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.
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 * The authors thank Henry F. Chambers, MD and Daniel H. Deck, PharmD for their contributions to previous editions.
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 if the isolate proves to be resistant to isoniazid, rifampin, or both. If therapy is initiated after the isolate is known to be susceptible to isoniazid and rifampin, ethambutol does not need to be added. The prevalence of isoniazid resistance among clinical isolates in the USA is approximately 10%. Prevalence of resistance to both isoniazid and rifampin (which is termed multidrug resistance) ranged from 1 to 1.6% from the years 2000 to 2013 in the USA. Multidrug resistance is much more prevalent in many other parts of the world. Resistance to rifampin alone is rare.
TABLE 47–1 Antimicrobials used in the treatment of tuberculosis.
1Assuming normal renal function.
2150 mg/d if used concurrently with a protease inhibitor or cobicistat; 600 mg/d with efavirenz.
3No longer recommended, but may be considered in selected cases if HIV-uninfected without cavitation on chest radiograph.
Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is a small molecule (molecular weight 137) that is freely soluble in water. The structural similarity to pyridoxine is shown below.