TRIMETH/SULFA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRIMETH/SULFA (TRIMETH/SULFA).
Trimethoprim inhibits bacterial dihydrofolate reductase (DHFR), blocking conversion of dihydrofolate to tetrahydrofolate; sulfamethoxazole inhibits bacterial dihydropteroate synthase, blocking incorporation of para-aminobenzoic acid into folic acid. Sequential blockade of folate synthesis produces synergistic bactericidal effect.
| Metabolism | Sulfamethoxazole is primarily metabolized via N-acetylation and glucuronidation; trimethoprim undergoes O-demethylation and N-oxidation. Major enzyme involved: CYP2C9 (sulfamethoxazole hydroxylamine formation). Both are excreted renally. |
| Excretion | Trimethoprim: 50-60% unchanged in urine; Sulfamethoxazole: 15-30% unchanged in urine, with acetylation and glucuronidation metabolites. Approximately 80-90% of dose recovered in urine within 72 hours; remainder via feces. |
| Half-life | Trimethoprim: 8-11 hours; Sulfamethoxazole: 9-11 hours. Prolonged in renal impairment (up to 24-30 hours for both). Clinical context: Dosing interval is typically 12 hours in normal renal function; adjust in CrCl <15-30 mL/min. |
| Protein binding | Trimethoprim: 40-45% bound to plasma proteins; Sulfamethoxazole: 60-70% bound to albumin. Binding is saturable and decreased in uremia. |
| Volume of Distribution | Trimethoprim: 1.3-1.8 L/kg (total body water, extensive tissue penetration, CSF levels 25-50% of serum); Sulfamethoxazole: 0.2-0.4 L/kg (primarily extracellular fluid, lower CSF penetration). |
| Bioavailability | Oral: Trimethoprim 100%; Sulfamethoxazole 85-90%. Bioavailability is high and complete for both components. Intravenous: 100%. |
| Onset of Action | Oral: 1-4 hours to reach therapeutic plasma concentrations; clinical effect (antimicrobial) begins within 12-24 hours. Intravenous: immediate therapeutic levels; clinical response usually within 12-24 hours. |
| Duration of Action | Antimicrobial effect persists for approximately 12 hours after a single dose, consistent with dosing every 12 hours. Clinical duration: Treatment course typically 5-14 days depending on infection. |
| Molecular Weight | Trimethoprim: 290.32 Da; Sulfamethoxazole: 253.28 Da |
1 double-strength tablet (160 mg trimethoprim / 800 mg sulfamethoxazole) orally every 12 hours for 14 days.
| Dosage form | SUSPENSION |
| Renal impairment | CrCl >30 mL/min: No adjustment. CrCl 15-30 mL/min: 50% of usual dose every 12 hours. CrCl <15 mL/min: Not recommended unless hemodialysis is available. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Use with caution, consider dose reduction. Child-Pugh C: Contraindicated due to risk of hepatotoxicity. |
| Pediatric use | 8 mg/kg/day trimethoprim and 40 mg/kg/day sulfamethoxazole in 2 divided doses. |
| Geriatric use | Monitor renal function and potassium levels; consider lower initial doses; use with caution due to increased risk of hyperkalemia and sulfonamide side effects. |
| 1st trimester | Avoid in first trimester due to teratogenic risk (folate antagonist). Associated with neural tube defects, cardiovascular malformations. |
| 2nd trimester | Use only if clearly needed; risk of jaundice and hemolytic anemia in neonates if used near term. |
| 3rd trimester | Avoid near term (after 32 weeks) because sulfamethoxazole displaces bilirubin from albumin leading to kernicterus. |
Clinical note
Comprehensive clinical and safety monograph for TRIMETH/SULFA (TRIMETH/SULFA).
| Placental transfer | Both trimethoprim and sulfamethoxazole cross the placenta readily. Trimethoprim achieves fetal serum concentrations approximately 50-100% of maternal levels; sulfamethoxazole achieves fetal concentrations 75-100% of maternal levels. |
| Breastfeeding | Both components are excreted into breast milk. Amounts are low but may cause kernicterus in premature or ill infants. Avoid in breastfeeding infants with G6PD deficiency. Usually considered compatible if infant is healthy and full-term. |
■ FDA Black Box Warning
Fatal hypersensitivity reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hepatic necrosis have occurred. Discontinue at first sign of rash. Contraindicated in patients with prior hypersensitivity to sulfonamides or trimethoprim.
| Serious Effects |
Megaloblastic anemia due to folate deficiencySevere hepatic parenchymal damageSevere renal impairment (CrCl <15 mL/min) unless dialysis availableKnown hypersensitivity to sulfonamides or trimethoprimHistory of drug-induced thrombocytopenia with a sulfonamideInfants <2 months of agePregnancy (especially near term)Breastfeeding in ill, preterm, or G6PD-deficient infants
| Precautions | Increased risk of hyperkalemia, especially in elderly, renal impairment, or high doses (trimethoprim inhibits renal potassium excretion), Folate deficiency may occur with prolonged use; monitor CBC and supplement if needed, Hemolytic anemia in G6PD deficiency, Increased INR with warfarin (sulfamethoxazole inhibits CYP2C9), May cause hypoglycemia (sulfamethoxazole potentiates sulfonylureas), Interstitial nephritis, crystaluria (ensure adequate hydration) |
| Food/Dietary |
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| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | First trimester: Folate antagonist; neural tube defects, cardiovascular malformations, oral clefts, urinary tract anomalies reported. Second/third trimesters: risk of kernicterus in neonates due to bilirubin displacement from albumin; avoid near term. |
| Fetal Monitoring | Monitor CBC, serum folate levels; assess for signs of megaloblastic anemia (macrocytosis). Fetal ultrasound for neural tube defects if exposed in first trimester. Newborn bilirubin monitoring after exposure near term. |
| Fertility Effects | No known adverse effects on fertility. Trimethoprim may inhibit folate metabolism, but impact on fertility is not clinically significant. |
| Avoid large amounts of potassium-rich foods (e.g., bananas, oranges, potatoes, spinach) as TMP-SMX can increase serum potassium. Limit high-tyramine foods (aged cheese, cured meats) in some patients; no significant interaction. Maintain adequate hydration, avoid alcohol. |
| Clinical Pearls | Trimethoprim/sulfamethoxazole (TMP-SMX) is a fixed-dose combination antibiotic with synergistic activity. Clinical pearls: 1) Use for Pneumocystis jirovecii pneumonia (PJP) prophylaxis or treatment; 2) Monitor for hyperkalemia, especially in elderly or renal impairment; 3) Can cause photosensitivity; 4) Avoid near term in pregnancy due to risk of kernicterus in neonate; 5) Check renal function and potassium levels; 6) May potentiate warfarin (increase INR) and sulfonylureas (hypoglycemia). |
| Patient Advice | Take exactly as prescribed; do not skip doses or stop early. · Drink plenty of fluids to prevent kidney stones. · Avoid prolonged sun exposure; use sunscreen. · Report any rash, fever, sore throat, or unusual bleeding. · If you have diabetes, monitor blood sugar closely as it may lower blood glucose. · Inform your doctor if you are pregnant, breastfeeding, or have kidney disease. · Take missed dose as soon as remembered unless near next dose; do not double. · Complete full course even if you feel better. |