Trimethoprim

Trimethoprim

Trimethoprim (INN)
Structural formula of trimethoprim
Ball-and-stick model of the trimethoprim molecule
Systematic (IUPAC) name
5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
Clinical data
Pronunciation
Trade names Proloprim, Monotrim, Triprim, others
AHFS/Drugs.com
MedlinePlus
Licence data US FDA:
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
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  Y
ATC code J01 QJ51
PubChem CID:
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
PDB ligand ID TOP (, )
Chemical data
Formula C14H18N4O3
Molecular mass 290.32 g/mol
 Y   

Trimethoprim (TMP) is an health system.[4] It is available as a generic medication and is not very expensive.[5] In the United States 10 days of treatment is about 21 USD.[1]

Contents

  • Medical uses 1
    • Co-trimoxazole 1.1
    • Susceptibility 1.2
  • Side effects 2
  • Mechanism of action 3
  • See also 4
  • References 5
  • External links 6

Medical uses

It is primarily used in the treatment of anaerobic infections such as Clostridium difficile colitis (the leading cause of antibiotic-induced diarrhoea).[6]

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.[7][8]

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,[9][10][11][12] and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 [13] 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.


Susceptibility

Micro-organism name Susceptible to trimethoprim?[6]
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 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
Viridans streptococci No
Yersinia sp. Yes

Side effects

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.[14] Because it crosses the placenta and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester.[15] 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.[16][17] 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.[18]

Mechanism of action

Tetrahydrofolate synthesis pathway

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF).[19] THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis.[19] Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase.[19] Sulfamethoxazole inhibits dihydropteroate synthetase, an enzyme involved further upstream in the same pathway.[19] Trimethoprim and sulfamethoxazole are commonly used in combination due to claimed synergistic effects,[19] and reduced development of resistance.[19] This benefit has been questioned.[7]

Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry [20]

See also

References

  1. ^ a b c d e "Trimethoprim". The American Society of Health-System Pharmacists. Retrieved Aug 1, 2015. 
  2. ^ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014. 
  3. ^ Huovinen, P (1 June 2001). "Resistance to trimethoprim-sulfamethoxazole.". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 32 (11): 1608–14.  
  4. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  5. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 113.  
  6. ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.  
  7. ^ 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.  
  8. ^ Brumfitt W, Hamilton-Miller JM (February 1993). "Limitations of and indications for the use of co-trimoxazole". J Chemother 6 (1): 3–11.  
  9. ^ Bean DC, Livermore DM, Papa I, Hall LM (November 2005). to sulphonamides and other antimicrobials now little used in man"Escherichia coli"Resistance among . J Antimicrob Chemother 56 (5): 962–4.  
  10. ^ 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.  
  11. ^ 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.  
  12. ^ 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.   - suggest some small advantage in UTIs
  13. ^ "Co-trimoxazole use restricted". Drug Ther Bull 33 (12): 92–3. December 1995.  
  14. ^ Kimmitt PT, Harwood CR, Barer MR (2000). : The Role of Antibiotics and the Bacterial SOS Response"Escherichia coli"Toxin Gene Expression by Shiga Toxin-producing (pdf). Emerg Infect Dis 6 (5): 458–465.  
  15. ^ "Use extra precautions when taking the contraceptive pill". netdoctor.co.uk. 
  16. ^ 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.  
  17. ^ Heelon MW; White M (1998). "Disulfiram cotrimoxazole reaction". J Pharmacotherapy 18 (4): 869–870.  
  18. ^ 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.  
  19. ^ 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.  
  20. ^ 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.  

External links

  • Nucleic acid inhibitors (PDF file).