COTRIM D.S.
Clinical safety rating: caution
Comprehensive clinical and safety monograph for COTRIM D.S. (COTRIM D.S.).
COTRIM D.S. is a combination of sulfamethoxazole, a competitive inhibitor of dihydropteroate synthase, and trimethoprim, a reversible inhibitor of dihydrofolate reductase. This sequential blockade of folate synthesis leads to bactericidal activity.
| Metabolism | Sulfamethoxazole is metabolized via N-acetylation and glucuronidation; trimethoprim undergoes metabolism to oxide and hydroxylated metabolites. Both are primarily eliminated renally. |
| Excretion | Sulfamethoxazole: ~20% unchanged in urine, remainder as acetylated and glucuronide metabolites. Trimethoprim: ~50-80% unchanged in urine, remainder as oxidative metabolites. Both undergo renal excretion via glomerular filtration and tubular secretion. Total renal elimination: 70-90% of dose combined. Biliary/fecal: <10%. |
| Half-life | Sulfamethoxazole: 9-12 hours (normal renal function). Trimethoprim: 8-11 hours. Both are prolonged in renal impairment (e.g., creatinine clearance <30 mL/min: >24 hours). Clinical context: dosing interval is typically 12 hours; dose adjustment required if CrCl <30 mL/min. |
| Protein binding | Sulfamethoxazole: ~70% bound to albumin. Trimethoprim: ~44% bound to albumin. |
| Volume of Distribution | Sulfamethoxazole: 0.2 L/kg (confined to extracellular fluid). Trimethoprim: 1.2-2.0 L/kg (tissue penetration, e.g., lungs, kidneys, prostate). Combined Vd reflects distribution to total body water and tissues. |
| Bioavailability | Oral (both components): 85-100% for sulfamethoxazole, 90-100% for trimethoprim. Food does not significantly affect absorption. IV: 100%. |
| Onset of Action | Oral: clinical effect (fever reduction, symptom improvement) within 24-48 hours. IV: onset within 12-24 hours. Not for immediate therapeutic effect. |
| Duration of Action | Dosing interval 12 hours provides sustained antibacterial effect over 24 hours. Concentration-dependent killing with post-antibiotic effect (PAE) of 2-4 hours for susceptible pathogens. |
| Molecular Weight | Trimethoprim: 290.32 Da; Sulfamethoxazole: 253.28 Da |
160 mg trimethoprim / 800 mg sulfamethoxazole (one double-strength tablet) orally every 12 hours.
| Dosage form | TABLET |
| Renal impairment | GFR 15-30 mL/min: reduce dose by 50% (e.g., one double-strength tablet every 24 hours). GFR <15 mL/min: contraindicated due to accumulation. |
| Liver impairment | Child-Pugh class A: no adjustment needed. Child-Pugh class B or C: use with caution; monitor for hepatotoxicity and reduce dose if toxicity develops. |
| Pediatric use | Based on trimethoprim component: 8 mg/kg/day divided every 12 hours for mild infections; for severe infections, up to 20 mg/kg/day divided every 6-8 hours. Maximum adult dose. |
| Geriatric use | Use lower doses due to increased risk of hyperkalemia, renal impairment, and bone marrow suppression. Monitor renal function and electrolytes. Consider avoiding in patients with GFR <30 mL/min. |
| 1st trimester | Avoid; risk of neural tube defects and congenital malformations due to folate antagonism. |
| 2nd trimester | Use only if clearly needed; theoretical risk of kernicterus due to sulfonamide displacement of bilirubin. |
| 3rd trimester | Avoid near term; risk of kernicterus and hemolytic anemia in G6PD-deficient neonates. |
Clinical note
Comprehensive clinical and safety monograph for COTRIM D.S. (COTRIM D.S.).
| Placental transfer | Both trimethoprim and sulfamethoxazole cross the placenta. Trimethoprim reaches fetal levels approximately 90% of maternal; sulfamethoxazole reaches 50-100% of maternal levels. |
| Breastfeeding | Contraindicated in breastfeeding infants with G6PD deficiency, hyperbilirubinemia, or prematurity; also contraindicated if infant has sulfonamide allergy. Excreted in breast milk in low amounts, but risk of kernicterus and hemolytic anemia in susceptible infants. Use caution and monitor infant. |
■ FDA Black Box Warning
Fatal hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Also associated with fatal hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Use caution in elderly and patients with folate deficiency.
| Serious Effects |
Hypersensitivity to trimethoprim, sulfonamides, or any componentMegaloblastic anemia due to folate deficiencySevere hepatic damageSevere renal impairment (CrCl <15 mL/min)Previous drug-induced thrombocytopenia with sulfonamidesG6PD deficiency (relative, but absolute in high-risk patients)Breastfeeding infants with G6PD deficiency or hyperbilirubinemiaPorphyria
| Precautions | Risk of severe hypersensitivity reactions (SJS, TEN), Hematologic toxicity: monitor CBC periodically, Hepatic injury: discontinue if signs of liver damage, Renal impairment: dose adjustment required, Hyperkalemia risk with high-dose trimethoprim, Elderly patients at increased risk for adverse effects, Folate deficiency: consider folinic acid supplementation |
| Food/Dietary |
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| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | First trimester: Avoid due to folate antagonist (trimethoprim) linked to neural tube defects and cardiovascular malformations (risk ratio ~2-3). Second/third trimesters: Risk of kernicterus in neonates from sulfonamide displacing bilirubin; avoid near term. |
| Fetal Monitoring | Monitor CBC with differential, renal function, and liver enzymes. Fetal ultrasound for neural tube defects if exposed in first trimester. Monitor newborn for jaundice and kernicterus. |
| Fertility Effects | Trimethoprim may impair spermatogenesis and reduce sperm count in males. Folate antagonism may affect female fertility by interfering with folate-dependent processes. |
| Avoid potassium-rich foods or supplements as hyperkalemia may occur. High-protein foods may reduce absorption; take on an empty stomach if possible. No significant interaction with alcohol, but limit to moderate intake as it may worsen gastrointestinal irritation. |
| Clinical Pearls | COTRIM D.S. (double strength) contains 800 mg sulfamethoxazole and 160 mg trimethoprim. Monitor renal function and potassium levels, as hyperkalemia can occur, especially in elderly or those with renal impairment. Avoid use in G6PD deficiency due to risk of hemolytic anemia. Use with caution in patients taking warfarin (potentiates anticoagulant effect), methotrexate (increases toxicity), or ACE inhibitors (increases risk of hyperkalemia). Adjust dose in creatinine clearance <30 mL/min; contraindicated if <15 mL/min. |
| Patient Advice | Take with a full glass of water to prevent crystalluria; maintain adequate fluid intake throughout treatment. · Complete the full course even if symptoms improve; do not skip doses. · Avoid prolonged sun exposure and use sunscreen as photosensitivity may occur. · Report rash, fever, sore throat, easy bruising, or unusual bleeding immediately. · If you have a history of kidney disease, liver disease, or glucose-6-phosphate dehydrogenase deficiency, inform your doctor before use. |