Describe the sulphonamides and trimethoprim. Explain the basis of their synergy and the uses of co-trimoxazole.

Sulphonamides and Trimethoprim — Mechanism

Bacteria must synthesise their own folate; man absorbs it preformed — the basis of selectivity → PABA + pteridine, by dihydropteroate synthase → dihydrofolate → sulphonamides are structural analogues of PABA and competitively inhibit dihydropteroate synthase → Dihydrofolate, by dihydrofolate reductase → tetrahydrofolate → trimethoprim inhibits bacterial dihydrofolate reductase, with many-thousandfold selectivity over the human enzyme → Tetrahydrofolate is needed for purine, thymidine and amino acid synthesis → Blocking two sequential steps gives synergy — the combination is bactericidal though each drug alone is bacteriostatic

Co-trimoxazole — Uses

• Co-trimoxazole = trimethoprim + sulphamethoxazole in a 1:5 ratio, which gives a 1:20 ratio in plasma — the optimum for synergy
• Pneumocystis jirovecii pneumonia — the drug of choice for both treatment (high dose) and prophylaxis in HIV and other immunosuppression; this remains its single most important indication
• Urinary tract infection, including prophylaxis
• Nocardiosis, toxoplasmosis (with pyrimethamine), listeriosis
• Melioidosis; Stenotrophomonas infection
• Community-acquired MRSA skin and soft tissue infection
• Chancroid, granuloma inguinale, traveller diarrhoea
• Silver sulphadiazine topically for burns; sulphasalazine in inflammatory bowel disease and rheumatoid arthritis

Adverse Effects

• Hypersensitivity — rashes are common, and sulphonamides are among the leading causes of stevens–johnson syndrome and toxic epidermal necrolysis
• Haematological — megaloblastic anaemia (folate antagonism, prevented by folinic acid), agranulocytosis, thrombocytopenia; haemolysis in G6PD deficiency
• Crystalluria with the older, less soluble sulphonamides — prevented by adequate hydration and urinary alkalinisation
• Kernicterus in neonates — sulphonamides displace bilirubin from albumin; hence they are contraindicated in the newborn and in the third trimester
• Hyperkalaemia — trimethoprim blocks the epithelial sodium channel like amiloride; important in the elderly and with ACE inhibitors
• Raised creatinine without true renal impairment, as trimethoprim blocks its tubular secretion
• Interactions — potentiates warfarin, phenytoin and sulphonylureas by displacement and enzyme inhibition; with methotrexate causes severe marrow suppression

Other Folate-related and Urinary Agents

Applied Aspects

• Screen for G6PD deficiency where feasible before sulphonamides, dapsone and nitrofurantoin, particularly in populations where it is common
• Check potassium and creatinine in elderly patients on co-trimoxazole, especially with an ACE inhibitor or spironolactone — the combination causes dangerous hyperkalaemia
• Give folinic acid, not folic acid, to protect the host during high-dose or prolonged treatment, since folinic acid bypasses the blocked enzyme
• Avoid co-trimoxazole with methotrexate — both are antifolates and the combination has caused fatal pancytopenia
• Co-trimoxazole prophylaxis in HIV is cheap and highly effective, preventing Pneumocystis, toxoplasmosis and several bacterial infections; it remains one of the highest-value interventions in HIV care in India
• Warn patients to stop immediately and seek help for any rash, given the risk of severe cutaneous reactions