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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for COTRIM D.S. (COTRIM D.S.).
| Breastfeeding | Both components excreted in breast milk. M/P ratio for trimethoprim ~0.5-1.5, sulfamethoxazole ~0.2-0.5. Avoid in G6PD-deficient infants. American Academy of Pediatrics considers compatible with caution. |
| 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 |
■ 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 sulfonamides or trimethoprim","Megaloblastic anemia due to folate deficiency","Marked hepatic damage or severe renal impairment (CrCl <15 mL/min)","Concomitant use with dofetilide (risk of serious arrhythmias)"]
| 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"] |
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| 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. |