SULFAMETHOPRIM-DS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SULFAMETHOPRIM-DS (SULFAMETHOPRIM-DS).
Sulfamethoprim-DS is a combination of sulfamethoxazole, a dihydropteroate synthase inhibitor, and trimethoprim, a dihydrofolate reductase inhibitor. The sequential inhibition of folate synthesis leads to bactericidal activity.
| Metabolism | Sulfamethoxazole undergoes hepatic metabolism via N-acetylation and glucuronidation; trimethoprim is metabolized primarily via hepatic oxidation (CYP450) and conjugation. |
| Excretion | Renal excretion of unchanged drug (50-70%) and metabolites (primarily N4-acetylated form, 15-30%); biliary/fecal excretion accounts for <5%. |
| Half-life | Terminal elimination half-life of sulfamethoxazole is 9-11 hours (prolonged to 20-50 hours in severe renal impairment). Clinically, this supports twice-daily dosing in normal renal function; dose adjustment required for CrCl <30 mL/min. |
| Protein binding | Sulfamethoxazole: ~65-70% bound primarily to albumin. N4-acetyl metabolite: ~90% bound. |
| Volume of Distribution | Vd: 0.21-0.36 L/kg (sulfamethoxazole). Distributes widely into tissues, including CSF (30-50% of serum concentration), sputum, and middle ear fluid. |
| Bioavailability | Oral: 85-90% (well absorbed). |
| Onset of Action | Oral: 1-4 hours (time to peak serum concentration); peak antibacterial effect correlates with serum levels above MIC, achieved within 1-2 doses. |
| Duration of Action | Duration of therapeutic serum concentrations: 8-12 hours (oral) based on dosing interval of 12 hours. Continuous coverage maintained with twice-daily administration. |
| Molecular Weight | Sulfamethoxazole: 253.3 Da; Trimethoprim: 290.3 Da |
Sulfamethoprim-DS (trimethoprim 160 mg-sulfamethoxazole 800 mg) orally every 12 hours for 10-14 days for uncomplicated UTI; for Pneumocystis jirovecii pneumonia: 3-5 mg/kg/day (based on TMP) orally or IV divided every 6-8 hours for 21 days.
| Dosage form | TABLET |
| Renal impairment | CrCl 15-30 mL/min: reduce dose by 50% and administer every 12 hours (standard dose every 24 hours alternative). CrCl <15 mL/min: contraindicated except for PCP where dosing interval extended to 24-48 hours with monitoring. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: caution, no specific guidelines; Child-Pugh C: avoid due to potential for accumulation and hepatotoxicity. |
| Pediatric use | Based on TMP 4-6 mg/kg/day orally divided every 12 hours for UTI; for PCP: TMP 15-20 mg/kg/day IV/orally divided every 6-8 hours. Use adjusted body weight for obese children. |
| Geriatric use | Caution due to increased risk of hyperkalemia, renal impairment, and drug interactions (e.g., ACE inhibitors, ARBs). Start with weight-based dosing (TMP 4-5 mg/kg/day) and monitor renal function and serum potassium. |
| 1st trimester | Contraindicated due to risk of teratogenicity (folate antagonism); associated with neural tube defects, cleft palate, and cardiovascular anomalies. |
| 2nd trimester | Use with caution; may cause hyperbilirubinemia and kernicterus in the newborn if used near term; avoid in G6PD deficiency. |
| 3rd trimester | Contraindicated near term (after 37 weeks) because of potential for neonatal kernicterus and hemolytic anemia. |
Clinical note
Comprehensive clinical and safety monograph for SULFAMETHOPRIM-DS (SULFAMETHOPRIM-DS).
| Placental transfer | Both components cross the placenta readily, achieving fetal serum concentrations 50–100% of maternal levels; trimethoprim has higher placental transfer than sulfamethoxazole. |
| Breastfeeding | Sulfamethoprim-DS (sulfamethoxazole/trimethoprim) is excreted into breast milk in low amounts. Although generally considered safe in healthy full-term infants, use caution in preterm infants, infants with G6PD deficiency, or hyperbilirubinemia due to risk of kernicterus and hemolysis. Monitor for jaundice and diarrhea. |
■ FDA Black Box Warning
Warning: Fatalities associated with sulfonamide hypersensitivity reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia) have been reported.
| Serious Effects |
Hypersensitivity to sulfonamides or trimethoprimMegaloblastic anemia due to folate deficiencySevere hepatic or renal impairment (CrCl <15 mL/min)Pregnancy near term (third trimester)Infants <2 months of ageConcomitant use with dofetilideG6PD deficiency (relative, but absolute if hemolytic risk is high)
| Precautions | Hypersensitivity reactions, hematologic toxicity (monitor CBC), renal impairment (dose adjustment), hyperkalemia (especially with high doses), folate deficiency (prolonged use), phototoxicity, and potential for kernicterus in neonates. Avoid use in pregnancy at term and in infants <2 months. |
| Food/Dietary | Avoid potassium-rich foods (e.g., bananas, oranges, salt substitutes) as sulfamethoxazole/trimethoprim can increase serum potassium. No significant food restrictions otherwise; maintain adequate fluid intake. |
Loading safety data…
| Lactation Rating | L3 (Moderately Safe) or 'Probably Compatible' - avoiding in ill/premature infants with G6PD deficiency. |
| Teratogenic Risk | FDA Category D: First trimester exposure associated with neural tube defects, cardiovascular malformations, and oral clefts due to folate antagonism. Second and third trimester: increased risk of kernicterus in neonates due to bilirubin displacement; avoid near term (after 36 weeks). |
| Fetal Monitoring | Monitor maternal CBC, renal function, blood pressure, and serum folate levels. Fetal monitoring for structural anomalies (ultrasound) if first-trimester exposure. Neonatal monitoring for jaundice and hemolysis. |
| Fertility Effects | No established adverse effects on fertility. Theoretical concern of folate antagonism could impair spermatogenesis, but clinical data lacking. |
| Clinical Pearls | Sulfamethoprim-DS is a fixed-dose combination of sulfamethoxazole and trimethoprim (co-trimoxazole). Monitor for hypersensitivity reactions, especially in HIV patients. Adjust dose in renal impairment (CrCl <30 mL/min: avoid or reduce). Use with caution in elderly, folate deficiency, or G6PD deficiency. Contraindicated in megaloblastic anemia due to folate deficiency. Avoid in pregnancy near term and breastfeeding. Consider leukovorin rescue if myelosuppression occurs. |
| Patient Advice | Take with a full glass of water to prevent crystalluria. · Complete the entire course even if you feel better. · Avoid prolonged sun exposure; use sunscreen as this drug increases photosensitivity. · Report rash, fever, sore throat, pallor, or unusual bleeding immediately. · Do not take if you are allergic to sulfa drugs or trimethoprim. |