Trimethoprim - Drug Monograph

Introduction

Trimethoprim is a synthetic antibacterial agent belonging to the diaminopyrimidine class. First introduced in the 1960s, it remains an important antimicrobial agent for treating various bacterial infections, particularly when used in combination with sulfamethoxazole (as co-trimoxazole). As a single agent, trimethoprim demonstrates specific utility in uncomplicated urinary tract infections and certain other indications.

Mechanism of Action

Trimethoprim exerts its antibacterial effect through selective inhibition of bacterial dihydrofolate reductase (DHFR). This enzyme catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid, which is essential for bacterial nucleic acid synthesis. By inhibiting this step in the folate pathway, trimethoprim disrupts thymidine and purine synthesis, ultimately preventing bacterial DNA and RNA production. The drug demonstrates concentration-dependent bactericidal activity against susceptible organisms and has approximately 50,000-100,000 times greater affinity for bacterial DHFR than mammalian DHFR.

Indications

• FDA-approved indications:

- Acute, uncomplicated urinary tract infections caused by susceptible strains of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Enterobacter species - Acute otitis media in children (when used in combination with sulfamethoxazole) - Treatment and prophylaxis of Pneumocystis jirovecii pneumonia (in combination with sulfamethoxazole) - Acute exacerbations of chronic bronchitis in adults (in combination with sulfamethoxazole) - Shigellosis (in combination with sulfamethoxazole) - Traveler's diarrhea caused by enterotoxigenic E. coli (in combination with sulfamethoxazole)

• Off-label uses:

- Prophylaxis of urinary tract infections - Treatment of nocardiosis (in combination with other agents) - Treatment of toxoplasmosis (in combination with sulfadiazine)

Dosage and Administration

• 100 mg every 12 hours OR 200 mg once daily for 10 days

• CrCl >30 mL/min: No dosage adjustment necessary
• CrCl 15-30 mL/min: Reduce dose by 50%
• CrCl <15 mL/min: Use not recommended

• 4-6 mg/kg/day divided every 12 hours (maximum 200 mg/day)

• Oral administration with or without food
• Maintain adequate hydration during therapy
• Complete full course of therapy unless otherwise directed

Pharmacokinetics

• Volume of distribution: ~1.5 L/kg
• Protein binding: 42-46%

• Half-life: 8-11 hours (prolonged in renal impairment)
• Time to peak concentration: 1-4 hours post-dose

Contraindications

• Documented hypersensitivity to trimethoprim
• Megaloblastic anemia due to folate deficiency
• Concomitant use with dofetilide
• Severe renal impairment (CrCl <15 mL/min)
• Pregnancy (first trimester) due to theoretical teratogenic risk

Warnings and Precautions

• Hematologic effects: May cause thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia
• Hyperkalemia: Particularly in elderly patients, those with renal impairment, or those taking other medications that affect potassium
• Foliate deficiency: May precipitate or exacerbate folate deficiency, especially in malnourished, elderly, or chronic alcohol users
• Renal impairment: Requires dosage adjustment; monitor renal function
• Hepatic impairment: Use with caution; monitor liver function tests
• Elderly patients: Increased risk of hyperkalemia, thrombocytopenia, and folate deficiency
• Porphyria: May precipitate acute attacks in susceptible individuals

Drug Interactions

• Angiotensin-converting enzyme inhibitors: Increased risk of hyperkalemia
• Potassium-sparing diuretics: Increased risk of hyperkalemia
• Dofetilide: Contraindicated due to increased dofetilide concentrations and risk of torsades de pointes
• Warfarin: May enhance anticoagulant effect; monitor INR closely
• Phenytoin: May increase phenytoin levels
• Methotrexate: Increased risk of hematologic toxicity
• Cyclosporine: Increased risk of nephrotoxicity
• Oral hypoglycemics: May enhance hypoglycemic effect

Adverse Effects

• Nausea, vomiting, epigastric distress
• Rash, pruritus
• Headache
• Elevated liver enzymes

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Agranulocytosis
• Aplastic anemia
• Hepatotoxicity
• Hyperkalemia
• Interstitial nephritis
• Clostridium difficile-associated diarrhea

Monitoring Parameters

• Baseline:

- Complete blood count with differential - Renal function tests (BUN, creatinine) - Electrolytes (particularly potassium) - Liver function tests - Folate levels in high-risk patients

• During therapy:

- CBC weekly for first month, then periodically - Potassium levels (especially in elderly and those with renal impairment) - Signs of infection (fever, sore throat) - Signs of bleeding or bruising - Skin reactions

• Follow-up:

- Clinical response to therapy - Repeat urine culture if symptoms persist - Monitor for superinfection

Patient Education

• Complete the full course of therapy even if symptoms improve
• Take with food if gastrointestinal upset occurs
• Maintain adequate fluid intake (6-8 glasses of water daily)
• Report any signs of allergic reaction (rash, itching, swelling)
• Report unusual bleeding or bruising, sore throat, fever, or fatigue
• Use sun protection as increased photosensitivity may occur
• Inform all healthcare providers of trimethoprim use
• Do not use antacids within 2 hours of taking medication
• Women of childbearing potential should use effective contraception
• Notify physician if pregnancy is suspected or planned

References

1. Stevens DL, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):e10-e52. 2. Gupta K, et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103-e120. 3. Trimethoprim [package insert]. Food and Drug Administration; 2021. 4. Gilbert DN, et al. The Sanford Guide to Antimicrobial Therapy. 52nd ed. Antimicrobial Therapy, Inc.; 2022. 5. McEvoy GK, ed. AHFS Drug Information. American Society of Health-System Pharmacists; 2022. 6. Lexicomp Online. Trimethoprim: Drug Information. Wolters Kluwer Clinical Drug Information, Inc.; 2023.