Trimethoprim

Summary

Trimethoprim is an antibiotic that works by inhibiting bacterial folate synthesis. Clinically, this drug is often used in combination with sulfonamide antibiotics like sulfamethoxazole to treat a wide variety of bacterial infections. Notably, trimethoprim has some cross-reactivity with human enzymes that produce folate, so side effects include folate deficiency, as well as teratogenicity in the form of neural tube defects. Trimethoprim can also cause hyperkalemia. Lastly, trimethoprim inhibits CYP enzymes, and should be used cautiously in conjunction with other medications that are metabolized by CYP enzymes.

Key Points

• Trimethoprim (TMP)
  • Mechanism
    • Inhibits folate synthesis in bacteria
      • Blocks bacterial dihydrofolate reductase (DHFR)
      • Unlike sulfonamides, trimethoprim does have some cross-reactivity with human DHFR, reducing folate levels
    • Bacteriostatic
  • Clinical Use
    • Broad-spectrum, especially when used in combination with sulfonamides (TMP-SMX, trade name: Bactrim)
      • Urinary tract infections (UTIs)
      • Shigella
      • Salmonella
      • Pneumocystis jirovecii pneumonia
      • Toxoplasmosis prophylaxis
      • Community-acquired MRSA
  • Adverse Effects
    • Hyperkalemia
      • Seen with high doses
    • Inhibits CYP Enzymes
      • Synergistic inhibition with sulfamethoxazole (SMX)
      • Causes drug interactions (e.g. raises warfarin levels)
      • Can also displace warfarin from albumin, increasing effective dosing
    • Folate deficiency
      • Presents as megaloblastic anemia, leukopenia, granulocytopenia; Bone marrow contains rapidly-dividing hematopoietic cells that are more affected by relative folate deprivation
      • Can be avoided with folinic acid (leucovorin) supplementation
    • Teratogenic (neural tube defects)
      • Thought to result from reduced active folate