SULFAMETHOPRIM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SULFAMETHOPRIM (SULFAMETHOPRIM).
Sulfamethoprim is a combination of sulfamethoxazole and trimethoprim. Sulfamethoxazole inhibits bacterial dihydropteroate synthase, blocking folic acid synthesis; trimethoprim inhibits bacterial dihydrofolate reductase, also blocking folic acid synthesis. This sequential blockade produces bactericidal effects.
| Metabolism | Sulfamethoxazole is metabolized via N-acetylation and glucuronidation; trimethoprim is metabolized via O-demethylation and alpha-hydroxylation. Enzymes involved include NAT2 for sulfamethoxazole and CYP3A4 for trimethoprim. |
| Excretion | Renal: 60-80% as unchanged drug via glomerular filtration and tubular secretion; biliary: 5-10%; fecal: <5%. |
| Half-life | Terminal elimination half-life: 8-12 hours in adults with normal renal function. Prolonged in renal impairment (up to 24-48 hours). |
| Protein binding | Extensive: 80-90% bound primarily to albumin; slight binding to α1-acid glycoprotein. |
| Volume of Distribution | Vd: 0.8-1.2 L/kg. Distributes widely into body fluids, including pleural, peritoneal, synovial, and ocular fluids; crosses blood-brain barrier and placenta. |
| Bioavailability | Oral: 95-100%; well absorbed from gastrointestinal tract. |
| Onset of Action | Oral: 30-60 minutes; Intravenous: immediate; Onset of antibacterial effect occurs within 24 hours. |
| Duration of Action | Duration: 12-24 hours post-dose. Clinical effect persists with trough concentrations above MIC. |
| Molecular Weight | 253.26 |
Oral or intravenous: 800 mg sulfamethoxazole / 160 mg trimethoprim every 12 hours.
| Dosage form | Injectable |
| Renal impairment | CrCl >30 mL/min: no adjustment; CrCl 15-30 mL/min: reduce dose by 50%; CrCl <15 mL/min: not recommended (alternative therapy preferred). |
| Liver impairment | No specific Child-Pugh based guidelines; use caution in severe hepatic impairment due to potential hepatotoxicity. |
| Pediatric use | Based on trimethoprim component: 8 mg/kg/day trimethoprim (plus 40 mg/kg/day sulfamethoxazole) divided every 12 hours; maximum single dose: 160 mg trimethoprim. |
| Geriatric use | Caution due to increased risk of hyperkalemia, renal impairment, and sulfonamide adverse effects; monitor renal function and serum potassium; adjust dose for renal function as per renal adjustment guidelines. |
| 1st trimester | Avoid; associated with neural tube defects and other congenital malformations (folate antagonist). |
| 2nd trimester | Avoid in late second trimester due to risk of hyperbilirubinemia and kernicterus in neonates. |
| 3rd trimester | Avoid; risk of kernicterus and hemolytic anemia in G6PD-deficient neonates. |
Clinical note
Comprehensive clinical and safety monograph for SULFAMETHOPRIM (SULFAMETHOPRIM).
| Placental transfer | Crosses placenta freely; achieves fetal serum concentrations approximately 50-80% of maternal levels. |
| Breastfeeding | Excreted into breast milk in low amounts; may cause hemolytic anemia in G6PD-deficient infants and interfere with folate metabolism. Use caution in preterm or ill infants. American Academy of Pediatrics considers compatible with breastfeeding, but alternative agents preferred. |
■ FDA Black Box Warning
Sulfamethoxazole/trimethoprim is contraindicated with concomitant use of dofetilide due to increased risk of serious ventricular arrhythmias.
| Serious Effects |
Hypersensitivity to sulfonamides or trimethoprimMegaloblastic anemia due to folate deficiencySevere hepatic or renal impairmentPregnancy (especially first trimester and near term)Breastfeeding infants with G6PD deficiency or hyperbilirubinemia
| Precautions | Severe hypersensitivity reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, Hematologic toxicity including agranulocytosis, aplastic anemia, and thrombocytopenia, Folate deficiency and megaloblastic anemia with prolonged use, Hyperkalemia in patients with renal impairment or those on potassium-sparing diuretics, Hypoglycemia in malnourished or diabetic patients, Increased risk of kernicterus in neonates due to bilirubin displacement from albumin, Renal impairment and interstitial nephritis |
| Food/Dietary | Avoid high-potassium foods (e.g., bananas, oranges, potatoes, spinach) in large amounts due to risk of hyperkalemia. Limit salt substitutes containing potassium. Take with food if gastrointestinal upset occurs. Avoid alcohol. Ensure adequate hydration with water; avoid excessive caffeine or diuretics. |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Risk of congenital malformations (neural tube defects, cardiovascular anomalies) due to folate antagonism; contraindicated. Second/third trimester: Risk of kernicterus in neonates (bilirubin displacement) and hemolytic anemia in G6PD-deficient patients; avoid near term. |
| Fetal Monitoring | Maternal: CBC, renal function, liver function, folate levels. Fetal: Ultrasound for neural tube defects if exposed in first trimester; neonatal monitoring for jaundice, hemolysis, G6PD status. |
| Fertility Effects | No direct evidence of impaired fertility in humans; theoretical risk of folate antagonism affecting spermatogenesis and ovulation, but not clinically significant with short-term use. |
| Clinical Pearls | Sulfamethoprim is a fixed-dose combination of sulfamethoxazole and trimethoprim. Monitor renal function and potassium levels, especially in elderly patients. Adjust dose in renal impairment (CrCl <30 mL/min: avoid or reduce dose). Avoid in pregnancy (first trimester) and lactation. Use with caution in patients with folate deficiency, G6PD deficiency, or sulfonamide allergy. Watch for photosensitivity and severe skin reactions (Stevens-Johnson syndrome). May increase effect of warfarin, phenytoin, and sulfonylureas. |
| Patient Advice | Take with a full glass of water to prevent crystalluria. · Complete the full course even if you feel better. · Drink plenty of fluids while on this medication. · Avoid prolonged sun exposure and use sunscreen or protective clothing. · Report any rash, fever, sore throat, or unusual bleeding immediately. · Do not take if pregnant or breastfeeding without consulting your doctor. · Avoid alcohol as it may increase side effects. · Inform your doctor of all other medications, especially blood thinners, seizure meds, and diabetes meds. |