Pharm 101: Trimethoprim


Antifolate antibiotic

  • Blocks step in folate synthesis
  • Selectively inhibits bacterial dihydrofolic acid reductaste that converts dihydrofolic acid to tetrahydrofolic acid, a step leading to synthesis of purines and ultimately DNA
    • Hence inhibits DNA synthesis
    • Much less efficient in inhibiting mammalian DHFR
  • Bacterostatic on its own
  • Mechanisms of resistance to trimethoprim:
    • Reduced cell permeability
    • Increased production of enzyme DHF reductase
    • Alteration in DHF reductase with reducing binding
Trimethoprim-sulfamethoxazole combination
  • Trimethoprim in combination with sulphonamides becomes bactericidal (synergistic effect), due to blockade of sequential steps in folate synthesis:
    • Sulphonamides inhibit dihydropteroate synthase, which catalyses PABA to DHFA (step before trimethoprim)
  • PO administration
  • Weak base
    • Concentrations in prostatic fluid and vaginal fluid (more acidic than plasma)
  • Well absorbed and well distributed including to CSF
  • 45% protein bound
  • 60% excreted in urine within 24 hours
Antimicrobial activity
Adverse effects
  • Haematological:
    • Megaloblastic anaemia
    • Leukopenia
    • Granulocytopaenia
  • Renal:
    • Mild elevation of serum creatinine without impairment of GFR (nontoxic)
Further reading

Pharmacology 101

Top 200 drugs

MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Adult/Paediatric Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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