Drug regimens for treating TB
Traditionally, isoniazid, rifampin, and ethambutol were the main-stays of multidrug TB therapy and successfully prevented the emergence of drug resistance.
Because of the current incidence of drug-resistant TB strains, a four-drug regimen is now recommended for initial treatment:
· streptomycin or ethambutol.
The antitubercular regimen should be modified if local testing shows resistance to one or more of these drugs. If local outbreaks of TB resistant to isoniazid and rifampin are occurring in facilities (for example, health care or correctional facilities), then five- orsix-drug regimens are recommended as initial therapy. (See Otherantitubercular drugs.)
Most antitubercular drugs are administered orally. When adminis-tered orally, these drugs are well absorbed from the GI tract and widely distributed throughout the body. They’re metabolized pri-marily in the liver and excreted by the kidneys.
Antitubercular drugs are specific for mycobacteria. At usual dos-es, ethambutol and isoniazid are tuberculostatic, meaning that they inhibit the growth of M. tuberculosis. In contrast, rifampin is tuberculocidal, meaning that it destroys the mycobacteria. Be-cause bacterial resistance to isoniazid and rifampin can develop rapidly, they should always be used with other antitubercular drugs.
The exact mechanism of action of ethambutol remains unclear, but it may be related to inhibition of cell metabolism, arrest of multiplication, and cell death. Ethambutol acts only against repli-cating bacteria.
Although isoniazid’s exact mechanism of action isn’t known, the drug is believed to inhibit the synthesis of mycolic acids, impor-tant components of the mycobacterium cell wall. This inhibition disrupts the cell wall. Only replicating, not resting, bacteria ap-pear to be inhibited.
Rifampin inhibits RNA synthesis in susceptible organisms. The drug is effective primarily in replicating bacteria, but may have some effect on resting bacteria as well.
The exact mechanism of action of pyrazinamide isn’t known, but the antimycobacterial activity appears to be linked to the drug’s conversion to the active metabolite pyrazinoic acid. Pyrazinoic acid, in turn, creates an acidic environment where mycobacteria can’t replicate.
Isoniazid usually is used with ethambutol, rifampin, or pyrazi-namide. This is because combination therapy for TB and other mycobacterial infections can prevent or delay the development of resistance.
Ethambutol is used with isoniazid and rifampin to treat the patient with uncomplicated pulmonary TB. It’s also used to treat infec-tions resulting from M. bovis and most strains of M. kansasii.
Although isoniazid is the most important drug for treating TB, bac-terial resistance develops rapidly if it’s used alone. However, resis-tance doesn’t pose a problem when isoniazid is used alone to pre-vent TB in the patient who has been exposed to the disease, and no evidence exists of cross-resistance between isoniazid and oth-er antitubercular drugs. Isoniazid is typically given orally, but may be given intravenously, if necessary.
Rifampin is a first-line drug for treating pulmonary TB with other antitubercular drugs. It combats many gram-positive and some gram-negative bacteria, but is seldom used for nonmycobacterial infections because bacterial resistance develops rapidly. It’s used to treat asymptomatic carriers of Neisseria meningitidis when the risk of meningitis is high, but it isn’t used to treat N. meningi tidis infections because of the potential for bacte-rial resistance.
Pyrazinamide is currently recommended as a first-line TB drug in combination with ethambutol, rifampin, and isoniazid. Pyrazinamide is ahighly specific drug that’s active only against M. tuberculosis. Resistance to pyrazinamide may develop rapidly when it’s used alone.
Antitubercular drugs may interact with many other drugs. (See Adverse reactions to antitubercular drugs.)
§ Cycloserine and ethionamide may produce additive CNS effects, such as drowsiness, dizziness, headache, lethargy, depression, tremor, anxiety, confusion, and tinnitus (ringing in the ears), when administered with isoniazid.
§ Isoniazid may increase levels of phenytoin, carbamazepine, di-azepam, ethosuximide, primidone, theophylline, and warfarin.
§ When corticosteroids and isoniazid are taken together, the ef-fectiveness of isoniazid is reduced while the effects of corticos-teroids are increased. Isoniazid may reduce the plasma levels of ketoconazole, itra-conazole, and oral antidiabetic agents.
§ Oral contraceptives and rifampin taken together may decrease the effectiveness of the oral contraceptive.
§ When given together, rifampin, isoniazid, ethionamide, and pyrazinamide increase the risk of hepatotoxicity.
§ Pyrazinamide combined with phenytoin may increase phenytoin levels.