Common side effects include nausea, changes in taste, and rash.[1] Rarely it may result in blood problems such as not enoughplatelets orwhite blood cells.[1] Trimethoprim may cause sun sensitivity.[1] There is evidence of potentialharm during pregnancy in some animals but not humans.[3] It works by blockingfolate metabolism viadihydrofolate reductase in some bacteria, preventing creation of bacterialDNA andRNA and leading to bacterial cell death.[1]
It may be involved in a reaction similar todisulfiram when alcohol is consumed after it is used, in particular when used in combination withsulfamethoxazole.[19][20]
Based on the studies that show that trimethoprim crosses theplacenta and can affect folate metabolism, there has been growing evidence of the risk of structural birth defects associated with trimethoprim, especially during the firsttrimester 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]
Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry2W9G[23]
Trimethoprim binds todihydrofolate reductase and inhibits the reduction ofdihydrofolic acid (DHF) totetrahydrofolic 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 inhibitsdihydropteroate 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]
^Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J.American Hospital Formulary Service- Drug Information 2002. Baltimore, MD: Williams and Wilkins. p. 236.
^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.
^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.PMID19280600.S2CID1373618.
^abcdBrogden 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.PMID7049657.S2CID21806926.
^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.PMID8195839.
