Trimethoprim is a synthetic antibacterial drug widely used to treat urinary tract, respiratory, and gastrointestinal infections. It acts as a folate antagonist by inhibiting the bacterial enzyme dihydrofolate reductase (DHFR), an essential enzyme in the synthesis of tetrahydrofolic acid required for DNA, RNA, and protein formation. This inhibition halts bacterial growth, making trimethoprim bacteriostatic when used alone, though it becomes bactericidal when combined with sulfamethoxazole in the synergistic formulation known as co-trimoxazole (TMP-SMX). Developed in the late 1950s and introduced in the 1960s, trimethoprim marked a significant advancement in antibacterial therapy by targeting bacterial folate metabolism. Its combination with sulfamethoxazole gained popularity due to their sequential inhibition of the folic acid pathway, enhancing antibacterial efficacy. Despite the rise of resistance over time, trimethoprim remains an important and cost-effective antibiotic, especially for urinary tract infections and certain respiratory or opportunistic infections.
BRAND NAMES
Trimethoprim brand names include Monotrim, Primsol, and Proloprim. It is often combined with sulfamethoxazole, and that combination is marketed under brand names like Bactrim, Septra, and Sulfatrim.
MECHANISM OF ACTION
Trimethoprim acts by inhibiting the bacterial enzyme dihydrofolate reductase (DHFR), thereby blocking the conversion of dihydrofolate to tetrahydrofolate. As tetrahydrofolate is crucial for the synthesis of purines needed for bacterial DNA and protein formation, this inhibition effectively stops bacterial growth and replication. Its effectiveness increases when combined with sulfamethoxazole, as the two drugs inhibit successive steps in the bacterial folic acid synthesis pathway, resulting in a stronger antibacterial effect.
PHARMACOKINETICS
Absorption
Trimethoprim is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations achieved within one to four hours. It has high oral bioavailability, typically ranging from 90% to 100%, ensuring effective systemic distribution after ingestion.
Distribution
The volume of distribution of trimethoprim ranges from approximately 1.1 to 1.6 L/kg in healthy adults, indicating extensive tissue penetration. However, this value can vary considerably between individuals due to factors such as age, body composition, and renal function.
Metabolism
Trimethoprim is mainly eliminated by the kidneys, with approximately 80% excreted unchanged in the urine. The remaining portion, about 20%, undergoes hepatic metabolism to form principal metabolites such as the 1-oxide, 3-oxide, and 3'- and 4'-hydroxy derivatives. Both the unchanged drug and its metabolites are excreted primarily in the urine, with a smaller amount eliminated through the feces.
Excretion
Trimethoprim is mainly excreted by the kidneys, with a large proportion of the drug eliminated unchanged in the urine. Its renal elimination occurs through both glomerular filtration and tubular secretion, contributing to efficient clearance from the body.
PHARMACODYNAMICS
Trimethoprim’s pharmacodynamics are based on its selective inhibition of bacterial dihydrofolate reductase (DHFR), the enzyme responsible for converting dihydrofolic acid (DHF) into tetrahydrofolic acid (THF). By blocking this step, trimethoprim interferes with the synthesis of purines, thymidine, and certain amino acids essential for bacterial DNA, RNA, and protein production. This inhibition halts bacterial growth and replication, producing a bacteriostatic effect.
ADMINISTRATION
Trimethoprim is administered orally or intravenously, depending on the severity and type of infection. The usual adult oral dose is 100–200 mg twice daily for mild to moderate infections, such as urinary tract infections, typically for 7 to 14 days. For intravenous use, it is given in cases where oral administration is not possible or when treating more serious infections. The drug can be taken with or without food, but taking it with meals may help reduce gastrointestinal discomfort. Dosage adjustments are necessary in patients with renal impairment to prevent accumulation and toxicity. Therapy duration and dosing should be guided by the infection type, clinical response, and bacterial susceptibility.
DOSAGE AND STRENGTH
Trimethoprim is available in oral as well as injectable formulations. The usual adult oral dose for most infections, particularly urinary tract infections, is 100 mg twice daily or 200 mg once daily for 7 to 14 days. For more severe infections, the dose may be adjusted based on clinical response and renal function.
Dosage forms and strengths:
Tablets: 100 mg and 200 mg
Oral suspension: 50 mg/5 mL (available in some formulations)
Injection (IV): Available for hospital use, typically in concentrations equivalent to 100 mg/mL
FOOD INTERACTIONS
Trimethoprim can be taken with or without food, as food does not significantly affect its absorption or bioavailability. However, taking it with meals may help reduce gastrointestinal discomfort, such as nausea or upset stomach, which can occasionally occur with oral administration. There are no major known food interactions that reduce its effectiveness.
DRUG INTERACTIONS
Trimethoprim can interact with certain medications, potentially increasing the risk of adverse effects. Concomitant use with ACE inhibitors or ARBs may elevate the risk of hyperkalemia, while co-administration with warfarin can enhance anticoagulant effects and increase bleeding risk. It may also raise phenytoin levels, leading to potential toxicity, and can exacerbate the myelosuppressive effects of methotrexate. Additionally, drugs that are renally excreted may compete with trimethoprim for elimination, affecting drug levels. Careful monitoring is recommended when trimethoprim is used alongside medications that influence potassium balance, renal function, or blood coagulation.
CONTRAINDICATIONS
Trimethoprim can interact with certain medications, potentially increasing the risk of adverse effects. Concomitant use with ACE inhibitors or ARBs may elevate the risk of hyperkalemia, while co-administration with warfarin can enhance anticoagulant effects and increase bleeding risk. It may also raise phenytoin levels, leading to potential toxicity, and can exacerbate the myelosuppressive effects of methotrexate. Additionally, drugs that are renally excreted may compete with trimethoprim for elimination, affecting drug levels. Careful monitoring is recommended when trimethoprim is used alongside medications that influence potassium balance, renal function, or blood coagulation.
SIDE EFFECTS
Nausea, vomiting, diarrhea.
Upset stomach, loss of appetite.
Headache.
Dizziness.
Sore tongue.
Skin rash or itching.
Hives.
Swelling of the face, lips, tongue, or throat.
Difficulty breathing or wheezing.
Fainting.
Anemia (fatigue).
Thrombocytopenia (unusual bruising or bleeding).
Leukopenia
OVERDOSE
Nausea and vomiting.
Dizziness and headache.
Confusion and mental depression.
Drowsiness.
Loss of appetite.
Fever and chills.
Severe abdominal pain.
Blood in the urine.
Pale, gray, or bluish skin.
Jaundice (yellowing of the skin or eyes).
Bone marrow depression.
TOXICITY
Trimethoprim toxicity may arise from high doses, prolonged use, or interactions with other drugs that affect folate metabolism or electrolyte balance. Since trimethoprim inhibits dihydrofolate reductase an enzyme crucial for bacterial folic acid synthesis excessive amounts can also interfere with human folate metabolism, particularly in individuals with pre-existing conditions.
