Treatment: Tuberculosis Drugs First-Line Agents  - Rifampin: Rifampin is the most important and potent antituberculous agent. The standard dosage in adults is 600 mg/d.
- - The drug distributes well throughout body tissues, including inflamed meninges. It turns body fluids (e.g., urine, saliva, tears) red-orange and is excreted through bile and the enterohepatic circulation.
- - Rifampin is usually well tolerated; adverse events are infrequent and generally mild.
- - Of note, rifampin is a potent inducer of the hepatic cytochrome P450 system and decreases the half-life of many other drugs.
- Isoniazid: Isoniazid is a critical drug for active and latent TB disease. The usual adult dosage is 300 mg/d or 900 mg twice per week.
- - Isoniazid is distributed well throughout the body and infected tissues, including CSF and body cavities.
- - The most important toxicities are hepatotoxicity and peripheral neuropathy.
- Isoniazid-associated hepatitis is idiosyncratic. Its frequency increases with age and alcohol use and in the postpartum period.
- Because peripheral neuropathy can result from interference with pyridoxine metabolism, pyridoxine (25-50 mg/d) should be given to pts with other risk factors for neuropathy, such as diabetes, alcohol abuse, or malnutrition.
- Ethambutol: The least potent first-line agent, ethambutol is synergistic with the other drugs in the standard first-line regimen. Ethambutol is usually given at a dosage of 15 mg/kg daily.
- - The drug is distributed throughout the body but reaches only low levels in CSF.
- - This agent can cause dose-dependent optic neuritis, producing central scotoma and impairing both visual acuity and the ability to see green.
- Pyrazinamide: The usual dosage is 15-30 mg/kg daily (maximum, 2 g/d). The drug distributes well throughout the body, including the CSF.
- - Hyperuricemia that can be managed conservatively is common.
- - Clinical gout is rare.
Other Effective Agents - Streptomycin: The usual adult dose is 0.75-1.0 g IM daily or 5 times per week. Streptomycin causes ototoxicity (primarily vestibulotoxicity) but is less nephrotoxic than other aminoglycosides.
- Rifabutin: Rifabutin has fewer drug interactions than rifampin and is recommended in place of rifampin for HIV-infected pts who are taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Rifabutin reaches tissue concentrations 5-10 times higher than those in plasma and has a much longer half-life than rifampin. The drug is well tolerated, and its adverse effects are dose related.
- Rifapentine: Rifapentine is similar to rifampin but can be given once or twice weekly. This drug is not approved for treatment in HIV-infected pts because of elevated rates of relapse.
Second-Line Agents - Fluoroquinolones:Levofloxacin, gatifloxacin (no longer marketed in the United States because of its severe toxicity), and moxifloxacin have solid, broad antimycobacterial activity. Ciprofloxacin and ofloxacin are no longer recommended for treatment of TB because of poor efficacy.
- Other agents (e.g., capreomycin, clofazimine, linezolid) are used uncommonly but may be needed in disease caused by resistant strains of M. tuberculosis.
Regimens See Table 94-1. - During the initial phase, the majority of tubercle bacilli are killed, symptoms resolve, and usually the pt becomes noninfectious. The continuation phase is required to eliminate persisting mycobacteria and prevent relapse.
- Nonadherence to the regimen is the most important impediment to cure. Directly observed treatment (especially during the initial 2 months) and fixed drug-combination products should be used if possible.
- Bacteriologic evaluation is the preferred method of monitoring response to treatment.
- - Virtually all pts should have negative sputum cultures after 3 months of treatment. If the culture remains positive, treatment failure and drug resistance should be suspected.
- - With extrapulmonary TB, bacteriologic monitoring may not be feasible. In these cases, the response to treatment must be assessed clinically and radiographically.
- Drug resistance may be either primary (i.e., present in a strain prior to therapy) or acquired (i.e., arising during treatment because of an inadequate regimen or noncompliance).
- Close monitoring for drug toxicity should take place during treatment and should include baseline LFTs and monthly questioning about possible hepatitis symptoms. High-risk pts (e.g., older pts, pts who use alcohol daily) should have LFT values monitored during treatment.
- For pts with symptomatic hepatitis and those with marked (five- to sixfold) elevations in serum levels of aspartate aminotransferase, treatment should be stopped and drugs reintroduced one at a time after liver function has returned to normal.
- Three important considerations are relevant to TB treatment in HIV-infected pts: an increased frequency of paradoxical reactions, interactions between antiretroviral agents and rifamycins, and development of rifampin monoresistance with widely spaced intermittent treatments.
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