Clinical safety rating: caution
TMP-SMX (Co-trimoxazole) is a folate antagonist with trimester-dependent risks. Trimethoprim inhibits dihydrofolate reductase, potentially impairing folate metabolism in early embryogenesis — associated with NTDs and cardiovascular defects in some studies. Sulfamethoxazole at term can displace bilirubin from albumin causing neonatal jaundice and theoretical kernicterus risk. Despite this, it remains essential for treating Pneumocystis jirovecii pneumonia (PCP), Toxoplasma gondii, and certain MDR UTIs. Supplementation with folic acid 5 mg/day is recommended if used in T1.
Sulfamethoxazole inhibits dihydropteroate synthase, blocking para-aminobenzoic acid incorporation into dihydrofolate; trimethoprim inhibits dihydrofolate reductase, preventing tetrahydrofolate formation. Sequential blockade of folate synthesis.
| Metabolism | Sulfamethoxazole: primarily by N-acetylation (N-acetyltransferase 2) and glucuronidation. Trimethoprim: oxidation and hydroxylation via cytochrome P450 (CYP3A4 and other isoforms). Both are partially metabolized; metabolites and parent drugs excreted renally. |
| Excretion | Trimethoprim: 50-60% excreted unchanged in urine via glomerular filtration and tubular secretion; 10-20% as metabolites. Sulfamethoxazole: 20-30% excreted unchanged in urine; 50-70% as N4-acetylated metabolite. Both undergo minimal biliary/fecal elimination (<5% total). |
| Half-life | Trimethoprim: 8-10 hours (normal renal function); prolonged to 24-30 hours in severe renal impairment (CrCl <10 mL/min). Sulfamethoxazole: 9-11 hours; prolonged in renal failure. The combination retains a half-life of ~10-12 hours in healthy adults, requiring dose adjustment in renal impairment. |
| Protein binding | Trimethoprim: 37-44% bound to alpha-1-acid glycoprotein and albumin. Sulfamethoxazole: 60-70% bound (primarily albumin). |
| Volume of Distribution | Trimethoprim: 1.3-1.8 L/kg (extensive tissue penetration, e.g., lung, kidney, prostate; exceeds total body water). Sulfamethoxazole: 0.15-0.2 L/kg (mainly extracellular fluid). |
| Bioavailability | Oral: 90-100% for both components; tablets and suspension are bioequivalent. Intravenous: 100% bioavailability. |
| Onset of Action | Oral: 1-2 hours for detectable serum levels; clinical effect (e.g., for UTI) typically within 24-48 hours. Intravenous: immediate; therapeutic levels achieved within 1 hour. |
| Duration of Action | 12 hours (dosing interval 8-12 hours for most infections). Clinical effect persists for 12-24 hours post-dose; longer in renal impairment due to reduced clearance. |
| Molecular Weight | Trimethoprim: 290.32 Da; Sulfamethoxazole: 253.28 Da |
Oral: 160 mg TMP/800 mg SMX every 12 hours; IV: 8-10 mg/kg/day (based on TMP) in 2-4 divided doses
| Renal impairment | CrCl >30 mL/min: no adjustment; CrCl 15-30 mL/min: reduce dose by 50%; CrCl <15 mL/min: use alternative or adjust with monitoring |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: use with caution; Child-Pugh C: avoid due to risk of hepatotoxicity |
| Pediatric use | 6-8 mg/kg/day (based on TMP) orally in 2 divided doses; for PCP: 15-20 mg/kg/day (TMP) IV/oral in 4 divided doses |
| Geriatric use | Use lower end of dosing range; monitor renal function and electrolytes frequently; avoid if CrCl <15 mL/min unless for PCP |
| 1st trimester | Avoid in first trimester due to teratogenic risk (folate antagonism). Associated with neural tube defects, cardiovascular anomalies. Use only if benefit outweighs risk. |
| 2nd trimester | Use caution in second trimester. Risk of folate antagonism persists; consider folic acid supplementation. May be used for specific infections if no alternative. |
| 3rd trimester | Avoid in third trimester due to risk of kernicterus in neonates (sulfonamide displaces bilirubin) and hemolytic anemia in G6PD-deficient fetuses. Not recommended near term. |
Clinical note
TMP-SMX (Co-trimoxazole) is a folate antagonist with trimester-dependent risks. Trimethoprim inhibits dihydrofolate reductase, potentially impairing folate metabolism in early embryogenesis — associated with NTDs and cardiovascular defects in some studies. Sulfamethoxazole at term can displace bilirubin from albumin causing neonatal jaundice and theoretical kernicterus risk. Despite this, it remains essential for treating Pneumocystis jirovecii pneumonia (PCP), Toxoplasma gondii, and certain MDR UTIs. Supplementation with folic acid 5 mg/day is recommended if used in T1.
| Placental transfer | Both trimethoprim and sulfamethoxazole cross the placenta; sulfamethoxazole reaches fetal concentrations 50-80% of maternal levels; trimethoprim concentrates in fetal tissues. |
■ FDA Black Box Warning
Fatal hypersensitivity reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Increased risk in elderly, patients with renal/hepatic impairment, and concomitant folate deficiency.
| Serious Effects |
Hypersensitivity to trimethoprim, sulfonamides, or any componentMegaloblastic anemia due to folate deficiencySevere hepatic or renal impairment (CrCl <15 mL/min) unless for treatment of Pneumocystis jirovecii pneumoniaInfants <2 months of age due to risk of kernicterusConcurrent use with dofetilide (increased risk of arrhythmias)Pregnancy (especially first and third trimesters) unless no alternativeBreastfeeding infants with G6PD deficiency or hyperbilirubinemia
| Precautions | Risk of severe hypersensitivity reactions, hematologic toxicity, hepatic necrosis, renal toxicity (especially interstitial nephritis), hyperkalemia (especially in elderly with renal dysfunction), hypoglycemia, and exacerbation of porphyria. Monitor CBC, renal function, liver function. Avoid in G6PD deficiency due to hemolysis. Use caution with potassium supplementation or potassium-sparing diuretics. Risk of kernicterus in neonates. |
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| Breastfeeding | Trimethoprim-sulfamethoxazole is excreted into breast milk in low concentrations. Risk of kernicterus in neonates is low with usual doses, but caution in ill, preterm, or jaundiced infants; may cause hemolysis in G6PD-deficient infants. Use only if no safer alternative available. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Associated with increased risk of neural tube defects, cardiovascular malformations, and oral clefts due to folate antagonism. Second trimester: Risk of kernicterus in neonates if administered near term due to bilirubin displacement. Third trimester: Avoid use, especially after 32 weeks gestation, due to risk of hyperbilirubinemia and kernicterus in the newborn. |
| Fetal Monitoring | Monitor maternal CBC, renal function, and liver enzymes periodically. Assess for hypersensitivity reactions, Stevens-Johnson syndrome, and blood dyscrasias. Fetal monitoring: Ultrasound for structural anomalies if exposed in first trimester; monitor newborn for jaundice, hemolysis, and hyperbilirubinemia if exposure near term. |
| Fertility Effects | No known direct impact on fertility. However, sulfonamides may rarely cause reversible sperm abnormalities. In females, no significant effects reported. |
| Food/Dietary |
| Avoid high-potassium foods (e.g., bananas, oranges, potatoes) in large amounts due to potential for hyperkalemia. No significant food-drug interactions, but maintain adequate fluid intake. |
| Clinical Pearls | Monitor for hypersensitivity reactions (especially in HIV patients). Adjust dose in renal impairment (CrCl <15-30 mL/min: avoid or reduce dose). Use with caution in elderly due to increased risk of hyperkalemia (trimethoprim inhibits renal potassium excretion). Co-trimoxazole is first-line for Pneumocystis jirovecii pneumonia (PJP) and Stenotrophomonas maltophilia infections. Always check G6PD status before use due to risk of hemolytic anemia. |
| Patient Advice | Take with a full glass of water and stay well-hydrated to prevent crystalluria. · Complete the full course even if you feel better. · Avoid prolonged sun exposure; use sunscreen as this drug may increase photosensitivity. · Report any signs of allergy (rash, itching, swelling) or severe skin reactions immediately. · Inform your doctor if you have kidney disease, G6PD deficiency, or are pregnant/breastfeeding. |