Chemotherapy Of Tuberculosis

Most patients are treated in the ambulatory setting, often after diagnosis and initial therapy in a general hospital. Patients must be seen frequently to follow the course of their disease and treatment. The local health department should be notified and contacts should be investigated for the possibility of disease and for the appropriateness of prophylactic therapy.

Most new cases of tuberculosis in the U.S. are caused by microorganisms that are sensitive to isoniazid, rifampin, ethambutol, and pyrazinamide. To prevent the development of resistance to these agents, treatment must include at least 2 drugs to which the bacteria are sensitive. The preferred 6-month treatment program for drug-sensitive tuberculosis in adults and children consists of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin (for sensitive organisms) for 4 additional months. The combination of isoniazid and rifampin for 9 months is equally effective for sensitive tuberculosis. Because of the increasing frequency of drug resistance, the Centers for Disease Control and Prevention (CDC) recommends initial therapy with a 4-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) pending sensitivity results. Directly observed therapy is best and ensures treatment completion rates of ~90%.

Drug interactions are a special concern in patients receiving highly active antiretroviral therapy (HAART). The rifamycins accelerate the metabolism of protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin has the least effect on serum levels and is indicated in this setting.

HIV-infected patients may benefit from longer (9-12-month) treatment regimens. Treatment should be initiated with at least a 4-drug regimen consisting of isoniazid, rifabutin, pyrazinamide, and ethambutol or streptomycin. An initial 5- or 6-drug regimen may be appropriate in patients likely infected with multidrug-resistant strains. Treatment should be continued for at least 6 months after three negative cultures have been obtained. If isoniazid or rifampin cannot be used, therapy should be continued for at least 18 months (12 months after cultures become negative). Chemo-prophylaxis (see below) should be undertaken if a patient with HIV infection has a positive tuberculin test (induration >5 mm), a history of a positive tuberculin skin test that was not treated with chemoprophylaxis, or recent close contact with a potentially infectious patient with tuberculosis. Isoniazid does not reduce the incidence of tuberculosis in anergic patients with HIV, so chemopro-phylaxis in this setting has been abandoned.

therapy of specific types of tuberculosis

Therapy for drug-sensitive pulmonary tuberculosis consists of isoniazid (5 mg/kg, up to 300 mg/day), rifampin (10 mg/kg/day, up to 600 mg daily), pyrazinamide (15—30 mg/kg/day or a maximum of 2 g/day), and a fourth agent, typically either ethambutol (usual adult dose of 15 mg/kg once per day) or streptomycin (1 g daily). The streptomycin dose is reduced to 1 g twice weekly after 2 months. Pyridoxine, 15—50 mg/day, also should be included for most adults to minimize adverse reactions to isoniazid. Isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin are given for 2 months; isoniazid and rifampin are then continued for 4 more months. Doses in children are isoniazid, 10 mg/kg/day (300 mg maximum); rifampin, 10—20 mg/kg/day (600 mg maximum); pyrazinamide, 15—30 mg/kg/day (2 g maximum). Isoniazid, rifampin, and ethambutol are considered safe during pregnancy.

Clinical improvement usually is seen within the first 2 weeks of therapy. Progressive radiological improvement also is evident. Over 90% of patients who receive optimal treatment will have negative cultures within 3-6 months. Cultures that remain positive after 6 months frequently yield resistant microorganisms; the need for an alternative therapeutic program should then be considered.

Chemotherapy failure may be due to (1) irregular or inadequate therapy (resulting in persistent or resistant mycobacteria) caused by poor patient adherence to the protracted therapeutic regimen; (2) the use of a single drug, with interruption necessitated by toxicity or hypersensitiv-ity; (3) an inadequate initial regimen; or (4) primary resistance of the microorganism.

PROBLEMS IN CHEMOTHERAPY Bacterial Resistance to Drugs

An important problem in the chemotherapy of tuberculosis is bacterial resistance, primarily due to poor patient adherence. To prevent noncompliance and the attendant development of drug-resistant tuberculosis, directly observed therapy is advisable for most patients (i.e., a health care provider observes the patient take the medications 2-5 times weekly).

Where drug resistance is suspected (i.e., in previously treated patients), therapy should be instituted with 5 or 6 drugs, including 2 or 3 that the patient has not previously received. Such a regimen might include isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin, and ethion-amide. Some physicians include isoniazid in the therapeutic regimen, even if microorganisms are resistant, on the belief that disease with isoniazid-resistant mycobacteria does not "progress" during such therapy. Others discontinue isoniazid to lessen the possibility of toxicity. Therapy should be continued for at least 24 months.

Nontuberculous (Atypical) Mycobacteria

These microorganisms (not including M. avium complex) frequently are resistant to many of the commonly used agents; drugs therefore should be selected based on sensitivity in vitro (Table 47-1). Surgical removal of infected tissue followed by long-term treatment with effective drugs may be needed.

M. kansasii and M. tuberculosis cause similar disease. Therapy of the former with isoniazid, rifampin, and ethambutol has been successful. Mycobacterium marinum causes skin lesions. A combination of rifampin and ethambutol is probably effective; minocycline or tetracycline is active in vitro and is used by some physicians. M. scrofulaceum is an uncommon cause of cervical lymphadenitis that is treated with surgical excision. Microbes of the M. fortuitum complex (including Mycobacterium chelonae) may cause chronic lung disease and infections of skin and soft tissues. The microorganisms are highly resistant to most drugs, but amikacin, cefoxitin, and tetracyclines are active in vitro.

chemoprophylaxis of tuberculosis Chemoprophylaxis of tuberculosis involves treating latent infection to prevent progression to active disease. Latent infection may be diagnosed by a positive reaction to a purified protein derivative (PPD) of tuberculosis injected intradermally (the "tuberculin test"). The CDC recommends prophylaxis with isoniazid for 6-9 months or rifampin for 4 months if isoniazid cannot be used. A 2-month regimen of daily rifampin and pyrazinamide has also been used in HIV-infected individuals.

Prophylactic therapy should be considered in patients exposed to tuberculosis who have evidence of infection, including immunosuppressed patients (e.g., HIV-infected) with >5 mm induration on PPD testing; immunocompetent patients with >10 mm induration on PPD testing and risk factors for TB but no apparent disease; and those with a history of tuberculosis in whom the disease is currently "inactive." The main risk of chemoprophylaxis is isoniazid-induced hepatitis. Monitored isoniazid prophylaxis minimizes this risk, even in patients over the age of 35.

Household contacts and other close associates of patients with tuberculosis who have negative tuberculin tests should receive isoniazid for at least 6 months after the contact has been broken, regardless of age. This is especially important for children. If the PPD test becomes positive, therapy should be continued for 12 months.

Patients with "inactive" tuberculosis who have not received adequate therapy should be considered for 1 year of isoniazid treatment. HIV-infected intravenous drug abusers with a positive PPD test have ~8% chance per year of developing active tuberculosis. Isoniazid prophylaxis in HIV-infected persons appears to be as effective as in non-immunocompromised persons. The CDC recommends that isoniazid prophylaxis be continued for 12 months. Persons infected with HIV who are exposed to multidrug-resistant tuberculosis should receive prophylaxis with rifampin and pyrazinamide (with close monitoring for hepatic toxicity) or high-dose ethambutol and pyrazi-namide, with or without a fluoroquinolone.

Isoniazid prophylaxis is contraindicated for patients who have active hepatic disease or who have had reactions to the drug. In these individuals, rifampin for 4 months can be given. In pregnant women, prophylaxis usually should be delayed until after delivery. For prophylaxis, isoniazid generally is given to adults in a daily dose of 300 mg. Children should receive 10 mg/kg to a maximal daily dose of 300 mg. Pyridoxine should be coadministered in individuals susceptible to isoniazid-induced neuropathy.

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