Trimethoprim 💊

⚠️ Trimethoprim is a widely used antibiotic for urinary tract and respiratory infections, but resistance is now common in the UK. It should not be used empirically for UTI in areas with resistance rates >20%. Always confirm local sensitivities and consider folate supplementation in prolonged use.

📖 About

• Trimethoprim is a synthetic antibiotic structurally related to folic acid.
• Highly effective against many Gram-negative and some Gram-positive bacteria, particularly E. coli, Proteus, and Klebsiella.
• Does not cover Pseudomonas or Enterococci well.
• May be used alone or (historically) with sulfamethoxazole as co-trimoxazole (now reserved for specific infections such as Pneumocystis jirovecii).
• Always check the BNF link here for up-to-date dosing and contraindications.

⚗️ Mode of Action

• Trimethoprim selectively inhibits bacterial dihydrofolate reductase, preventing the reduction of dihydrofolic acid to tetrahydrofolic acid.
• This blocks thymidine synthesis → impaired DNA synthesis → bacteriostasis.
• Humans are less affected as our reductase enzyme is structurally different, though high doses may interfere with folate metabolism.
• When combined with sulfamethoxazole (which blocks an earlier folate synthesis step), the combination is synergistic and bactericidal.

🎯 Indications

• Uncomplicated lower UTI (cystitis): 200 mg BD for 3 days (women) or 7 days (men).
• Prostatitis: 200 mg BD for 4–6 weeks (good prostatic penetration).
• Respiratory infections: occasionally used in chronic bronchitis exacerbations (if sensitive organisms).
• Prophylaxis of recurrent UTI: 100 mg nocte or post-coital.
• Pneumocystis jirovecii pneumonia (PCP): As co-trimoxazole - see dedicated entry.

💊 Dose Range (Adults - check BNF)

⚠️ Cautions

• Renal impairment: Risk of accumulation and hyperkalaemia - reduce dose if eGFR <30 mL/min/1.73 m².
• Elderly patients: Risk of raised serum potassium, especially with ACE inhibitors, ARBs, or spironolactone.
• Folate deficiency or megaloblastic anaemia: May worsen due to interference with folate metabolism.
• Pregnancy: Avoid, particularly in 1st trimester (folate antagonism → neural tube defects) and near term (risk of neonatal jaundice).
• Breastfeeding: Avoid in premature infants or G6PD deficiency due to risk of haemolysis.

💊 Interactions

• Methotrexate, azathioprine, mercaptopurine: Additive antifolate effect → risk of marrow suppression; consider folinic acid rescue.
• ACE inhibitors/ARBs, spironolactone: Risk of severe hyperkalaemia and sudden death - avoid combination if possible.
• Warfarin: Potentiates anticoagulant effect by gut flora suppression - monitor INR closely.
• Phenytoin: Trimethoprim can increase phenytoin levels (CYP2C9 inhibition).

🚫 Contraindications

• First-trimester pregnancy or breastfeeding (folate antagonism).
• Known folate deficiency or megaloblastic anaemia.
• Severe renal impairment without dose adjustment.
• Documented hypersensitivity to trimethoprim or other diaminopyrimidines.

💥 Side Effects

• Gastrointestinal: Nausea, vomiting, diarrhoea.
• Dermatological: Rash, pruritus, photosensitivity, urticaria (rarely Stevens–Johnson syndrome).
• Haematological: Megaloblastic anaemia, thrombocytopenia, leucopenia - especially in folate deficiency or long-term use.
• Hepatic: Elevated LFTs, cholestatic jaundice (rare).
• Metabolic: Hyperkalaemia and hyponatraemia (via ENaC blockade in distal nephron).
• Renal: Crystalluria (rare), transient rise in creatinine due to reduced tubular secretion (not true renal impairment).
• Teratogenicity: Neural tube defects if used early in pregnancy.

🧠 Pharmacokinetics

• Absorption: ~90–100% orally bioavailable; peak plasma in 1–4 hours.
• Distribution: Widely distributed, including kidneys, prostate, and respiratory tissues; poor CSF penetration.
• Protein binding: ~45%; volume of distribution ≈ 1.6 L/kg.
• Metabolism: Hepatic (10–20%) via CYP2C9.
• Elimination: Primarily renal (glomerular filtration and tubular secretion); t½ ≈ 8–10 hours (longer in renal impairment).
• Folate antagonism: Reversible with folinic acid (leucovorin) if necessary.

💡 Clinical Pearls

• Resistance among E. coli now exceeds 30% in many UK regions - always check local antibiogram before empirical use.
• Excellent choice for prostatitis due to high prostatic tissue levels.
• Monitor K⁺ and renal function if used with renin–angiotensin system blockers or in older adults.
• In recurrent UTIs, consider nightly or post-coital dosing for prophylaxis (often 6–12 months, review regularly).
• Folate supplementation (e.g. folic acid 5 mg daily) may prevent marrow suppression with long-term use.

📚 References

• BNF: Trimethoprim
• Public Health England. Management of Infection Guidance for Primary Care (2024).
• Katzung BG, Basic & Clinical Pharmacology, 15th ed.
• Sanford Guide to Antimicrobial Therapy, 2024.