14] 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.[15]

Chemistry[edit]

Trimethoprim can be prepared from 3,4,5-trimethoxybenzaldehyde, 3-ethoxypropionitrile, and guanidine:[16]

Trimethoprim syn.png

References[edit]

  1. ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  2. ^ a b c d e f 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. 
  3. ^ 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.  edit
  4. ^ Brumfitt W, Hamilton-Miller JM (December 1993). "Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines". J Chemother 5 (6): 465–9. PMID 8195839. 
  5. ^ Brumfitt W, Hamilton-Miller JM (February 1993). "Limitations of and indications for the use of co-trimoxazole". J Chemother 6 (1): 3–11. PMID 8071675. 
  6. ^ Bean DC, Livermore DM, Papa I, Hall LM (November 2005). "Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man". J Antimicrob Chemother 56 (5): 962–4. doi:10.1093/jac/dki332. PMID 16150859. 
  7. ^ Felmingham D, Reinert RR, Hirakata Y, Rodloff A (September 2002). "Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and compatative in vitro activity of the ketolide, telithromycin". J Antimicrob Chemother 50 (Suppl S1): 25–37. doi:10.1093/jac/dkf808. PMID 12239226. 
  8. ^ Johnson JR, Manges AR, O'Bryan TT, Riley LW (June 29, 2002). "A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis". Lancet 359 (9325): 2249–51. doi:10.1016/S0140-6736(02)09264-4. PMID 12103291. 
  9. ^ Lawrenson RA, Logie JW (December 2001). "Antibiotic failure in the treatment of urinary tract infections in young women". J Antimicrob Chemother 48 (6): 895–901. doi:10.1093/jac/48.6.895. PMID 11733475.  - suggest some small advantage in UTIs
  10. ^ "Co-trimoxazole use restricted". Drug Ther Bull 33 (12): 92–3. December 1995. doi:10.1136/dtb.1995.331292. PMID 8777892. 
  11. ^ 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" (pdf). Emerg Infect Dis 6 (5): 458–465. PMC 2627954. PMID 10998375. 
  12. ^ "Use extra precautions when taking the contraceptive pill". netdoctor.co.uk. 
  13. ^ 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. 
  14. ^ Heelon MW; White M (1998). "Disulfiram cotrimoxazole reaction". J Pharmacotherapy 18 (4): 869–870. PMID 9692665. 
  15. ^ 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. 
  16. ^ Stenbuck, P.; Hood, H. M.; 1962, U.S. Patent 3,049,544

External links[edit]