Trimethoprim
Encyclopedia
Trimethoprim (icon) is a bacteriostatic antibiotic
mainly used in the prophylaxis and treatment of urinary tract infection
s.
It belongs to the class of chemotherapeutic
agents known as dihydrofolate reductase inhibitor
s. Trimethoprim was formerly marketed by GlaxoSmithKline
under trade name
s 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.
Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase
, inhibiting synthesis of tetrahydrofolic acid
. Tetrahydrofolic acid is an essential precursor in the de novo synthesis
of the intermediate Thymidine monophosphate (dTMP), precursor of DNA metabolite Thymidine triphosphate
. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) and are thus dependent on their own de novo synthesis. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication
causing, in certain circumstances, cell lethality due to thymineless death
.
This drug was developed by George H. Hitchings and collaborators, who shared the Nobel Prize for Physiology or Medicine in 1988 for the discovery of antifolates.
, 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.
The combinations 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, and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 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.
s. (Co-trimoxazole
, with its greater efficacy against a limited number of bacteria, and parasites remains indicated for some infections, see above.)
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
.
Due to the fact that it crosses the placenta
and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester
. It may be involved in a reaction similar to disulfiram
when alcohol is consumed after it is used, particularly when used in combination with sulfamethoxazole
.
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
mainly used in the prophylaxis and treatment of urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
s.
It belongs to the class of chemotherapeutic
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agents known as dihydrofolate reductase inhibitor
Dihydrofolate reductase inhibitor
A dihydrofolate reductase inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage. For example, methotrexate is used as cancer...
s. Trimethoprim was formerly marketed by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
under trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
s including Proloprim, Monotrim and Triprim; but these trade names have been licensed to various generic pharmaceutical
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
manufacturers. In clinical use it is often abbreviated TRI or TMP; its common laboratory abbreviation is W.
Mechanism of action
Dihydrofolate reductase
- Function :Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids...
, inhibiting synthesis of tetrahydrofolic acid
Tetrahydrofolic acid
Tetrahydrofolic acid, or tetrahydrofolate, is a folic acid derivative.-Metabolism:-Human synthesis:It is produced from dihydrofolic acid by dihydrofolate reductase...
. Tetrahydrofolic acid is an essential precursor in the de novo synthesis
De novo synthesis
De novo synthesis refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to their being recycled after partial degradation. For example, nucleotides are not needed in the diet as they can be constructed from small precursor molecules such as...
of the intermediate Thymidine monophosphate (dTMP), precursor of DNA metabolite Thymidine triphosphate
Thymidine triphosphate
5-Methyluridine triphosphate or m5UTP is one of five nucleoside triphosphates. It is the ribonucleoside triphosphate of thymidine, but the 5-methyluridine nomenclature is used because the term thymidine triphosphate is used for the deoxyribonucleoside by convention.-References:...
. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) and are thus dependent on their own de novo synthesis. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
causing, in certain circumstances, cell lethality due to thymineless death
Thymineless death
Thymineless death is the phenomenon by which bacteria, yeasts and mammalian cells undergo irreversible cell death when they are starved of thymidine triphosphate , an essential precursor for DNA replication...
.
This drug was developed by George H. Hitchings and collaborators, who shared the Nobel Prize for Physiology or Medicine in 1988 for the discovery of antifolates.
Co-trimoxazole
Trimethoprim was commonly (from 1969 to 1980 in the UK) used in a 1:5 combination with sulfamethoxazoleSulfamethoxazole
Sulfamethoxazole is a sulfonamide bacteriostatic antibiotic.It is most often used as part of a synergistic combination with trimethoprim in a 5:1 ratio in co-trimoxazole , also known under trade names such as Bactrim, Septrin, or Septra; in Eastern Europe it is marketed as Biseptol...
, a sulfonamide
Sulfonamide (medicine)
Sulfonamide or sulphonamide is the basis of several groups of 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...
antibiotic, which inhibits an earlier step in the folate synthesis pathway (see diagram below). This combination, also known as co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
, TMP-sulfa, or TMP-SMX, results in an in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
synergistic antibacterial effect by inhibiting successive steps in folate synthesis. This claimed benefit was not seen in general clinical use.
The combinations use has been declining due to reports of sulfamethoxazole bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
toxicity, resistance and lack of greater efficacy in treating common urine and chest infections, and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 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
Pneumocystis pneumonia
Pneumocystis pneumonia or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus Pneumocystis jirovecii...
(e.g. AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients and those with some hematological malignancies
Hematological malignancy
Hematological malignancies are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is technically a disease of the lymph...
) and as therapy in Whipple's disease
Whipple's disease
Whipple's disease is a rare, systemic infectious disease caused by the bacterium Tropheryma whipplei. First described by George Hoyt Whipple in 1907 and commonly considered a gastrointestinal disorder, Whipple's disease primarily causes malabsorption but may affect any part of the body including...
. Gram positive bacteria are generally or moderately susceptible.
Clinical indications
Trimethoprim, used as monotherapy (since 1980 in the UK), is indicated for the prophylaxis and treatment of urinary tract infectionUrinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
s. (Co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
, with its greater efficacy against a limited number of bacteria, and parasites remains indicated for some infections, see above.)
Contraindications and reactions
Trimethoprim can cause thrombocytopenia (low levels of platelets) by lowering folic acidFolic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
levels; this may also cause megaloblastic anemia
Megaloblastic anemia
Megaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
.
Trimethoprim antagonises the epithelial sodium channel
Epithelial sodium channel
The epithelial sodium channel is a membrane-bound ion-channel that is permeable for Li+-ions, protons and especially Na+-ions. It is a constitutively active ion-channel...
(ENaC) in the distal tubule, thus acting like amiloride
Amiloride
Amiloride is a potassium-sparing diuretic, first approved for use in 1967 , used in the management of hypertension and congestive heart failure. Amiloride was also tested as treatment of cystic fibrosis, but it was revealed inefficient in vivo due to it's short time of action, therefore...
, this can cause hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
. Trimethoprim also competes with creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
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
Shiga toxin
Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, whose genes are considered to be part of the genome of lambdoid prophages. The toxins are named for Kiyoshi Shiga, who first described the bacterial origin of dysentery caused by Shigella dysenteriae. The most common...
.
Due to the fact that it crosses the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester
Trimester
Trimester may refer to:* An academic term comprising one-third of an academic year* The division of pregnancy into three-month sections...
. It may be involved in a reaction similar to disulfiram
Disulfiram
Disulfiram is a drug discovered in the 1920s and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals...
when alcohol is consumed after it is used, particularly when used in combination with sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole is a sulfonamide bacteriostatic antibiotic.It is most often used as part of a synergistic combination with trimethoprim in a 5:1 ratio in co-trimoxazole , also known under trade names such as Bactrim, Septrin, or Septra; in Eastern Europe it is marketed as Biseptol...
.
Chemistry
Stenbuck, P.; Hood, H. M.; 1962, .External links
- Nucleic acid inhibitors (PDF file).