Drugs for Tuberculosis

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.

Isoniazid

Mechanisms

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 katG gene 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.

Pharmacokinetics

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.

Clinical Use

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.

Toxicity and Interactions

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). Hemolysis has occurred in patients with glucose-6-phosphate dehydrogenase (G6PDH) deficiency. A lupus-like syndrome has been reported.

Rifampin

Mechanisms

Rifampin, a derivative of rifamycin, is bactericidal against M tuberculosis. The drug inhibits DNA-dependent RNA polymerase (encoded by the rpo gene) in M tuberculosis and many other microorganisms. Resistance via changes in drug sensitivity of the polymerase often emerges rapidly if the drug is used alone.

Pharmacokinetics

When given orally, rifampin is well absorbed and is distributed to most body tissues, including the central nervous system (CNS). The drug undergoes enterohepatic cycling and is partially metabolized in the liver. Both free drug and metabolites, which are orange-colored, are eliminated mainly in the feces.

Clinical Uses

In the treatment of tuberculosis, rifampin is almost always used in combination with other drugs. However, rifampin can be used as the sole drug in treatment of latent tuberculosis in INH-intolerant patients or in close contacts of patients with INH-resistant strains of the organism. In leprosy, rifampin given monthly delays the emergence of resistance to dapsone. Rifampin may be used with vancomycin for infections due to resistant staphylococci (methicillin-resistant Staphylococcus aureus [MRSA] strains) or pneumococci (penicillin-resistant Streptococcus pneumoniae [PRSP] strains). Other uses of rifampin include the meningococcal and staphylococcal carrier states.

Toxicity and Interactions

Rifampin commonly causes light-chain proteinuria and may impair antibody responses. Occasional adverse effects include skin rashes, thrombocytopenia, nephritis, and liver dysfunction. If given less often than twice weekly, rifampin may cause a flu-like syndrome and anemia. Rifampin strongly induces liver drug-metabolizing enzymes and enhances the elimination rate of many drugs, including anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, terbinafine, and warfarin. Rifabutin , another rifamycin, is less likely to cause drug interactions than rifampin and is equally effective as an antimycobacterial agent. It is usually preferred over rifampin in the treatment of tuberculosis or other mycobacterial infections in AIDS patients.

Ethambutol

Mechanisms

Ethambutol inhibits arabinosyl transferases (encoded by the embCAB operon) involved in the synthesis of arabinogalactan, a component of mycobacterial cell walls. Resistance occurs rapidly via mutations in the emb gene if the drug is used alone.

Pharmacokinetics

The drug is well absorbed orally and distributed to most tissues, including the CNS. A large fraction is eliminated unchanged in the urine. Dose reduction is necessary in renal impairment.

Clinical Use

The main use of ethambutol is in tuberculosis, and it is always given in combination with other drugs.

Toxicity

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