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Drugs Used in the Treatment of Tuberculosis, Mycobacterium avium Complex, and Leprosy

Mycobacterial Species

First-Line Therapy

Alternative Agents

M. tuberculosis

M. avium complex

M. kansasii

Isoniazid + rifampin*+ pyrazinamide + ethambutol or streptomycin

Clarithromycin or azithromycin + ethambutol with or without rifabutin Isoniazid + rifampin*+ ethambutol

M. fortuitum complex Amikacin + doxycycline

M. marinum

M. leprae

Rifampin + ethambutol

Dapsone + rifampin : clofazimine

Moxifloxacin or gatifloxacin; cycloserine; capreomycin; kanamycin; amikacin; ethionamide; clofazimine; aminosalicylic acid Rifabutin; rifampin; ethionamide; cycloserine; moxifloxacin or gatifloxacin Trimethoprim-sulfamethoxazole; ethionamide; cycloserine; clarithromycin; amikacin; streptomycin; moxifloxacin or gatifloxacin Cefoxitin; rifampin; a sulfonamide; moxifloxacin or gatifloxacin; clarithromycin; trimethoprim-sulfamethoxazole; imipenem Trimethoprim-sulfamethoxazole; clarithromycin; minocycline; doxycycline Minocycline; moxifloxacin or gatifloxacin; clarithromycin; ethionamide

*In HIV-infected patients, the substitution of rifabutin for rifampin minimizes drug interactions with the HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors.

THERAPEUTIC USES Isoniazid is the most important drug for the treatment of tuberculosis. Toxic effects are minimized by prophylactic therapy with pyridoxine and careful patient surveillance. For treatment of active infections, the drug is combined with another agent, although it is used alone for prophylaxis.

Isoniazid usually is given orally in a single daily dose of 5 mg/kg, with a maximum of 300 mg. Children should receive 10—20 mg/kg/day (300 mg maximum). After 2 months of daily therapy with isoniazid, rifampin, and pyrazinamide, patients with sensitive strains of M. tuberculosis may be treated twice-weekly with isoniazid (15 mg/kg orally) plus rifampin (10 mg/kg, up to 600 mg/dose) for 4 months.

Pyridoxine, vitamin B6, (10—50 mg/day) is coadministered with isoniazid to minimize the risk of peripheral neuropathy and central nervous system (CNS) toxicity in malnourished patients and those predisposed to neuropathy (e.g., slow acetylators, elderly, pregnant women, human immunodeficiency virus [HIV]-infected subjects, diabetics, alcoholics, and uremics).

UNTOWARD EFFECTS Adverse reactions to isoniazid occur in ~5%, including rash (2%), fever (1.2%), jaundice (0.6%), and peripheral neuritis (0.2%). Isoniazid hypersensitivity may result in fever, rashes, and hepatitis. Hematological reactions also may occur (e.g., agranulocytosis, eosinophilia, thrombocytopenia, and anemia). Vasculitis associated with antinuclear antibodies may appear but disappears when the drug is stopped.

Peripheral neuritis occurs in ~2% of patients receiving 5 mg/kg of drug daily if pyridoxine is not given concurrently. Prophylactic administration of pyridoxine considerably decreases the risk of peripheral neuritis and other nervous system disorders.

Isoniazid may precipitate convulsions, usually in patients with known seizure disorders. Optic neuritis also has occurred. Muscle twitching, dizziness, ataxia, paresthesias, stupor, and potentially fatal encephalopathy are other manifestations of neurotoxicity. A number of mental abnormalities may appear, including euphoria, transient memory impairment, loss of self-control, and psychosis.

Isoniazid inhibits phenytoin parahydroxylation, and signs and symptoms of toxicity occur in ~25% of patients given both drugs, particularly in slow acetylators. Concentrations of phenytoin in plasma should be monitored, and its dose adjusted if necessary.

Severe hepatic injury leading to death may occur in individuals receiving isoniazid, typically presenting 4-8 weeks after initiation of therapy. Liver biopsy reveals bridging and multilobular necrosis. Drug continuation after hepatic dysfunction develops may worsen the damage. Alcoholic hepatitis increases the risk, but chronic carriers of the hepatitis B virus tolerate isoniazid. Age is the most important risk factor for isoniazid-induced hepatotoxicity; it is rare in patients <20 years old, occurs in 0.3% of those 20—34 years old, and increases to 1.2% and 2.3% in individuals 35-49 and >50 years of age, respectively. Up to 12% of patients receiving isoniazid may have elevated serum transaminase levels. Patients receiving isoniazid should be evaluated monthly for symptoms of hepatitis and warned to discontinue the drug if symptoms occur. Some clinicians follow serum transaminases at monthly intervals in high-risk individuals (older age, excessive alcohol intake, history of liver disease); an elevation >five times normal is cause for drug discontinuation. Isoni-azid should be administered with great care to those with preexisting hepatic disease.

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