SEPTRA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SEPTRA (SEPTRA).
SEPTRA (trimethoprim/sulfamethoxazole) is a combination of two antifolate agents: sulfamethoxazole inhibits dihydropteroate synthase, blocking the conversion of PABA to dihydrofolic acid; trimethoprim inhibits dihydrofolate reductase, preventing the reduction of dihydrofolic acid to tetrahydrofolic acid. This sequential blockade disrupts bacterial folate synthesis and nucleic acid production.
| Metabolism | Sulfamethoxazole is primarily metabolized via N-acetylation in the liver, with some glucuronidation; trimethoprim is metabolized by O-demethylation and N-oxidation. Both are excreted renally. |
| Excretion | Renal excretion of unchanged sulfamethoxazole (~20%) and trimethoprim (~50-60%) with additional hepatic metabolism (acetylation, glucuronidation) of sulfamethoxazole; total renal elimination accounts for ~80-90% of the dose (sulfamethoxazole 30% parent, 40% metabolites; trimethoprim 60-80% parent, remainder as metabolites). Biliary/fecal <5%. |
| Half-life | Sulfamethoxazole: 9-12 hours (normal renal function); Trimethoprim: 8-11 hours (normal renal function). In severe renal impairment (CrCl <15 mL/min), half-life prolongs significantly (up to 24-30 hours for sulfamethoxazole, 20-30 hours for trimethoprim). |
| Protein binding | Sulfamethoxazole: 65-70% bound primarily to albumin; Trimethoprim: 40-45% bound primarily to albumin. |
| Volume of Distribution | Sulfamethoxazole: Vd 0.36 L/kg (reflects distribution into extracellular fluid); Trimethoprim: Vd 1.3-1.8 L/kg (indicates extensive tissue penetration and accumulation in tissues, e.g., prostate, lungs, kidneys). |
| Bioavailability | Oral: sulfamethoxazole 85-100%, trimethoprim 90-100% (both well absorbed; absorption of trimethoprim may be slightly delayed by food). |
| Onset of Action | Oral: clinical effect within 24-48 hours (therapeutic concentrations achieved in 2-4 hours); intravenous: onset within 12-24 hours due to rapid attainment of steady-state. |
| Duration of Action | Therapeutic effect persists for 12-24 hours after a single dose; dosing interval is typically every 12 hours to maintain adequate serum levels above MIC for susceptible pathogens. |
Trimethoprim-sulfamethoxazole (TMP-SMX) 160 mg/800 mg (double strength) orally every 12 hours; for severe infections, intravenous dosing: 8-10 mg/kg/day (TMP component) divided every 6, 8, or 12 hours.
| Dosage form | SUSPENSION |
| Renal impairment | CrCl >30 mL/min: no adjustment; CrCl 15-30 mL/min: reduce dose by 50% (e.g., 1 DS tablet every 24 hours); CrCl <15 mL/min: contraindicated (except for prophylaxis of Pneumocystis jirovecii pneumonia with TMP-SMX 80/400 mg every 24 hours). |
| Liver impairment | No specific guidelines; use caution in severe hepatic impairment (Child-Pugh C) due to potential hepatotoxicity and altered clearance. |
| Pediatric use | For urinary tract infection or acute otitis media: TMP 8 mg/kg/day + SMX 40 mg/kg/day orally divided every 12 hours. For Pneumocystis jirovecii pneumonia: TMP 15-20 mg/kg/day + SMX 75-100 mg/kg/day intravenously divided every 6 or 8 hours. |
| Geriatric use | Increased risk of hyperkalemia, thrombocytopenia, and allergic reactions; consider dose reduction based on renal function; monitor potassium and renal function closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SEPTRA (SEPTRA).
| Breastfeeding | Both trimethoprim and sulfamethoxazole are excreted in breast milk. M/P ratio for trimethoprim: ~1.25; sulfamethoxazole: ~0.1. Use caution in nursing mothers of infants with G6PD deficiency, hyperbilirubinemia, or illness. Avoid in infants <2 months due to risk of kernicterus. |
| Teratogenic Risk | First trimester: FDA Category D. Folate antagonist; increases risk of neural tube defects, cardiovascular malformations, and oral clefts. Second and third trimesters: Risk of kernicterus in neonates due to bilirubin displacement, especially in G6PD deficiency; avoid near term. |
■ FDA Black Box Warning
Fatal reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias have been reported. Hypersensitivity reactions may occur even with repeat administration. Use caution in patients with hypersensitivity to sulfonamides or thiazide diuretics.
| Serious Effects |
["Hypersensitivity to trimethoprim, sulfonamides, or any component","Megaloblastic anemia due to folate deficiency","Children under 2 months of age","Severe hepatic or renal impairment (CrCl <15 mL/min)","Pregnancy (especially third trimester) and lactation","Concurrent use with dofetilide (QT prolongation)"]
| Precautions | ["Folate deficiency: May cause megaloblastic anemia; consider leucovorin rescue","Hypersensitivity: Cross-reactivity with sulfonamides; monitor for rash, fever, arthralgia","Hematologic: Risk of agranulocytosis, aplastic anemia; monitor CBC","Hepatic: Risk of hepatic necrosis; discontinue if hepatotoxicity suspected","Renal: Interstitial nephritis, crystalluria; maintain adequate hydration","Electrolytes: Hyperkalemia, especially in elderly or with renal impairment","Acute psychosis: Rarely reported, especially in elderly","Phototoxicity: Avoid prolonged sun exposure"] |
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| Fetal Monitoring |
| Monitor maternal CBC, renal function, and folate levels. Assess for hypersensitivity reactions, hemolysis in G6PD deficiency. Fetal ultrasound for neural tube defects if exposed in first trimester; monitor neonatal bilirubin levels near term. |
| Fertility Effects | No known significant impact on human fertility. In animal studies, high doses of trimethoprim may impair spermatogenesis; clinical relevance uncertain. |