Antituberculous Drugs

Antituberculous drugs are antibacterial agents active against Mycobacterium tuberculosis, always given in combination because a single drug selects resistant mutants within weeks. The first-line drugs (isoniazid, rifampicin, pyrazinamide, ethambutol) cure drug-susceptible disease in 6 months. Fluoroquinolones, bedaquiline, linezolid and other agents are reserved for resistant disease.

Why combinations. Spontaneous resistance mutations occur in roughly 1 in a million bacilli for isoniazid and 1 in 100 million for rifampicin. A cavity can hold 100 million to 1 billion organisms, so a single drug, or one drug added to a failing regimen, selects resistance. Treatment starts with at least three active drugs.

Mechanism.

• Isoniazid: prodrug activated by bacterial catalase-peroxidase; blocks mycolic acid synthesis. Bactericidal against dividing bacilli.
• Rifampicin, rifapentine and rifabutin: inhibit bacterial DNA-dependent RNA polymerase. Bactericidal and sterilising.
• Pyrazinamide: prodrug converted to pyrazinoic acid, active in acidic inflamed lesions and inside macrophages. Sterilising; allows 6 rather than 9 months of treatment.
• Ethambutol: blocks arabinosyl transferases in cell wall synthesis. Bacteriostatic at usual doses; protects against emerging resistance.
• Fluoroquinolones inhibit DNA gyrase. Bedaquiline inhibits ATP synthase. Linezolid binds the 50S ribosomal subunit. Delamanid and pretomanid are nitroimidazoles that block mycolic acid synthesis. Aminoglycosides bind the 30S subunit.

Phases. The intensive phase (usually 2 months) rapidly lowers bacillary load. The continuation phase (usually 4 months) removes persisting organisms and prevents relapse.

• First-line: isoniazid, rifampicin, pyrazinamide, ethambutol. Rifapentine serves short-course regimens and preventive therapy. Rifabutin replaces rifampicin when induction would defeat a co-prescribed drug, such as a protease inhibitor.
• Core resistant-disease drugs: levofloxacin, moxifloxacin, bedaquiline, linezolid, pretomanid.
• Add-on drugs: clofazimine, cycloserine or terizidone, delamanid.
• Companion drugs: amikacin, streptomycin, ethionamide or prothionamide, para-aminosalicylic acid, imipenem-cilastatin or meropenem with clavulanic acid.
• Kanamycin and capreomycin are no longer advised because of poorer outcomes and toxicity.

Elimination. Isoniazid is acetylated by NAT2; slow acetylators have higher levels, more neuropathy and more hepatotoxicity, and their frequency varies by ancestry. Rifampicin is cleared by bile and induces its own metabolism over 1 to 2 weeks. Pyrazinamide and ethambutol depend on renal clearance.

Activity profile. Isoniazid kills fast-growing bacilli early. Rifampicin and pyrazinamide kill slowly metabolising bacilli and determine how short treatment can be.

• Drug-susceptible tuberculosis (pulmonary and most extrapulmonary): 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, then 4 months of isoniazid and rifampicin, all daily.
• Adult daily doses: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g), ethambutol 15 mg/kg.
• Child daily doses: isoniazid 10 mg/kg, rifampicin 15 mg/kg, pyrazinamide 35 mg/kg, ethambutol 20 mg/kg.
• Fixed-dose combinations are preferred. The adult four-drug tablet (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg, ethambutol 275 mg) is given as 3 tablets for 38 to 54 kg, 4 tablets for 55 to 70 kg and 5 tablets over 70 kg.
• Tuberculous meningitis, bone and joint disease need longer treatment, often 9 to 12 months.
• Rifampicin resistance on rapid molecular testing moves the patient to a resistant-disease regimen with specialist input. Never add a single drug to a failing regimen.
• With HIV coinfection, start antiretroviral therapy within 2 weeks if the CD4 count is under 50 cells/mm3 and within 8 weeks otherwise. In tuberculous meningitis, start later because of paradoxical deterioration. With rifampicin, dolutegravir is increased to 50 mg twice daily.

Hepatotoxicity. Isoniazid, rifampicin and pyrazinamide all cause it. Check baseline liver enzymes in high-risk patients (alcohol use, chronic liver disease, HIV, age over 35 years, pregnancy). Stop all hepatotoxic drugs if ALT is more than 3 times the upper limit of normal with symptoms or jaundice, or more than 5 times without symptoms.

Other class effects.

• Isoniazid: peripheral neuropathy (give pyridoxine 10 to 25 mg daily), rash, drug-induced lupus.
• Rifampicin: orange discolouration of fluids, thrombocytopenia, haemolysis, flu-like illness, enzyme induction.
• Pyrazinamide: hyperuricaemia, arthralgia.
• Ethambutol: dose-related optic neuritis; check visual acuity and red-green colour vision at baseline and when symptoms arise.

Monitoring. Weigh at start and monthly, review adherence and symptoms monthly, repeat sputum smear or culture at the end of the intensive phase and at month 5 to 6. Persistent positivity needs a repeat molecular test for resistance.

Special groups.

• Pregnancy: isoniazid, rifampicin, pyrazinamide and ethambutol are used; add pyridoxine. Streptomycin is avoided because of foetal ototoxicity.
• Breastfeeding: first-line drugs are compatible; give the breastfed infant pyridoxine if the mother takes isoniazid.
• Kidney impairment: pyrazinamide and ethambutol are given 3 times weekly when creatinine clearance is under 30 mL/min.
• Liver disease: use the fewest hepatotoxic drugs possible, often with ethambutol, a fluoroquinolone and a companion agent.

Referral and escalation. Refer for drug resistance, treatment failure, hepatitis that does not settle, visual loss, severe cutaneous reactions or drug-drug interactions with antiretroviral or anticonvulsant therapy.