TRIMETHOPRIM
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Trimethoprim inhibits bacterial dihydrofolate reductase (DHFR), preventing the reduction of dihydrofolate to tetrahydrofolate, thereby inhibiting thymidine synthesis and bacterial DNA replication. It has bacteriostatic activity against susceptible organisms.
| Metabolism | Trimethoprim is primarily metabolized in the liver via oxidative O-demethylation and N-oxidation. Metabolites include 1-oxide, 3-oxide, and 4-hydroxy derivatives. The drug undergoes conjugation with glucuronic acid. The cytochrome P450 enzyme system plays a minor role; specific isoforms are not well characterized. Approximately 80-90% of the drug is excreted unchanged in the urine within 24 hours via glomerular filtration and tubular secretion. |
| Excretion | Renal excretion: approximately 50-60% of the dose is excreted unchanged in urine via glomerular filtration and tubular secretion; about 10-20% as metabolites (conjugated and oxidized forms); biliary/fecal excretion accounts for less than 10%. |
| Half-life | Terminal elimination half-life is 8-12 hours in adults with normal renal function; prolonged to 20-40 hours in severe renal impairment (CrCl <15 mL/min). |
| Protein binding | Approximately 40-45% bound to plasma proteins (mainly albumin). |
| Volume of Distribution | 1.2-1.8 L/kg, indicating extensive tissue distribution including lungs, kidneys, and prostate. |
| Bioavailability | Oral: 90-100% (well absorbed). |
| Onset of Action | Oral: 2-4 hours; intravenous: rapid, within 30 minutes. |
| Duration of Action | Oral: 12 hours; intravenous: 12 hours. |
| Molecular Weight | 290.32 |
Adult: 100 mg orally twice daily or 200 mg once daily for uncomplicated UTI; for severe infections, up to 20 mg/kg/day in divided doses. IV: 10-20 mg/kg/day divided every 6-12 hours.
| Dosage form | TABLET |
| Renal impairment | CrCl >30 mL/min: No adjustment. CrCl 15-30 mL/min: 50% of normal dose. CrCl <15 mL/min: Not recommended or use 50% dose with therapeutic drug monitoring; for hemodialysis, administer after dialysis. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Consider dose reduction (use with caution). Child-Pugh C: Avoid use or use with caution; no specific guidelines. |
| Pediatric use | Infants >6 weeks and children: 4-6 mg/kg/day orally in two divided doses; for P. jirovecii pneumonia, 15-20 mg/kg/day IV in 3-4 divided doses (with sulfamethoxazole). |
| Geriatric use | Use reduced initial dose (e.g., 100 mg once daily) due to age-related renal decline; monitor renal function and adjust based on CrCl; increased risk of hyperkalemia, avoid in elderly with CrCl <15 mL/min. |
| 1st trimester | Contraindicated in first trimester due to teratogenic effects (folate antagonist). Use only if benefit outweighs risk. |
| 2nd trimester | Use with caution; folate supplementation recommended. Potential risk of neural tube defects. |
| 3rd trimester | Avoid near term due to risk of neonatal hyperbilirubinemia and kernicterus (displaces bilirubin from albumin). |
Clinical note
May increase levels of phenytoin and digoxin Can cause hyperkalemia and blood dyscrasias.
| Placental transfer | Crosses placenta rapidly; peak cord blood levels 50-100% of maternal serum levels. |
| Breastfeeding | Excreted into breast milk in small amounts; considered compatible with breastfeeding, but monitor infant for rash, diarrhea, or changes in gut flora. Use caution in infants with G6PD deficiency or hyperbilirubinemia. |
■ FDA Black Box Warning
None
| Common Effects | Nausea |
| Serious Effects |
Hypersensitivity to trimethoprim or any componentMegaloblastic anemia due to folate deficiencySevere hepatic impairmentKnown Glucose-6-phosphate dehydrogenase (G6PD) deficiency
| Precautions | Hematotoxicity: Trimethoprim may cause megaloblastic anemia, leukopenia, neutropenia, or thrombocytopenia, especially in patients with folate deficiency, elderly, or those on prolonged therapy. Folinic acid (leucovorin) can be administered to prevent or reverse toxicity without antagonizing antibacterial effect., Renal Impairment: Dose adjustment required in patients with creatinine clearance <30 mL/min; increased risk of hyperkalemia due to potassium-sparing diuretic-like effect., Hypersensitivity Reactions: Rash and pruritus are common; rare severe reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis., Hyperkalemia: Risk increases with high doses, concomitant use of potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers, or in patients with renal impairment., Porphyria: May precipitate acute attacks in patients with porphyria; use with caution., Pregnancy: Use during the first trimester is associated with neural tube defects; avoid in pregnancy unless benefits outweigh risks. Additionally, caution in lactation., Elderly: Higher risk of adverse effects including bone marrow suppression and hyperkalemia., G6PD Deficiency: Use may rarely cause hemolysis; caution advised. |
Loading safety data…
| Lactation Rating |
| L2 (Safer) |
| Teratogenic Risk | Trimethoprim is a folate antagonist. First trimester exposure is associated with increased risk of neural tube defects, cardiovascular malformations, and oral clefts due to folate depletion. Second and third trimester use may be associated with low birth weight and preterm delivery. Risk is dose-dependent and mitigated by folate supplementation. |
| Fetal Monitoring | Monitor complete blood count (CBC), serum folate levels, and renal function in mother. Fetal ultrasound for neural tube defects if exposed in first trimester. Assess for signs of megaloblastic anemia in mother and infant. In neonates, monitor for hyperbilirubinemia and hemolysis if G6PD deficient. |
| Fertility Effects | Trimethoprim may impair fertility due to its antifolate effect, potentially reducing sperm quality in males and ovulation in females. Folate supplementation may mitigate these effects. Use with caution in patients planning conception. |
| Food/Dietary | No significant food interactions. However, avoid excessive potassium-rich foods (bananas, oranges, potatoes) if hyperkalemia risk. Maintain adequate hydration; do not restrict water. Alcohol does not interact directly but may worsen gastrointestinal side effects. |
| Clinical Pearls | Trimethoprim achieves high concentrations in prostatic tissue and vaginal fluid, making it effective for prostatitis and uncomplicated cystitis. It is often combined with sulfamethoxazole (co-trimoxazole) for synergy, but double-strength tablets (160 mg/800 mg) are not interchangeable with single-strength. Use with caution in elderly patients and those with renal impairment due to risk of hyperkalemia. Monitor serum potassium and creatinine. Trimethoprim can cause false elevation in serum creatinine by inhibiting tubular secretion. It may interact with other dihydrofolate reductase inhibitors like methotrexate, increasing toxicity. |
| Patient Advice | Take exactly as prescribed; do not skip doses or stop early even if you feel better. · Drink plenty of fluids (at least 2 liters per day) to prevent crystal formation. · Avoid prolonged sun exposure; use sunscreen as this drug may increase photosensitivity. · Report any skin rash, sore throat, fever, or unusual bleeding/bruising immediately. · Inform your doctor if you are pregnant or breastfeeding. · Avoid using potassium supplements or salt substitutes without consulting your doctor. · Take with a full glass of water; can be taken with or without food. |