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The chemotherapy of infections caused by Mycobacterium tuberculosis, M leprae, and M avium-intracellulare is complicated by numerous factors, including (1) limited information about the mechanisms of antimycobacterial drug actions; (2) the development of resistance; (3) the intracellular location of mycobacteria; (4) the chronic nature of mycobacterial disease, which requires protracted drug treatment and is associated with drug toxicities; and (5) patient compliance. Chemotherapy of mycobacterial infections almost always involves the use of drug combinations to delay the emergence of resistance and to enhance antimycobacterial efficacy.

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The major drugs used in tuberculosis are isoniazid (INH), rifampin, ethambutol, pyrazinamide, and streptomycin. Actions of these agents on M tuberculosis are bactericidal or bacteriostatic depending on drug concentration and strain susceptibility. Appropriate drug treatment involves antibiotic susceptibility testing of mycobacterial isolates. Initiation of treatment of pulmonary tuberculosis usually involves a 3- or 4-drug combination regimen depending on the known or anticipated rate of resistance to isoniazid (INH). Directly observed therapy (DOT) regimens are recommended in noncompliant patients and in drug-resistant tuberculosis.

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Isoniazid

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Mechanisms

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Isoniazid (INH) is a structural congener of pyridoxine. Its mechanism of action involves inhibition of mycolic acids, characteristic components of mycobacterial cell walls. Resistance can emerge rapidly if the drug is used alone. High-level resistance is associated with deletion in the katGgene that codes for a catalase-peroxidase involved in the bioactivation of INH. Low-level resistance occurs via deletions in the inhA gene that encodes the "target enzyme," an acyl carrier protein reductase. INH is bactericidal for actively growing tubercle bacilli but is less effective against dormant organisms.

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Pharmacokinetics

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INH is well absorbed orally and penetrates cells to act on intracellular mycobacteria. The liver metabolism of INH is by acetylation and is under genetic control. Patients may be fast or slow inactivators of the drug. INH half-life in "fast acetylators" is 60–90 min; in "slow acetylators" it may be 3–4 h. The proportion of fast acetylators is higher among people of Asian origin (including Native Americans) than those of European or African origin. Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic effects.

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Clinical Use

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INH is the single most important drug used in tuberculosis and is a component of most drug combination regimens. In the treatment of latent infection (formerly known as "prophylaxis") including skin test converters and for close contacts of patients with active disease, INH is given as the sole drug.

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Toxicity and Interactions

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Neurotoxic effects are common and include peripheral neuritis, restlessness, muscle twitching, and insomnia. These effects can be alleviated by administration of pyridoxine (25–50 mg/d orally). INH is hepatotoxic and may cause abnormal liver function tests, jaundice, and hepatitis. Fortunately, hepatotoxicity is rare in children. INH may inhibit the hepatic metabolism of drugs (eg, carbamazepine, phenytoin, warfarin). ...

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