First Line Tuberculosis Drugs

First-line tuberculosis drugs are isoniazid, rifampicin, pyrazinamide and ethambutol, which together cure more than 85% of drug-susceptible disease in 6 months when taken correctly. They are given daily as a fixed-dose combination. Rifapentine and rifabutin are rifamycin relatives used in specific settings.

Mechanism and kinetics.

• Isoniazid: inhibits mycolic acid synthesis after activation by bacterial catalase-peroxidase. Rapidly absorbed; best on an empty stomach. Metabolised by NAT2; half-life about 1 to 4 hours depending on acetylator status.
• Rifampicin: inhibits bacterial RNA polymerase. Well absorbed on an empty stomach, biliary excretion, potent inducer of CYP3A4, CYP2C9, CYP2C19 and P-glycoprotein.
• Pyrazinamide: converted to pyrazinoic acid, acts at acidic pH. Well absorbed, renal excretion of metabolites.
• Ethambutol: blocks arabinosyl transferases. About 80% absorbed, mostly renal excretion unchanged.

Dosing summary.

• Isoniazid: most potent early bactericidal drug; the main cause of neuropathy and drug-induced lupus; inhibits metabolism of phenytoin, carbamazepine and warfarin.
• Rifampicin: the key sterilising drug; stopping it lengthens treatment to 9 to 12 months or more. It reduces levels of many drugs, including hormonal contraceptives, warfarin, direct oral anticoagulants, tacrolimus, ciclosporin, azole antifungals, methadone, and several antiretrovirals.
• Pyrazinamide: shortens treatment; the most frequent cause of hyperuricaemia; contributes substantially to hepatotoxicity.
• Ethambutol: not hepatotoxic; its main risk is optic neuritis. It is the companion drug protecting against resistance until susceptibility is known.
• Rifapentine: longer half-life, allowing weekly use in preventive therapy, and is combined with moxifloxacin in a 4-month regimen for drug-susceptible disease in patients aged 12 years and over.
• Rifabutin: weaker CYP3A4 inducer; used instead of rifampicin with protease inhibitors, at 150 mg daily or 300 mg three times weekly adjusted for the boosted drug, with specialist input.

Treatment of active disease. 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, then 4 months of isoniazid and rifampicin. Ethambutol is dropped early only when susceptibility to isoniazid and rifampicin is proven. Tuberculous meningitis, bone and joint disease are given 9 to 12 months; adjunctive corticosteroid is used in meningitis and pericarditis with the dose set by a specialist.

Four-month regimen. For patients aged 12 years and over without severe disease: 2 months of rifapentine 1200 mg, isoniazid 300 mg, pyrazinamide and moxifloxacin 400 mg daily, then 2 months of rifapentine, isoniazid and moxifloxacin. Available only where rifapentine is supplied.

Preventive therapy (latent infection or close contacts, after active disease is excluded).

• Isoniazid 5 mg/kg daily (maximum 300 mg) for 6 months; child 10 mg/kg.
• Rifampicin 10 mg/kg daily (maximum 600 mg) for 4 months.
• Isoniazid with rifampicin daily for 3 months.
• Rifapentine 900 mg with isoniazid 900 mg once weekly for 12 weeks, or rifapentine 600 mg with isoniazid 300 mg daily for 1 month in adolescents and adults.

Region. In East Africa, HIV coinfection is the commonest reason for modification. Preventive therapy is advised for people living with HIV and for household contacts under 5 years. Where only isoniazid is available, add pyridoxine.

Contraindications. Isoniazid: previous isoniazid hepatitis. Rifampicin: previous severe reaction to any rifamycin, and use with drugs that cannot be dose-adjusted. Pyrazinamide: acute gout and severe liver disease. Ethambutol: optic neuritis, and use with caution when vision cannot be assessed.

Serious adverse effects. Hepatitis (stop when ALT is more than 3 times the upper limit of normal with symptoms, or more than 5 times without); severe cutaneous reactions; rifampicin-induced thrombocytopenia, haemolytic anaemia and acute kidney injury, mainly after interrupted treatment; optic neuritis.

Common prescribing errors. Dosing by fixed tablets in underweight patients; failing to adjust for weight gain; omitting pyridoxine; giving ethambutol at doses over 25 mg/kg; forgetting that rifampicin cancels hormonal contraception, so a non-hormonal method is needed.

Monitoring. Baseline liver enzymes, creatinine, HIV status and visual acuity. Repeat liver enzymes at 2 and 4 weeks, and then as needed, in patients at risk or with symptoms.

Special groups.

• Kidney impairment: isoniazid and rifampicin unchanged. When creatinine clearance is under 30 mL/min, pyrazinamide 25 to 35 mg/kg and ethambutol 15 to 25 mg/kg three times weekly, dosed after dialysis.
• Liver disease: avoid pyrazinamide in severe disease.
• Pregnancy: all four are used with pyridoxine 25 mg daily. Breastfeeding: compatible.
• Children: ethambutol is used at 20 mg/kg with a low risk of eye toxicity.