Trimethoprim

Usage

Trimethoprim is primarily prescribed for urinary tract infections (UTIs). It can also be used for other bacterial infections like otitis media, shigellosis, and Pneumocystis jirovecii pneumonia (PCP), and as prophylaxis against UTIs and PCP. Its pharmacological classification is antibiotic. Trimethoprim inhibits dihydrofolate reductase, a bacterial enzyme essential for folic acid synthesis and subsequently DNA formation. This inhibits bacterial growth and replication.

Alternate Names

Trimethoprim is also known as TMP. Brand names include Trimethoprim Viatris, TMP Tablet®, Proloprim, and Trimpex. It is often used in combination with sulfamethoxazole (co-trimoxazole), which is marketed under brand names like Bactrim®, Septra®, and Sulfatrim®.

How It Works

Pharmacodynamics: Trimethoprim exerts its antibacterial effect by inhibiting dihydrofolate reductase. This enzyme is crucial for the synthesis of tetrahydrofolic acid, a cofactor needed for the production of purines and pyrimidines, the building blocks of DNA. By blocking this pathway, Trimethoprim prevents bacterial DNA synthesis, halting bacterial growth and replication.

Pharmacokinetics: Trimethoprim is well-absorbed orally, reaching peak plasma concentrations within 1 to 4 hours. It is widely distributed throughout the body, achieving therapeutic levels in tissues and fluids, including the kidneys and lungs. Trimethoprim is primarily excreted unchanged by the kidneys through glomerular filtration and tubular secretion. The half-life is approximately 8 to 12 hours, prolonged in patients with renal impairment.

Mode of Action: Trimethoprim selectively targets bacterial dihydrofolate reductase, which has a much higher affinity for Trimethoprim than the human enzyme. This selective action allows for effective antibacterial action while minimizing the impact on human cells.

Receptor Binding/Enzyme Inhibition: Trimethoprim’s mechanism of action involves competitive inhibition of bacterial dihydrofolate reductase.

Elimination Pathways: Trimethoprim is primarily eliminated via renal excretion, with a small portion undergoing hepatic metabolism.

Dosage

Standard Dosage

Adults:

For UTIs, the standard oral dose is 100 mg every 12 hours or 200 mg once daily for 10 days. For prophylaxis, 100 mg daily is usually recommended.

Children:

The pediatric dose is weight-based, typically 4 mg/kg every 12 hours. Children younger than 2 months are usually not treated with trimethoprim alone but may receive it in combination with sulfamethoxazole. Liquid formulations are available for children who have difficulty swallowing tablets.

Special Cases:

• Elderly Patients: Dose adjustments may be necessary based on renal function.
• Patients with Renal Impairment: Dose reduction is required based on creatinine clearance. For CrCl 15-30 mL/min, the dose is halved. Trimethoprim is usually avoided in patients with CrCl < 15 mL/min.
• Patients with Hepatic Dysfunction: Caution is advised, though dose adjustment is generally not required.
• Patients with Comorbid Conditions: Close monitoring is recommended for patients with folate deficiency, diabetes, or those on medications known to interact with Trimethoprim.

Clinical Use Cases Dosages for specific medical settings beyond standard UTI treatment should be determined based on individual patient needs and may vary between different guidelines. The doses below are general and should be adjusted according to the specific circumstances and clinical response.

• Intubation: Not specifically indicated.
• Surgical Procedures: Prophylactic use may be considered for certain procedures, but the dosage is specific to the procedure and patient risk.
• Mechanical Ventilation: Not specifically indicated.
• Intensive Care Unit (ICU) Use: Higher doses might be required for serious infections in ICU patients, and these doses are determined by the severity of the infection and the patient’s condition.
• Emergency Situations: Dosages vary widely depending on the indication and must be titrated to patient response.

Dosage Adjustments

Dose adjustments are needed for patients with renal impairment based on creatinine clearance (CrCl). For CrCl 15-30 mL/min, the dose is typically reduced by 50%. Trimethoprim is usually avoided in patients with severe renal impairment (CrCl < 15 mL/min).

Side Effects

Common Side Effects:

Nausea, vomiting, diarrhea, rash, itching.

Rare but Serious Side Effects:

Bone marrow suppression (thrombocytopenia, leukopenia, agranulocytosis), hyperkalemia, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Long-Term Effects:

Megaloblastic anemia, folate deficiency (with prolonged use).

Adverse Drug Reactions (ADR):

Severe skin reactions, allergic reactions, hyperkalemia, acute renal failure.

Contraindications

Hypersensitivity to trimethoprim, documented megaloblastic anemia due to folate deficiency, severe hepatic impairment, pregnancy (especially first trimester).

Drug Interactions

Trimethoprim interacts with several medications, including:

• Anticoagulants (e.g., warfarin): Increased risk of bleeding.
• Antihypertensives (e.g., ACE inhibitors): Increased risk of hyperkalemia.
• Diuretics (e.g., thiazides): Increased risk of hyperkalemia and thrombocytopenia.
• Methotrexate: Enhanced toxicity of methotrexate.
• Other folate antagonists (e.g., pyrimethamine): Increased risk of megaloblastic anemia.

Pregnancy and Breastfeeding

Trimethoprim is generally avoided during pregnancy, particularly in the first trimester, due to its potential to interfere with folate metabolism and increase the risk of birth defects. While it can be used in later trimesters if the benefits outweigh the risks, careful monitoring is essential. Trimethoprim is present in breast milk at low concentrations. While generally considered safe during breastfeeding, it might affect the infant’s folate levels. Close monitoring of the infant is recommended, especially for infants younger than 4 months.

Drug Profile Summary

• Mechanism of Action: Dihydrofolate reductase inhibitor, inhibiting bacterial DNA synthesis.
• Side Effects: Nausea, vomiting, diarrhea, rash, pruritus (common); bone marrow suppression, SJS/TEN, hyperkalemia (rare but serious).
• Contraindications: Hypersensitivity, megaloblastic anemia due to folate deficiency, severe hepatic impairment, pregnancy (1st trimester).
• Drug Interactions: Anticoagulants, antihypertensives, diuretics, methotrexate, other folate antagonists.
• Pregnancy & Breastfeeding: Avoided in the first trimester; use with caution later in pregnancy and during breastfeeding.
• Dosage: Adults: 100 mg BID or 200 mg QD for 10 days (UTI); Children: 4 mg/kg BID.
• Monitoring Parameters: Renal function, complete blood count, potassium levels (especially in high-risk patients).

Popular Combinations

Trimethoprim is frequently combined with sulfamethoxazole (co-trimoxazole). This combination exhibits synergistic activity against a broader range of bacteria than either drug alone.

Precautions

Assess renal function before and during treatment, particularly with prolonged use. Monitor potassium levels, especially in patients with renal impairment, diabetes, or those on interacting medications. Ensure adequate folate intake, especially during long-term therapy. Monitor for signs of bone marrow suppression or hypersensitivity reactions.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Trimethoprim?

A: Adults: 100 mg BID or 200 mg QD for 10 days (UTI). Children: 4 mg/kg BID. Dose adjustments are required for patients with renal impairment.

Q2: What are the common side effects of Trimethoprim?

A: Common side effects include nausea, vomiting, diarrhea, rash, and itching.

Q3: What are the serious side effects of Trimethoprim?

A: Rare but serious side effects include bone marrow suppression, hyperkalemia, and severe skin reactions like Stevens-Johnson syndrome.

Q4: Can Trimethoprim be used during pregnancy?

A: Trimethoprim is generally avoided during pregnancy, especially in the first trimester, due to the potential risk of birth defects. Its use during later trimesters should be carefully considered.

Q5: Can Trimethoprim be used during breastfeeding?

A: Trimethoprim is excreted in breast milk but is generally considered safe for breastfeeding mothers. However, monitoring the infant is recommended, especially if the infant is younger than 4 months.

Q6: How does Trimethoprim interact with other medications?

A: Trimethoprim can interact with several medications, including anticoagulants, antihypertensives, diuretics, methotrexate, and other folate antagonists. These interactions can enhance the risks of bleeding, hyperkalemia, and other side effects.

Q7: What are the contraindications for Trimethoprim?

A: Trimethoprim is contraindicated in individuals with hypersensitivity to the drug, documented megaloblastic anemia due to folate deficiency, and severe hepatic impairment.

Q8: What is the mechanism of action of Trimethoprim?

A: Trimethoprim inhibits bacterial dihydrofolate reductase, a key enzyme in the folate pathway, thus preventing bacterial DNA synthesis.

Q9: What are the monitoring parameters for Trimethoprim?

A: Monitor renal function, complete blood count, and potassium levels, especially in high-risk patients and during prolonged therapy.

Q10: Can Trimethoprim be used for infections other than UTIs?

A: Yes, Trimethoprim can be used to treat certain other bacterial infections such as otitis media, shigellosis, and Pneumocystis jirovecii pneumonia. It’s also used for prophylaxis of UTIs and P. jirovecii pneumonia.