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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SULFAMETHOPRIM (SULFAMETHOPRIM).
| Breastfeeding | Excreted into breast milk; M/P ratio not established. Risk of kernicterus in jaundiced or G6PD-deficient infants; caution advised. Consider alternative if infant has hyperbilirubinemia or G6PD deficiency. |
| 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. |
■ FDA Black Box Warning
Sulfamethoxazole/trimethoprim is contraindicated with concomitant use of dofetilide due to increased risk of serious ventricular arrhythmias.
| Serious Effects |
["History of hypersensitivity to sulfonamides or trimethoprim","Known megaloblastic anemia due to folate deficiency","Severe hepatic or renal impairment (CrCl <15 mL/min)","Pregnancy (especially first trimester and near term) due to risk of kernicterus and neural tube defects","Neonates less than 2 months of age","Concomitant use with dofetilide"]
| 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"] |
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| 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. |