Trimethoprim

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Trimethoprim
Trimethoprim.svg
Trimethoprim-from-hydrochloride-xtal-1984-3D-balls.png
Clinical data
Pronunciation /traɪˈmɛθəprɪm/
Trade names Proloprim, Monotrim, Triprim, others
AHFS/Drugs.com Monograph
MedlinePlus a684025
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
Drug class Diaminopyrimidines
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 90–100%
Protein binding 44%
Metabolism Liver
Elimination half-life 8–12 hours
Excretion Kidney (50–60%), faeces (4%)
Identifiers
  • 5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.010.915 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H18N4O3
Molar mass 290.323 g·mol−1
3D model (JSmol)
  • Nc1nc(N)ncc1Cc(cc2OC)cc(OC)c2OC
  • InChI=1S/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18) Yes check.svgY
  • Key:IEDVJHCEMCRBQM-UHFFFAOYSA-N Yes check.svgY
   (verify)

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. [1] Other uses include for middle ear infections and travelers' diarrhea. [1] With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS. [1] [2] It is taken orally (swallowed by mouth). [1]

Contents

Common side effects include nausea, changes in taste, and rash. [1] Rarely it may result in blood problems such as not enough platelets or white blood cells. [1] Trimethoprim may cause sun sensitivity. [1] There is evidence of potential harm during pregnancy in some animals but not humans. [3] 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. [1]

Trimethoprim was first used in 1962. [4] It is on the World Health Organization's List of Essential Medicines. [5] It is available as a generic medication. [6]

Medical uses

It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species. [7] It may also be used to treat and prevent Pneumocystis jirovecii pneumonia. [7] It is generally not recommended for the treatment of anaerobic infections such as Clostridioides difficile colitis (the leading cause of antibiotic-induced diarrhea). [7] Trimethoprim has been used in trials to treat retinitis. [8]

Resistance to trimethoprim is increasing, but it is still a first-line antibiotic in many countries. [9]

Spectrum of susceptibility

Cultures and susceptibility tests should be done to make sure bacteria are treated by trimethoprim. [10] [11]

Side effects

Common

Rare

Contraindications

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. [19] [20]

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. [21]

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. [22]

Mechanism of action

Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry 2W9G Wild-type staphylococcus aureus DHFR in complex with NADPH and trimethoprim.gif
Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry 2W9G

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). [24] THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis. [24] Trimethoprim's inhibitory activity for bacterial dihydrofolate reductase is sixty thousand times greater than for human dihydrofolate reductase. [25] Sulfamethoxazole inhibits dihydropteroate synthase, an enzyme involved further upstream in the same pathway. [24] Trimethoprim and sulfamethoxazole are commonly used in combination due to possible synergistic effects, and reduced development of resistance. [24] This benefit has been questioned. [26]

Tetrahydrofolate synthesis pathway THFsynthesispathway.png
Tetrahydrofolate synthesis pathway

History

Trimethoprim was first used in 1962. [4] In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland. [4]

Its name is derived from trimethyloxy-pyrimidine.

Related Research Articles

<span class="mw-page-title-main">Ciprofloxacin</span> Fluoroquinolone antibiotic

Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra-abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin infections, typhoid fever, and urinary tract infections, among others. For some infections it is used in addition to other antibiotics. It can be taken by mouth, as eye drops, as ear drops, or intravenously.

<span class="mw-page-title-main">Urinary tract infection</span> Infection that affects part of the urinary tract

A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra (urethritis) while upper urinary tract infections affect the kidney (pyelonephritis). Symptoms from a lower urinary tract infection include suprapubic pain, painful urination (dysuria), frequency and urgency of urination despite having an empty bladder. Symptoms of a kidney infection, on the other hand, are more systemic and include fever or flank pain usually in addition to the symptoms of a lower UTI. Rarely, the urine may appear bloody. Symptoms may be vague or non-specific at the extremities of age.

<span class="mw-page-title-main">Dihydrofolate reductase</span> Mammalian protein found in humans

Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in one-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene. It is found in the q14.1 region of chromosome 5.

<span class="mw-page-title-main">Sulfonamide (medicine)</span> Molecular moiety or the drug class that uses it

Sulfonamide is a functional group that is the basis of several groups of drugs, which are called sulphonamides, sulfa drugs or sulpha drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based upon the antibacterial sulfonamides.

<span class="mw-page-title-main">Nitrofurantoin</span> Antibacterial drug

Nitrofurantoin, sold under the brand name Macrobid among others, is an antibacterial medication of the nitrofuran class used to treat urinary tract infections (UTIs), although it is not as effective for kidney infections. It is taken by mouth.

<span class="mw-page-title-main">Cefazolin</span> Antibiotic medication

Cefazolin, also known as cefazoline and cephazolin, is a first-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. Specifically it is used to treat cellulitis, urinary tract infections, pneumonia, endocarditis, joint infection, and biliary tract infections. It is also used to prevent group B streptococcal disease around the time of delivery and before surgery. It is typically given by injection into a muscle or vein.

<span class="mw-page-title-main">Trimethoprim/sulfamethoxazole</span> Combination of two antibiotic drugs

Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazole. It is used to treat urinary tract infections, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others. It is used both to treat and prevent pneumocystis pneumonia and toxoplasmosis in people with HIV/AIDS and other causes of immunosuppression. It can be given orally or intravenous infusion.

<span class="mw-page-title-main">Amoxicillin/clavulanic acid</span> Combination antibiotic medication

Amoxicillin/clavulanic acid, also known as co-amoxiclav or amox-clav, sold under the brand name Augmentin, among others, is an antibiotic medication used for the treatment of a number of bacterial infections. It is a combination consisting of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor. It is specifically used for otitis media, streptococcal pharyngitis, pneumonia, cellulitis, urinary tract infections, and animal bites. It is taken by mouth or by injection into a vein.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Sulfamethoxazole</span> Chemical compound

Sulfamethoxazole is an antibiotic. It is used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is effective against both gram negative and positive bacteria such as Escherichia coli and Listeria monocytogenes.

<span class="mw-page-title-main">Pyelonephritis</span> Inflammation of the kidney

Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications may include pus around the kidney, sepsis, or kidney failure.

<span class="mw-page-title-main">4-Aminosalicylic acid</span> Anti-tuberculosis and anti-inflammatory drug

4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

<span class="mw-page-title-main">Pyrimethamine</span> Medication

Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin to treat the parasitic diseases toxoplasmosis and cystoisosporiasis. It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia in people with HIV/AIDS. It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.

<span class="mw-page-title-main">Sulfadiazine</span> Chemical compound

Sulfadiazine is an antibiotic. Used together with pyrimethamine, a dihydrofolate reductase inhibitor, it is the treatment of choice for toxoplasmosis, which is caused by a protozoan parasite. It is a second-line treatment for otitis media, prophylaxis of rheumatic fever, chancroid, chlamydia, and infections by Haemophilus influenzae. It is also used as adjunct therapy for chloroquine-resistant malaria and several forms of bacterial meningitis. It is taken by mouth. Sulfadiazine is available in multiple generic tablets of 500 mg. For urinary tract infections, the usual dose is 4 to 6 grams daily in 3 to 6 divided doses.

<span class="mw-page-title-main">Dihydropteroate</span> Chemical compound

Dihydropteroate is an important intermediate in folate biosynthesis. It is a pterin created from para-aminobenzoic acid (PABA) by the enzyme dihydropteroate synthase.

<span class="mw-page-title-main">Antifolate</span> Class of antimetabolite medications

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

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<span class="mw-page-title-main">Chronic bacterial prostatitis</span> Bacterial infection of the prostate gland

Chronic bacterial prostatitis (CBP) is a bacterial infection of the prostate gland and a form of prostatitis. It should be distinguished from other forms of prostatitis such as acute bacterial prostatitis (ABP) and chronic pelvic pain syndrome (CPPS).

<span class="mw-page-title-main">Ceftazidime/avibactam</span> Combination antibiotic medication

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<span class="mw-page-title-main">Urinary anti-infective agent</span> Medication for urinary tract infections

Urinary anti-infective agent, also known as urinary antiseptic, is medication that can eliminate microorganisms causing urinary tract infection (UTI). UTI can be categorized into two primary types: cystitis, which refers to lower urinary tract or bladder infection, and pyelonephritis, which indicates upper urinary tract or kidney infection. Escherichia coli is the predominant microbial trigger of UTIs, accounting for 75% to 95% of reported cases. Other pathogens such as Proteus mirabilis, Klebsiella pneumoniae, and Staphylococcus saprophyticus can also cause UTIs.

References

  1. 1 2 3 4 5 6 7 8 "Trimethoprim". The American Society of Health-System Pharmacists. Archived from the original on 24 September 2015. Retrieved 1 August 2015.
  2. ↑ Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE (May 2014). "Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America". Clinical Infectious Diseases. 58 (9): 1308–1311. doi:10.1093/cid/ciu094. PMC   3982842 . PMID   24585567.
  3. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Archived from the original on 8 April 2014. Retrieved 22 April 2014.
  4. 1 2 3 Huovinen P (June 2001). "Resistance to trimethoprim-sulfamethoxazole". Clinical Infectious Diseases. 32 (11): 1608–1614. doi: 10.1086/320532 . PMID   11340533.
  5. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  6. ↑ Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 113. ISBN   978-1-284-05756-0.
  7. 1 2 3 Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN   978-0-9805790-9-3.
  8. ↑ Pradhan E, Bhandari S, Gilbert RE, Stanford M (May 2016). "Antibiotics versus no treatment for toxoplasma retinochoroiditis". The Cochrane Database of Systematic Reviews. 2016 (5): CD002218. doi:10.1002/14651858.CD002218.pub2. PMC   7100541 . PMID   27198629.
  9. ↑ "Three-day courses of antibiotics for uncomplicated urinary tract infection | Guidance and guidelines | NICE". 15 January 2015. Archived from the original on 8 December 2015. Retrieved 30 December 2015.
  10. ↑ "TRIMETHOPRIM- trimethoprim tablet". DailyMed. U.S. National Library of Medicine. Archived from the original on 30 September 2015. Retrieved 4 November 2015.
  11. ↑ "PRIMSOL- trimethoprim hydrochloride solution". DailyMed. U.S. National Library of Medicine. Archived from the original on 17 November 2015. Retrieved 4 November 2015.
  12. ↑ "PROLOPRIM® (trimethoprim)100-mg and 200-mg Scored Tablets". DailyMed. U.S. National Library of Medicine. Archived from the original on 17 November 2015. Retrieved 4 November 2015.
  13. ↑ Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J. American Hospital Formulary Service- Drug Information 2002. Baltimore, MD: Williams and Wilkins. p. 236.
  14. ↑ MICROMEDEX Thomson Health Care. USPDI (2002). Drug Information for the Health Care Professional. Vol. 1 (22nd ed.). Greenwood Village, CO.: Thomson Health Care. p. 2849.
  15. ↑ Choi MJ, Fernandez PC, Patnaik A, Coupaye-Gerard B, D'Andrea D, Szerlip H, et al. (March 1993). "Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS". The New England Journal of Medicine. 328 (10): 703–706. doi: 10.1056/NEJM199303113281006 . PMID   8433730.
  16. ↑ Naderer O, Nafziger AN, Bertino JS (November 1997). "Effects of moderate-dose versus high-dose trimethoprim on serum creatinine and creatinine clearance and adverse reactions". Antimicrobial Agents and Chemotherapy. 41 (11): 2466–2470. doi:10.1128/AAC.41.11.2466. PMC   164146 . PMID   9371351.
  17. ↑ 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". Emerging Infectious Diseases. 6 (5): 458–465. doi:10.3201/eid0605.000503. PMC   2627954 . PMID   10998375.
  18. ↑ "PRIMSOL- trimethoprim hydrochloride solution". DailyMed. U.S. National Library of Medicine. Archived from the original on 17 November 2015. Retrieved 4 November 2015.
  19. ↑ Edwards DL, Fink PC, Van Dyke PO (December 1986). "Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole". Clinical Pharmacy. 5 (12): 999–1000. PMID   3492326. Archived from the original on 24 January 2009.
  20. ↑ Heelon MW, White M (1998). "Disulfiram-cotrimoxazole reaction". Pharmacotherapy. 18 (4): 869–870. doi:10.1002/j.1875-9114.1998.tb03913.x. PMID   9692665. S2CID   23968977. Archived from the original on 24 January 2009.
  21. ↑ Sivojelezova A, Einarson A, Shuhaiber S, Koren G (September 2003). "Trimethoprim-sulfonamide combination therapy in early pregnancy". Canadian Family Physician. 49: 1085–1086. PMC   2214286 . PMID   14526858.
  22. ↑ Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen EW, Andersen NL, et al. (August 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. PMC   9151599 . PMID   23010291. S2CID   19917493.
  23. ↑ Heaslet H, Harris M, Fahnoe K, Sarver R, Putz H, Chang J, et al. (August 2009). "Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim". Proteins. 76 (3): 706–717. doi:10.1002/prot.22383. PMID   19280600. S2CID   1373618.
  24. 1 2 3 4 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): 405–430. doi:10.2165/00003495-198223060-00001. PMID   7049657. S2CID   21806926.
  25. ↑ Burchall JJ (November 1973). "Mechanism of action of trimethoprim-sulfamethoxazole. II". The Journal of Infectious Diseases. 128: Suppl: 437-Suppl: 441. doi:10.1093/infdis/128.Supplement_3.S437. JSTOR   30105875. PMID   4585969.
  26. ↑ Brumfitt W, Hamilton-Miller JM (December 1993). "Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines". Journal of Chemotherapy. 5 (6): 465–469. doi:10.1080/1120009X.1993.11741097. PMID   8195839.
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