trimethoprim-sulfamethoxazole (TMP-SMX)
Brand: Bactrim, Bactrim DS, Septra
Prototype Drug
Drug Class: antibiotic
Drug Family: antibiotic
Subclass: sulfonamide + dihydrofolate reductase inhibitor combination
Organ Systems: infectious-disease
Mechanism of Action
Sequential blockade of bacterial folate synthesis — sulfamethoxazole inhibits dihydropteroate synthase (PABA incorporation step) and trimethoprim inhibits dihydrofolate reductase; synergistic combination depletes tetrahydrofolate required for nucleotide synthesis; bactericidal.
dihydropteroate synthase (sulfamethoxazole)dihydrofolate reductase (trimethoprim)
Indications
- UTI (E. coli, community-acquired — first-line if local resistance <20%)
- MRSA skin/soft tissue infections (mild-moderate)
- Pneumocystis jirovecii pneumonia (PCP) treatment and prophylaxis
- Nocardia infections
- community-acquired MRSA decolonization
- traveler's diarrhea
Contraindications
- severe sulfonamide allergy
- megaloblastic anemia from folate deficiency
- third trimester of pregnancy (kernicterus risk)
- CrCl <15 mL/min (TMP-SMX accumulation)
- concurrent methotrexate (additive antifolate)
Adverse Effects
Common
- nausea
- vomiting
- rash (maculopapular)
- megaloblastic anemia (impairs folate)
- hyperkalemia (trimethoprim blocks renal potassium secretion — similar to potassium-sparing diuretics)
- elevated SCr (trimethoprim blocks creatinine secretion — false elevation, not true GFR change)
Serious
- Stevens-Johnson syndrome/TEN
- agranulocytosis
- aplastic anemia
- severe hyperkalemia in patients on RAAS inhibitors or with CKD
- hepatotoxicity
Pharmacokinetics (ADME)
| Absorption | ~100% oral bioavailability; IV formulation available for PCP |
| Distribution | Widely distributed; Vd 1.6 L/kg; crosses BBB; protein binding 44–70% |
| Metabolism | SMX by CYP2C9 to acetyl-SMX; TMP minimal metabolism |
| Excretion | Renal; dose adjustment for CrCl <30 mL/min |
| Half-life | TMP 8–10 hours; SMX 9–11 hours |
| Onset | 1–4 hours |
| Peak | 1–4 hours |
| Duration | 12 hours (BID dosing) |
| Protein Binding | 44–70% |
| Vd | 1.6 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| warfarin | CYP2C9 inhibition increases warfarin levels; major bleeding risk | major |
| ACE inhibitors/ARBs/potassium-sparing diuretics | additive hyperkalemia — trimethoprim blocks ENaC; can be life-threatening in CKD | major |
| methotrexate | additive dihydrofolate reductase inhibition; bone marrow suppression | major |
Nursing Considerations
- Monitor serum potassium closely, especially in patients taking ACE inhibitors, ARBs, or spironolactone — trimethoprim's potassium-sparing effect can cause severe, life-threatening hyperkalemia
- TMP-SMX causes a false elevation in serum creatinine by ~0.1–0.2 mg/dL by inhibiting tubular creatinine secretion — this does not represent true renal injury; GFR (cystatin C or creatinine clearance using cystatin) is not affected
- Ensure adequate hydration during therapy to prevent crystalluria; patients with sulfonamide allergy should be asked about nature of reaction before prescribing
- For PCP prophylaxis (HIV with CD4 <200): SS tablet (TMP 80 mg / SMX 400 mg) once daily is first-line; monitor CBC monthly for hematologic toxicity
Clinical Pearls
- Trimethoprim is structurally similar to potassium-sparing diuretics (amiloride) — it blocks ENaC in the collecting duct, reducing potassium excretion; this interaction with RAAS inhibitors and CKD causes clinically significant and sometimes fatal hyperkalemia
- TMP-SMX is the preferred antibiotic for community-acquired MRSA soft tissue infections (IDSA guidelines) — clinical trials demonstrated equivalence or superiority to doxycycline for MRSA SSTIs
Safety Profile
Pregnancy avoid
Lactation use-with-caution
Renal Adjustment Required
Hepatic Adjustment Not required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.