Makindo Medical Notes

💊 Co-trimoxazole (Trimethoprim + Sulfamethoxazole) is a synergistic folate antagonist. It should be used only when clearly indicated due to the risk of bone marrow suppression, hyperkalaemia, and severe skin reactions. Avoid in the elderly, pregnancy, and those on methotrexate or ACE inhibitors. Always check the BNF link here.

📖 About

• Fixed-dose combination of trimethoprim (1 part) and sulfamethoxazole (5 parts).
• The combination achieves sequential blockade of bacterial folate synthesis — enhancing bactericidal activity.
• Historically used broadly for respiratory, urinary, and gastrointestinal infections, but now restricted due to toxicity and resistance.
• Still valuable for Pneumocystis jirovecii pneumonia (PCP), Nocardia infections, toxoplasmosis, and Stenotrophomonas maltophilia.

⚗️ Mode of Action

• Sulfamethoxazole is a sulfonamide that competes with para-aminobenzoic acid (PABA) to inhibit bacterial dihydropteroate synthase — blocking dihydrofolic acid formation.
• Trimethoprim then inhibits dihydrofolate reductase, preventing conversion to tetrahydrofolate — needed for thymidine and purine synthesis.
• The sequential blockade is synergistic and bactericidal, whereas either drug alone is bacteriostatic.
• Rapidly absorbed, widely distributed (including lungs, kidneys, and CSF), and renally excreted.

🎯 Indications

• Pneumocystis jirovecii pneumonia (PCP) – treatment and prophylaxis (especially in HIV).
• Toxoplasmosis – as an alternative to pyrimethamine + sulfadiazine.
• Nocardiosis and Stenotrophomonas maltophilia infections.
• Urinary and respiratory infections (only when culture-confirmed sensitive).

💊 Adult Dosing (check BNF for specifics)

⚠️ Interactions

• Warfarin: Potentiates anticoagulant effect via displacement from albumin and CYP2C9 inhibition — monitor INR closely.
• Methotrexate, azathioprine, mercaptopurine: Additive antifolate toxicity → pancytopenia; avoid combination or give folinic acid rescue.
• Phenytoin: Inhibits phenytoin metabolism → toxicity (ataxia, nystagmus).
• ACE inhibitors / ARBs / spironolactone: Risk of severe hyperkalaemia.
• Sulphonylureas: Enhanced hypoglycaemic effect.

🚫 Contraindications

• History of sulfonamide hypersensitivity.
• Pregnancy (especially 1st and 3rd trimesters) — risk of neural tube defects and neonatal kernicterus.
• Breastfeeding (in preterm or G6PD-deficient infants).
• Severe hepatic or renal impairment.
• Megaloblastic anaemia due to folate deficiency.

💥 Side Effects

• Common: Nausea, vomiting, rash, pruritus.
• Serious:
  • Hypersensitivity: Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), serum sickness-like reactions.
  • Haematological: Pancytopenia, megaloblastic anaemia, agranulocytosis (especially with prolonged use or folate deficiency).
  • Metabolic: Hyperkalaemia (via trimethoprim’s ENaC blockade), hyponatraemia.
  • Renal: Crystalluria, interstitial nephritis, transient rise in creatinine (due to tubular competition).
  • Neonatal: Kernicterus if used near term (displaces bilirubin from albumin).

🧬 Pharmacokinetics

• Absorption: Rapid and nearly complete orally; bioavailability ≈ 90–100%.
• Distribution: Wide tissue distribution (lungs, kidneys, prostate, CSF); both cross placenta and enter breast milk.
• Protein binding: Sulfamethoxazole ≈ 70%, Trimethoprim ≈ 45%.
• Metabolism: Hepatic acetylation and glucuronidation.
• Elimination: Renal (filtration + secretion); t½ ≈ 8–10 h for trimethoprim, 9–12 h for sulfamethoxazole.
• Synergistic ratio: Plasma 1:20 (trimethoprim:sulfamethoxazole), achieved by 1:5 dosing formulation.

💡 Clinical Pearls

• Still first-line for Pneumocystis pneumonia treatment and prophylaxis — co-administer with folinic acid in high-risk patients.
• Monitor FBC, renal function, electrolytes (especially K⁺) if used for >1 week or in renal impairment.
• Use folinic acid (leucovorin) 5 mg daily to prevent marrow suppression if on long-term therapy or with methotrexate.
• Educate patients to report rash or sore throat immediately (early sign of SJS or marrow suppression).
• Ensure adequate hydration to minimise crystalluria risk.

📚 References

• BNF: Co-trimoxazole
• Sanford Guide to Antimicrobial Therapy, 2024.
• Mandell, Douglas & Bennett’s Principles and Practice of Infectious Diseases, 9th ed.
• NICE NG51: Sepsis and Antimicrobial Stewardship (2023).