COTRIM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for COTRIM (COTRIM).
COTRIM is a combination of trimethoprim and sulfamethoxazole; sulfamethoxazole inhibits dihydropteroate synthase, and trimethoprim inhibits dihydrofolate reductase, sequentially blocking bacterial folate synthesis.
| Metabolism | Trimethoprim is primarily metabolized by the liver via CYP450 enzymes (CYP3A4, CYP1A2) and excreted in urine; sulfamethoxazole undergoes N-acetylation and glucuronidation, also excreted renally. |
| Excretion | Renal: 50-70% unchanged sulfamethoxazole, 15-30% N4-acetylated metabolite; trimethoprim: 50-60% unchanged, 10-20% metabolites. Biliary/fecal: minimal. |
| Half-life | Sulfamethoxazole: 9-11 hours (normal renal function); trimethoprim: 8-10 hours. Extended in renal impairment (SMX up to 30h, TMP up to 24h). |
| Protein binding | Sulfamethoxazole: 70% bound to albumin; trimethoprim: 44% bound to alpha-1 acid glycoprotein and albumin. |
| Volume of Distribution | Sulfamethoxazole: 0.2-0.3 L/kg; trimethoprim: 1.3-2.0 L/kg. TMP distributes extensively into tissues, including CNS (50% of serum concentration). |
| Bioavailability | Oral: 85-100% for both components; IV: 100%. |
| Onset of Action | Oral: 1-4 hours; IV: 30-60 minutes. |
| Duration of Action | 12-24 hours; clinical effect persists for duration of therapy. Half-life determines dosing interval (usually q12h). |
| Molecular Weight | Sulfamethoxazole: 253.3 Da; Trimethoprim: 290.3 Da; Fixed combination (80/400) not applicable. |
1 double-strength tablet (160 mg trimethoprim + 800 mg sulfamethoxazole) orally every 12 hours for 5-14 days; 15-20 mg/kg/day (based on trimethoprim) IV divided every 6-8 hours for severe infections.
| Dosage form | TABLET |
| Renal impairment | CrCl >30 mL/min: no adjustment; CrCl 15-30 mL/min: reduce dose by 50%; CrCl <15 mL/min: contraindicated unless for prophylaxis against Pneumocystis jirovecii, in which case use 50% dose. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: use with caution, monitor liver function; Child-Pugh C: contraindicated due to risk of hepatotoxicity. |
| Pediatric use | Pneumocystis jirovecii pneumonia: 15-20 mg/kg/day (based on trimethoprim) IV divided every 6-8 hours for 21 days; mild infections: 8-12 mg/kg/day oral divided every 12 hours; maximum: 640 mg/day trimethoprim. |
| Geriatric use | Assess renal function; CrCl >30 mL/min: standard adult dosing; reduce dose or extend interval if CrCl 15-30 mL/min; avoid if CrCl <15 mL/min; monitor for electrolyte abnormalities and hypersensitivity. |
| 1st trimester | Contraindicated due to teratogenicity (folate antagonism); associated with neural tube defects and cardiovascular anomalies. |
| 2nd trimester | Contraindicated; risk of kernicterus due to bilirubin displacement from albumin by sulfonamides. |
| 3rd trimester | Contraindicated; risk of kernicterus and hemolytic anemia in G6PD-deficient neonates. |
Clinical note
Comprehensive clinical and safety monograph for COTRIM (COTRIM).
| Placental transfer | Both components cross the placenta; sulfamethoxazole achieves fetal concentrations ~50-100% of maternal levels; trimethoprim crosses readily with fetal levels exceeding maternal. This transfer underlies the risk of teratogenicity and kernicterus. |
| Breastfeeding | Both sulfamethoxazole (SMX) and trimethoprim (TMP) are excreted into breast milk; concentrations are low, but caution is advised in infants with G6PD deficiency, hyperbilirubinemia, or prematurity. American Academy of Pediatrics considers compatible with breastfeeding, but alternatives preferred. |
■ FDA Black Box Warning
Fatal hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS); agranulocytosis, aplastic anemia, and other blood dyscrasias; use in patients with G6PD deficiency may cause hemolytic anemia.
| Serious Effects |
Hypersensitivity to sulfonamides, trimethoprim, or any componentMegaloblastic anemia due to folate deficiencySevere hepatic or renal impairment (CrCl <15 mL/min)Concurrent methotrexate therapyPregnancy (especially first trimester and near term)Breastfeeding infants with G6PD deficiency or hyperbilirubinemia
| Precautions | Monitor for hypersensitivity reactions; avoid use in elderly with renal impairment due to risk of sulfonamide-induced blood dyscrasias; monitor renal function and electrolytes (hyperkalemia with high doses); caution in folate deficiency; use with other drugs prolonging QT interval; monitor for neutropenia with prolonged therapy. |
| Food/Dietary | Avoid high-potassium foods (e.g., bananas, oranges, potatoes) if on high doses or with renal impairment; avoid alcohol as it may cause disulfiram-like reaction; avoid folic acid-rich foods (e.g., liver) as they may reduce efficacy. |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy category C/D. First trimester: Folate antagonist; neural tube defects, cardiovascular malformations, cleft palate reported. Second/third trimester: Kernicterus risk in neonate due to bilirubin displacement; hemolytic anemia in G6PD deficiency. Avoid near term. |
| Fetal Monitoring | Monitor CBC, folate levels, liver function, and renal function. In late pregnancy, monitor neonatal bilirubin and signs of kernicterus. Assess G6PD status before use. |
| Fertility Effects | No direct evidence of impaired fertility. Folate antagonism may theoretically affect ovulation/spermatogenesis; clinical significance unknown. Reversible upon discontinuation. |
| Clinical Pearls | Monitor for hyperkalemia, especially in elderly or patients with renal impairment; sulfonamide component can cause crystalluria — ensure adequate hydration; beware of hypoglycemia when used with sulfonylureas; avoid near term of pregnancy due to risk of kernicterus. |
| Patient Advice | Take with a full glass of water to prevent kidney stones. · Complete the full course even if feeling better. · Avoid prolonged sun exposure and use sunscreen due to photosensitivity risk. · Report any rash, fever, sore throat, or unusual bruising immediately. · Do not take if you are allergic to sulfa drugs. |