SULFAMETHOXAZOLE AND TRIMETHOPRIM SINGLE STRENGTH
Clinical safety rating: avoid
May increase levels of phenytoin and digoxin Can cause hyperkalemia and blood dyscrasias.
Sulfamethoxazole inhibits bacterial dihydropteroate synthase, blocking folate synthesis. Trimethoprim inhibits bacterial dihydrofolate reductase, blocking tetrahydrofolate synthesis. Together, they provide sequential blockade of folate metabolism, leading to bactericidal activity.
| Metabolism | Sulfamethoxazole is metabolized primarily via N-acetylation (N-acetyltransferase 2, NAT2) and glucuronidation; trimethoprim undergoes O-demethylation (CYP3A4) and oxidation to metabolites. Both are excreted renally. |
| Excretion | Sulfamethoxazole: primarily renal (70-90% as unchanged drug and acetylated metabolite); Trimethoprim: renal (50-60% unchanged, rest as metabolites); small biliary/fecal elimination (<5% each). |
| Half-life | Sulfamethoxazole: 10-12 hours (prolonged in renal impairment); Trimethoprim: 8-11 hours (prolonged in hepatic impairment). |
| Protein binding | Sulfamethoxazole: ~70% bound to albumin; Trimethoprim: ~40-50% bound to plasma proteins. |
| Volume of Distribution | Sulfamethoxazole: 0.21-0.36 L/kg; Trimethoprim: 1.3-1.8 L/kg (total body water, indicating extensive tissue distribution). |
| Bioavailability | Oral: >90% absorbed for both components; IV: 100%. |
| Onset of Action | Oral: 1-4 hours to peak plasma concentrations; clinical effect typically within 24-48 hours. |
| Duration of Action | Approximately 12 hours; dosing interval is every 12 hours. |
| Molecular Weight | Sulfamethoxazole: 253.28 Da; Trimethoprim: 290.32 Da |
1 double-strength tablet (800 mg sulfamethoxazole/160 mg trimethoprim) orally every 12 hours for most infections; single-strength tablet (400 mg/80 mg) is used for prophylaxis: 1 tablet orally daily.
| 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. |
| Liver impairment | Child-Pugh Class A: no adjustment; Child-Pugh Class B: use with caution, consider dose reduction; Child-Pugh Class C: contraindicated due to risk of sulfonamide accumulation. |
| Pediatric use | UTI or other infections: 8 mg/kg/day trimethoprim divided every 12 hours orally; PCP prophylaxis: 150 mg/m2/day trimethoprim divided every 12 hours orally for 3 days per week. |
| Geriatric use | Use with caution due to increased risk of hyperkalemia and renal impairment; adjust dose based on renal function; avoid in elderly with CrCl <30 mL/min. |
| 1st trimester | Avoid in first trimester due to potential teratogenic effects (folate antagonism). Use only if benefits outweigh risks. |
| 2nd trimester | Use with caution; increased risk of hyperbilirubinemia and kernicterus in neonates if used near term. Second trimester relatively safer but monitor. |
| 3rd trimester | Avoid near term (especially after 32 weeks) due to risk of neonatal hyperbilirubinemia and hemolytic anemia from displacement of bilirubin from albumin. |
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 reaches fetal serum levels similar to maternal. High degree of transfer. |
| Breastfeeding |
■ FDA Black Box Warning
Fatal hypersensitivity reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hepatic necrosis have occurred. Discontinue at first sign of skin rash or any sign of adverse reaction.
| Common Effects | Nausea |
| Serious Effects |
Known hypersensitivity to sulfonamides or trimethoprimMegaloblastic anemia due to folate deficiencySevere hepatic damageSevere renal impairment (CrCl <15 mL/min) unless for Pneumocystis jirovecii pneumoniaConcomitant use with certain class III antiarrhythmics (e.g., dofetilide, pimozide) due to QT prolongation risk
| Precautions | Hypersensitivity: Discontinue at first sign of skin rash; risk of severe cutaneous reactions (SJS, TEN)., Hematologic: May cause agranulocytosis, aplastic anemia, megaloblastic anemia; monitor CBC in patients on long-term therapy., Hepatic: Fatal hepatic necrosis reported; caution in hepatic impairment., Renal: Dose adjustment required for creatinine clearance 15-30 mL/min; contraindicated if <15 mL/min (except for PCP prophylaxis)., Pregnancy: Avoid at term; risk of kernicterus in neonates (sulfonamide competes for bilirubin binding)., Glucose-6-phosphate dehydrogenase deficiency: Risk of hemolytic anemia., Hyperkalemia: Trimethoprim can cause hyperkalemia, especially with renal impairment, drugs causing hyperkalemia, or in elderly., Folate deficiency: Risk of megaloblastic anemia; consider folinic acid supplementation in prolonged therapy. |
Loading safety data…
| Small amounts excreted in breast milk. Avoid in breastfeeding infants with G6PD deficiency, hyperbilirubinemia, or prematurity. Consider monitoring infant for jaundice, rash, or diarrhea. |
| Lactation Rating | L3 (Moderately Safe) - potential for adverse effects in premature or G6PD-deficient infants. |
| Teratogenic Risk | First trimester: Folate antagonism may increase risk of neural tube defects, cleft palate, and cardiovascular anomalies. Second and third trimesters: Risk of kernicterus in neonates due to bilirubin displacement from albumin; hemolytic anemia in G6PD-deficient fetuses. Avoid near term due to competition with bilirubin for albumin binding. |
| Fetal Monitoring | Monitor maternal CBC, renal function, and liver function. Assess for signs of folate deficiency. In fetus: ultrasound for congenital anomalies if exposure in first trimester. Monitor neonate for jaundice, hemolysis, and kernicterus if used near term. |
| Fertility Effects | No significant adverse effects on fertility reported. Folate antagonism may theoretically impair spermatogenesis or oogenesis but clinical evidence is lacking. |
| Food/Dietary | No significant food interactions. Maintain adequate fluid intake. Avoid potassium-rich foods (bananas, oranges, potatoes) if hyperkalemia risk. No alcohol restriction. |
| Clinical Pearls | Monitor for hyperkalemia, especially in elderly or renal impairment; trimethoprim inhibits renal potassium excretion. Use caution in patients with folate deficiency; megaloblastic anemia may occur. Adjust dose for creatinine clearance <30 mL/min. Contraindicated in pregnancy at term and breastfeeding. Check for G6PD deficiency before use; hemolysis risk. Avoid in infants <2 months due to kernicterus risk. Sulfonamide component may cause Stevens-Johnson syndrome; discontinue at first sign of rash. |
| Patient Advice | Complete the full course even if feeling better. · Take with a full glass of water to prevent crystalluria. · Avoid excessive sun exposure; use sunscreen due to photosensitivity. · Report rash, fever, sore throat, or unusual bleeding immediately. · Do not take if pregnant, planning pregnancy, or breastfeeding without consulting doctor. · May cause dizziness; avoid driving if affected. |