SULFAMETHOXAZOLE AND TRIMETHOPRIM DOUBLE STRENGTH
Clinical safety rating: avoid
May increase levels of phenytoin and digoxin Can cause hyperkalemia and blood dyscrasias.
Sulfamethoxazole inhibits bacterial dihydropteroate synthase, blocking folic acid synthesis. Trimethoprim inhibits bacterial dihydrofolate reductase, blocking reduction of dihydrofolate to tetrahydrofolate. Sequential blockade produces bactericidal effect.
| Metabolism | Sulfamethoxazole is metabolized via N-acetylation (NAT2) and glucuronidation. Trimethoprim undergoes O-demethylation, N-oxidation, and conjugative metabolism. CYP450 involvement is minimal. |
| Excretion | Both sulfamethoxazole and trimethoprim are primarily excreted via the kidneys. Sulfamethoxazole: ~30% as unchanged drug, ~50% as N4-acetyl metabolite; trimethoprim: ~80% as unchanged drug. Fecal elimination is minimal (<5%). |
| Half-life | Sulfamethoxazole: 9-11 hours; trimethoprim: 8-11 hours. In severe renal impairment (CrCl <15 mL/min), half-life prolongs significantly (up to 30 hours for trimethoprim). |
| Protein binding | Sulfamethoxazole: ~70% bound to albumin; trimethoprim: ~44% bound to albumin. |
| Volume of Distribution | Sulfamethoxazole: ~0.21 L/kg; trimethoprim: ~1.2-2.2 L/kg. Trimethoprim's higher Vd indicates extensive tissue distribution. |
| Bioavailability | Oral: >90% for both components. Oral absorption is rapid and complete. |
| Onset of Action | Oral: 1-4 hours; IV: within 1-2 hours. Clinical effect correlates with achieving therapeutic serum concentrations. |
| Duration of Action | 12 hours (twice daily dosing). Dosing interval is every 12 hours to maintain effective concentrations. |
| Molecular Weight | Sulfamethoxazole: 253.28 Da; Trimethoprim: 290.32 Da |
One double-strength tablet (160 mg trimethoprim/800 mg sulfamethoxazole) orally every 12 hours.
| Dosage form | TABLET |
| Renal impairment | CrCl >30 mL/min: standard dose. CrCl 15–30 mL/min: half the usual dose (i.e., one double-strength tablet daily). CrCl <15 mL/min: not recommended (contraindicated). |
| Liver impairment | Avoid in severe hepatic impairment (Child-Pugh class C). For mild to moderate impairment (Child-Pugh A or B): use with caution; consider dose reduction and monitor for hepatotoxicity. |
| Pediatric use | Based on trimethoprim component: 8 mg/kg/day divided every 12 hours (e.g., for infection: 4 mg/kg TMP every 12 hours; max single dose 160 mg TMP). For prophylaxis: 2 mg/kg TMP once daily. Use suspension (40 mg TMP/200 mg SMX per 5 mL) for weight-based dosing. |
| Geriatric use | Use with caution due to increased risk of adverse effects (hyperkalemia, renal impairment, folate deficiency). Start at lower end of dosing range; monitor renal function and electrolytes (especially potassium). Avoid if CrCl <15 mL/min. |
| 1st trimester | Avoid in first trimester due to potential teratogenic effects (folate antagonist). Use only if benefit outweighs risk. |
| 2nd trimester | Use with caution; may increase risk of kernicterus if given near term. Avoid in G6PD deficiency. |
| 3rd trimester | Avoid in third trimester (especially near term) due to risk of kernicterus and hemolytic anemia in neonates. |
Clinical note
May increase levels of phenytoin and digoxin Can cause hyperkalemia and blood dyscrasias.
| FDA category | Positive |
| Placental transfer | Both components cross the placenta; trimethoprim transfers more readily. Peak cord blood concentrations are 30-50% of maternal levels. |
| Breastfeeding |
■ FDA Black Box Warning
Fatal hypersensitivity reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias have occurred. Clostridioides difficile colitis. Avoid use in pregnancy at term and in nursing mothers due to risk of kernicterus.
| Common Effects | Nausea |
| Serious Effects |
Hypersensitivity to sulfonamides or trimethoprimMegaloblastic anemia due to folate deficiencySevere hepatic necrosisSevere renal impairment (CrCl <15 mL/min) not on dialysisHistory of drug-induced thrombocytopenia with sulfonamides or trimethoprimPregnancy (avoid in first trimester and near term)
| Precautions | Fatal hypersensitivity reactions; monitor for rash, fever, mucosal lesions. Hematologic toxicity; monitor CBC. Folate deficiency; use caution in elderly, alcoholics, malnourished. Photosensitivity. Severe dermatologic reactions. C. difficile diarrhea. Hyperkalemia (high-dose trimethoprim). Hypoglycemia. Phenylalanine restriction (contains aspartame). |
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| Excreted into breast milk in low concentrations. Avoid in mothers of infants with G6PD deficiency, hyperbilirubinemia, or ill/premature infants. Monitor infant for jaundice, hemolysis, and rash. |
| Lactation Rating | L2 (Safer) if infant healthy and full-term; otherwise L3 (Moderately Safe) if infant at risk. |
| Teratogenic Risk | First trimester: Associated with increased risk of neural tube defects, cardiovascular malformations, and oral clefts due to folate antagonism. Second and third trimesters: Risk of kernicterus in neonates if used near term due to bilirubin displacement by sulfamethoxazole; also associated with hemolytic anemia in G6PD-deficient fetuses. Avoid in first trimester and near term. |
| Fetal Monitoring | Monitor maternal CBC, renal function, and hepatic function periodically. Assess for signs of folate deficiency. In fetus: ultrasound for anomalies if exposure in first trimester. Monitor neonate for jaundice, hemolysis, and kernicterus if drug used near term. |
| Fertility Effects | No evidence of significant fertility impairment in males or females. Trimethoprim may theoretically affect spermatogenesis at high doses, but clinical data are limited. No known effect on ovulation or implantation. |
| Food/Dietary | Avoid potassium-rich foods (e.g., bananas, oranges, potatoes) due to risk of hyperkalemia. Take with food if GI upset occurs. Avoid alcohol as it may increase side effects. |
| Clinical Pearls | Double strength formulation (800 mg sulfamethoxazole / 160 mg trimethoprim) is contraindicated in G6PD deficiency, pregnancy, and infants <2 months. Monitor for hyperkalemia, especially in elderly and those with renal impairment. Adjust dose for CrCl <30 mL/min; avoid if CrCl <15 mL/min. Use with caution with warfarin, methotrexate, and ACE inhibitors. |
| Patient Advice | Take with a full glass of water to prevent crystalluria. · Complete the entire course unless instructed otherwise. · Avoid prolonged sun exposure; use sunscreen as sun sensitivity may occur. · Report rash, sore throat, fever, or unusual bruising immediately. · Do not take if pregnant or breastfeeding. |