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OVERVIEW

The two main aims of TB treatment are (1) to prevent morbidity and death by curing TB while preventing the emergence of drug resistance and (2) to interrupt transmission by rendering patients noninfectious to others. Chemotherapy for TB became possible with the discovery of streptomycin in 1943. Randomized clinical trials clearly indicated that the administration of streptomycin to patients with chronic TB reduced mortality rates and led to cure in the majority of cases. However, monotherapy with streptomycin was soon associated with the development of resistance to this drug and the resulting failure of treatment. With the introduction into clinical practice of para-aminosalicylic acid (PAS) and isoniazid, it became axiomatic in the early 1950s that cure of TB required the concomitant administration of at least two agents to which the organism was susceptible. Furthermore, early clinical trials demonstrated that a long period of treatment—i.e., 12–24 months—was required to prevent recurrence. The introduction of rifampin (rifampicin) in the early 1970s heralded the era of effective short-course chemotherapy, with a treatment duration of <12 months. The discovery that pyrazinamide, which was first used in the 1950s, augmented the potency of isoniazid/rifampin regimens led to the use of a 6-month course of this triple-drug regimen as standard therapy. Streptomycin was added as the fourth drug mainly to prevent the emergence of drug resistance. These four drugs (with streptomycin eventually replaced by ethambutol) still form the basis of the optimal treatment regimen for rifampin-susceptible TB. The emergence of drug-resistant TB in the 1990s prompted attempts to standardize the approach to treatment of this condition mainly on the basis of expert opinion. This event has also stimulated research on and development of new anti-TB agents in the past 15 years. In 2013 and 2014, respectively, bedaquiline and delamanid—the first two drugs specifically developed for TB during nearly half a century—received conditional approval by the U.S. Food and Drug Administration (FDA) and other drug-regulatory authorities; approval was based on the results of phase 2b clinical trials in which the drugs were added to the 18- to 24-month WHO-recommended regimen for MDR-TB. Bedaquiline and delamanid are being used increasingly for treatment of MDR-TB under specific conditions.

DRUGS FOR THE TREATMENT OF TUBERCULOSIS

Four major drugs are considered first-line agents for the treatment of TB: isoniazid, rifampin, pyrazinamide, and ethambutol. Table 173-2 presents currently recommended dosages in adults and children. Some studies have suggested increased effectiveness when isoniazid, rifampin, and pyrazinamide are given at higher dosage; thus, if these findings are confirmed, dosages may be revised in the future. These drugs are well absorbed after oral administration, with peak serum levels at 2–4 h and nearly complete elimination within 24 h. Isoniazid and rifampin, two key anti-TB drugs, are recommended on the basis of their bactericidal activity (i.e., their ability to rapidly reduce the number of viable organisms and render patients noninfectious). All four agents are recommended in light of their ...

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