A 60-year-old man presents to the emergency department with a 2-month history of fatigue, weight loss (10 kg), fevers, night sweats, and a productive cough. He is currently living with friends and has been intermittently homeless, spending time in shelters. He reports drinking about 6 beers per day. In the emergency department, a chest x-ray shows a right apical infiltrate. Given the high suspicion for pulmonary tuberculosis, the patient is placed in respiratory isolation. His first sputum smear shows many acid-fast bacilli, and an HIV test returns with a positive result. What drugs should be started for treatment of presumptive pulmonary tuberculosis? Does the patient have a heightened risk of developing medication toxicity? If so, which medication(s) would be likely to cause toxicity?
Mycobacteria are intrinsically resistant to most antibiotics*. Because they grow more slowly than other bacteria, antibiotics that are most active against rapidly growing cells are relatively ineffective. Mycobacterial cells can also be dormant and, thus, resistant to many drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Finally, mycobacteria are notorious for their ability to develop resistance. Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. The drugs used to treat tuberculosis, atypical mycobacterial infections, and leprosy are described in this chapter.
DRUGS USED IN TUBERCULOSIS
Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide, and ethambutol are the traditional first-line agents for treatment of tuberculosis (Table 47–1). Isoniazid and rifampin are the most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95–98% of cases of tuberculosis caused by susceptible strains. An initial intensive phase of treatment is recommended for the first 2 months due to the prevalence of resistant strains. The addition of pyrazinamide during this intensive phase allows the total duration of therapy to be reduced to 6 months without loss of efficacy. In practice, therapy is usually initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol until susceptibility of the clinical isolate has been determined. In susceptible isolates, the continuation phase consists of an additional 4 months with isoniazid and rifampin (Table 47–2). Neither ethambutol nor other drugs such as streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if another drug is used), but the fourth drug provides additional coverage ...