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| Systematic (IUPAC) name | |
|---|---|
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5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
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| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a684025 |
| Licence data | US FDA:link |
| Pregnancy category |
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| Legal status |
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| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Bioavailability | 90–100% |
| Protein binding | 44% |
| Metabolism | hepatic |
| Biological half-life | 8-12 hours |
| Excretion | Urine (50–60%), faeces (4%) |
| Identifiers | |
| CAS Registry Number | 738-70-5 Y |
| ATC code | J01EA01 QJ51EA01 |
| PubChem | CID: 5578 |
| DrugBank | DB00440 Y |
| ChemSpider | 5376 Y |
| UNII | AN164J8Y0X Y |
| KEGG | D00145 Y |
| ChEBI | CHEBI:45924 Y |
| ChEMBL | CHEMBL22 Y |
| PDB ligand ID | TOP (PDBe, RCSB PDB) |
| Chemical data | |
| Formula | C14H18N4O3 |
| Molecular mass | 290.32 g/mol |
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SMILES
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InChI
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| Y (what is this?) (verify) | |
Trimethoprim (INN) /traɪˈmɛθəprɪm/ is a bacteriostatic antibiotic used mainly in the prevention 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.
Trimethoprim is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[1]
Trimethoprim and sulfamethoxazole were commonly used in combination.
The abbreviations TRI and TMP (in clinical use) or W (in laboratory use) are common for referring to trimethoprim, but abbreviating drug names is not best practice in medicine.
Contents
- 1 Medical uses
- 2 Mechanism of action
- 3 Co-trimoxazole
- 4 Contraindications and reactions
- 5 See also
- 6 References
- 7 External links
Medical uses
It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species.[2] It may also be used to treat and prevent Pneumocystis jiroveci pneumonia.[2] It is generally not recommended for the treatment of anaerobic infections such as pseudomembranous colitis (the leading cause for antibiotic-induced diarrhoea).[2]
| Micro-organism name | Susceptible to trimethoprim?[2] |
|---|---|
| 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 - groups A, B, C, G | Yes |
| Streptococcus pneumoniae | No |
| Streptococcus viridans group | No |
| Yersinia sp. | Yes |
Mechanism of action
Tetrahydrofolate synthesis pathway
Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF).[3] THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.[3] Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase.[3] Sulfamethoxazole inhibits dihydropteroate synthetase, an enzyme involved further upstream in the same pathway.[3] Trimethoprim and sulfamethoxazole was commonly used in combination due to claimed synergistic effects,[3] and reduced development of resistance,[3] but now has a limited clinical role.[4]
Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry 2W9G [5]
Co-trimoxazole
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. 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][6]
The combination's use has been declining due to reports of sulfamethoxazole having bone marrow toxicity, resistance and lack of greater efficacy in treating common urinary and chest infections,[7][8][9][10] and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 [11] 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.
Contraindications and reactions
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 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.[12] Because it crosses the placenta and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester.[13] 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.[14][15] 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.[16]
See also
- Tetroxoprim
- Iclaprim
References
- ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ 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.
- ^ 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.
- ^ a b Brumfitt, W; Hamilton-Miller, JM (December 1993). "Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines". Journal of Chemotherapy 5 (6): 465–9. PMID 8195839.
- ^ 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
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
- ^ "Co-trimoxazole use restricted". Drug Ther Bull 33 (12): 92–3. December 1995. doi:10.1136/dtb.1995.331292. PMID 8777892.
- ^ 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. doi:10.3201/eid0605.000503. PMC 2627954. PMID 10998375.
- ^ "Use extra precautions when taking the contraceptive pill". netdoctor.co.uk.
- ^ 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.
- ^ Heelon MW; White M (1998). "Disulfiram cotrimoxazole reaction". J Pharmacotherapy 18 (4): 869–870. PMID 9692665.
- ^ 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.
External links
- Nucleic acid inhibitors (PDF file).
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English Journal
- Investigation of biotransformation, sorption, and desorption of multiple chemical contaminants in pilot-scale drinking water biofilters.
- Greenstein KE1, Lew J1, Dickenson ERV1, Wert EC2.
- Chemosphere.Chemosphere.2018 Jun;200:248-256. doi: 10.1016/j.chemosphere.2018.02.107. Epub 2018 Feb 19.
- PMID 29494905
- Molecular characterization and drug susceptibility of non-O1/O139 V. cholerae strains of seafood, environmental and clinical origin, Italy.
- Ottaviani D1, Medici L2, Talevi G2, Napoleoni M2, Serratore P3, Zavatta E3, Bignami G3, Masini L2, Chierichetti S2, Fisichella S2, Leoni F2.
- Food microbiology.Food Microbiol.2018 Jun;72:82-88. doi: 10.1016/j.fm.2017.11.011. Epub 2017 Nov 23.
- PMID 29407408
- The prevalence of multidrug-resistant Aeromonas spp. in the municipal wastewater system and their dissemination in the environment.
- Harnisz M1, Korzeniewska E2.
- The Science of the total environment.Sci Total Environ.2018 Jun 1;626:377-383. doi: 10.1016/j.scitotenv.2018.01.100. Epub 2018 Feb 19.
- PMID 29353783
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Related Pictures
★リンクテーブル★
| リンク元 | 「トリメトプリム」 |
「トリメトプリム」
- 葉酸合成拮抗薬
- ジアミノピリミジン系抗菌薬