Tuberculosis: Treatment of Disease

Philip A. LoBue

Although the principles of effective antituberculous chemotherapy are reasonably straightforward, even well-trained physicians may treat tuberculosis patients inappropriately. The problem likely reflects the relatively limited experience many physicians have with this disease. As a consequence, local health departments have assumed a greater role in the management of patients with tuberculosis. Whether care is being managed primarily by a private physician or by the health department, the medical provider has two major responsibilities: (1) to prescribe a treatment regimen with appropriate drugs, dosages, and duration, and (2) to ensure adherence to the regimen until the treatment is complete. When non–health department providers assume a primary patient-management role, they should work in partnership with the health department to ensure these responsibilities are met.

Drugs used to treat tuberculosis can be divided into first- and second-line agents. The first-line (i.e., most effective and least toxic) drugs consist of isoniazid, rifampin, pyrazinamide, and ethambutol. Isoniazid and rifampin are very effective bactericidal drugs. Isoniazid’s major adverse reactions include hepatitis and neuritis. The major adverse effects of rifampin are hepatotoxicity and hypersensitivity reactions. Some evidence suggests that the combination of rifampin and isoniazid can be associated with a greater incidence of liver injury than with either drug alone. Hypersensitivity reactions, including a flulike syndrome, thrombocytopenia, and, rarely, acute renal failure, have been reported, usually with intermittent rifampin therapy. Rifampin increases hepatic metabolism of some drugs, causing important drug interactions. Oral contraceptives can be ineffective at normal doses because their hepatic metabolism is increased. In addition, rifampin can induce methadone withdrawal. Pyrazinamide is used for the first 2 months in many treatment regimens. Its principal side effects are hepatotoxicity and hyperuricemia, with the latter rarely leading to gout or renal failure. Ethambutol is a bacteriostatic agent that has been in general use for over three decades. Retrobulbar optic neuritis has occasionally complicated therapy with doses in excess of 20 mg/kg for prolonged periods, but is almost never seen when using 15 mg/kg.

Second-line medications are generally reserved for therapy of drug-resistant disease or for patients intolerant of first-line medications. Fluoroquinolones are among the latest additions to the array of antituberculous drugs. They are generally well-tolerated and several have good in vitro activity against Mycobacterium tuberculosis. Levofloxacin has in vitro activity superior to older fluoroquinolones and a good safety profile with long-term use. The newer fluoroquinolones, such as moxifloxacin, have better in vitro activity, but there is less clinical experience with their use for tuberculosis treatment. Rare gastrointestinal side effects, such as nausea and bloating, and neurologic side effects, including dizziness, insomnia, tremulousness, and headache, may occur with fluoroquinolones. Several second-line medications require intramuscular or intravenous administration. Streptomycin, the first drug available for tuberculosis therapy, is still used occasionally; however, its value is limited by dose-related renal and eighth cranial nerve toxicities and an increasing incidence of drug resistance. Other injectable agents, such as capreomycin, kanamycin, and amikacin, have similar toxicities and may be slightly less effective. p-Aminosalicylic acid (PAS), ethionamide, and cycloserine are oral preparations that are usually used only in multidrug-resistant (MDR) tuberculosis. PAS and ethionamide can cause severe gastrointestinal distress, whereas cycloserine is associated with personality changes, depression, frank psychoses, and, in high doses, seizures. Linezolid, clofazimine, imipenem, macrolides, and amoxicillin/clavulanate are sometimes used as “third-line” drugs in patients with disease-resistant to first- and second-line medications.

Since the development of streptomycin in the 1940s, the treatment of tuberculosis has changed considerably. Although individual patients or situations can require tailored regimens, the combination of isoniazid, rifampin, and pyrazinamide is currently the mainstay of treatment for patients with susceptible organisms. Other drugs, especially ethambutol, fluoroquinolones, and injectable agents have important roles in certain contexts.

For patients with isoniazid- and rifampin-susceptible pulmonary tuberculosis, standard treatment is divided into an initial phase of 2 months (8 weeks) followed by a continuation phase of 4 months (18 weeks). Because of the relatively high rate of isoniazid resistance found in adults, their initial-phase treatment should consist of isoniazid, rifampin, pyrazinamide, and ethambutol pending availability of drug-susceptibility test results. For children, ethambutol usually is not needed, unless there is particular concern for isoniazid resistance or the child has a clinical pattern usually seen in adults (i.e., upper lobe infiltration, cavity formation). Once susceptibility results become available, ethambutol may be discontinued (or omitted if drug susceptibility results are known before treatment is started) if the organism is susceptible to isoniazid and rifampin. The initial phase may be given daily throughout, daily for 2 weeks and then twice weekly for 6 weeks, or three times weekly throughout. Twice-weekly therapy is never recommended for human immunodeficiency virus (HIV)-infected patients with CD4 counts less than 100 in the initial or continuation phases of tuberculosis treatment (see below).

The standard continuation-phase therapy for drug-susceptible tuberculosis consists of isoniazid and rifampin. Treatment may be given daily, two times weekly (except if HIV-infected and CD4 count below 100), or three times weekly. For HIV-negative patients with non–cavitary pulmonary tuberculosis and negative sputum smear results at the completion of 2 months of treatment, an alternative continuation-phase treatment is isoniazid and rifapentine (a long-acting analog of rifampin) given once weekly. The duration of the continuation phase is 4 months (6 months total treatment) for most patients with drug-susceptible tuberculosis. Patients with positive sputum cultures after 2 months of therapy and cavities on chest radiograph are more likely to fail treatment or relapse. Therefore, such patients should have their continuation phase extended to 7 months (9 months total treatment), as should patients being treated with once-weekly isoniazid and rifapentine with positive sputum cultures after 2 months of treatment, regardless of chest radiographic findings.

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