Trimethoprim (TMP) is an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

used mainly in the treatment of bladder infections. Other uses include for

middle ear infections Otitis media is a group of inflammatory diseases of the middle ear. One of the two main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, ...

and

travelers' diarrhea Travelers' diarrhea (TD) is a stomach and intestinal infection. TD is defined as the passage of unformed stool (one or more by some definitions, three or more by others) while traveling. It may be accompanied by abdominal cramps, nausea, fever, ...

. With sulfamethoxazole or

dapsone Dapsone, also known as 4,4'-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment a ...

it may be used for ''Pneumocystis'' pneumonia in people with

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

. It is taken by mouth. Common side effects include nausea, changes in taste, and rash. Rarely it may result in blood problems such as not enough

platelets Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ...

white blood cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

. Trimethoprim may cause sun sensitivity. There is evidence of potential harm during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

in some animals but not humans. It works by blocking

folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing an ...

metabolism via

dihydrofolate reductase 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 1-carbon transfer chemistry ...

in some bacteria which results in their death. Trimethoprim was first used in 1962. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

Medical uses

It is primarily used in the treatment of

urinary tract infections A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidne ...

, although it may be used against any susceptible aerobic bacterial species. It may also be used to treat and prevent ''

Pneumocystis jirovecii ''Pneumocystis jirovecii'' (previously ''P. carinii'') is a yeast-like fungus of the genus ''Pneumocystis''. The causative organism of ''Pneumocystis'' pneumonia, it is an important human pathogen, particularly among immunocompromised hosts. P ...

'' pneumonia. It is generally not recommended for the treatment of anaerobic infections such as ''Clostridium difficile'' colitis (the leading cause of antibiotic-induced diarrhea). Trimethoprim has been used in trials to treat retinitis. Resistance to trimethoprim is increasing, but it is still a first line antibiotic in many countries.

Spectrum of susceptibility

Cultures and susceptibility tests should be done to make sure bacteria are treated by trimethoprim. * ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...

'' * '' Proteus mirabilis'' * '' Klebsiella pneumoniae'' * ''

Enterobacter ''Enterobacter'' is a genus of common Gram-negative, facultatively anaerobic, rod-shaped, non-spore-forming bacteria of the family Enterobacteriaceae. It is the type genus of the order Enterobacterales. Several strains of these bacteria are ...

'' species *

Coagulase-negative Coagulase is a protein enzyme produced by several microorganisms that enables the conversion of fibrinogen to fibrin. In the laboratory, it is used to distinguish between different types of ''Staphylococcus'' isolates. Importantly, '' S. aureus'' ...

Staphylococcus ''Staphylococcus'' is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical ( cocci), and form in grape-like clusters. ''Staphylococcus'' species are faculta ...

'' species, including ''S. saprophyticus'' * ''

Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They ar ...

'' * ''

Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bact ...

Side effects

Common

* Nauseas * Change in taste * Vomiting * Diarrhea * Rashes * Sun sensitivity * Itchiness

Rare

* Can cause

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

(low levels of

) by lowering

folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...

levels; this may also cause

megaloblastic anemia Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synth ...

. * Trimethoprim antagonizes the

epithelial sodium channel The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...

in the distal tubule, thus acting like amiloride. This can cause increased potassium levels in the body (

hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occa ...

). * Can compete with creatinine for secretion into the renal tubule. This can cause an artificial rise in the serum creatinine. * Use in EHEC infections may lead to an increase in expression of

Shiga toxin Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, expressed by genes considered to be part of the genome of lambdoid prophages. The toxins are named after Kiyoshi Shiga, who first described the bacterial origi ...

Contraindications

* Known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

to trimethoprim * History of

due to folate deficiency

Pregnancy

Based on the studies that show that trimethoprim crosses the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

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. It may be involved in a reaction similar to

disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects o ...

when alcohol is consumed after it is used, in particular when used in combination with sulfamethoxazole. 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.

Mechanism of action

Wild-type staphylococcus aureus DHFR in complex with NADPH and trimethoprim

Trimethoprim binds to

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

History

Trimethoprim was first used in 1962. In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland. Its name is derived from ''trimeth''yl''o''xy- ''p''y''rim''idine.

References

External links

* {{portal bar, Medicine Antibiotics Antimetabolites Aromatic amines Bacterial dihydrofolate reductase inhibitors Phenol ethers Protozoal dihydrofolate reductase inhibitors Pyrimidines World Health Organization essential medicines Wikipedia medicine articles ready to translate CYP2C8 inhibitors