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Approximately one-third of the total population of the world, or 2 billion people, are infected with Mycobacterium tuberculosis. An estimated 8.8 million new cases of disease are diagnosed, and 1.6 million persons die from tuberculosis (TB) annually.3 In 2011, the incidence of TB in the United States was the lowest recorded (10,521 new cases) since the inception of national reporting in 1953.22 The introduction of isoniazid (INH) into clinical practice in 1952 produced a steady decline in the number of TB cases in the United States over the subsequent 30 years. However, between 1985 and 1991, there was a resurgence in TB cases in the United States resulting primarily from the effects of human immunodeficiency virus (HIV), homelessness, deterioration in the health care infrastructure, and an increase in immigration. With the initiation and implementation of containment strategies, the spread of the infection slowed by aggressive case identification and patient-centered management, including directly observed therapy, social support, housing, and substance abuse treatment. These methods have decreased the prevalence rate in the United States as well as worldwide. In 2005, the TB incidence was stable or declining worldwide, although the total number of new TB cases continued to increase slowly. Also in that year, extensively drug-resistant tuberculosis (XDR-TB) was recognized.7,21,94 In 2010, at least 5% to 10% of multidrug-resistant tuberculosis (MDR-TB) strains were extensively drug-resistant to both INH and rifampin, all fluoroquinolones, and at least one of three injectable drugs (capreomycin, kanamycin, and amikacin).133 At present, populations that remain at risk for TB include HIV-positive patients, homeless people, people with alcoholism, injection drug users, health care workers, prisoners, prison workers, and Native Americans. In addition, the TB rate in foreign born persons is nearly 10 times higher than in US born persons. In the US population, countries of birth generating the highest number of TB cases are Mexico, the Philippines, India, and Vietnam.7,21 The use of second-line (reserve) drugs and multidrug antituberculous regimens for MDR-TB and XDR-TB resulted in an incidence of adverse drug effects increasing to 40% to 70% and sometimes requiring discontinuation of the treatment. Hepatotoxicity, peripheral neuropathy, and ocular neuropathy are often irreversible and potentially fatal.



Isoniazid (INH, or isonicotinic hydrazide) is structurally related to nicotinic acid (niacin, or vitamin B3), nicotinamide adenosine dinucleotide (NAD), and pyridoxine (vitamin B6) (Fig. 58–1). The pyridine ring is essential for antituberculous activity. INH itself does not have direct antibacterial activity. It is a prodrug that undergoes metabolic activation by KatG, a catalase peroxidase in M. tuberculosis that produces a highly reactive intermediate,95,135 which in turn interacts with InhA, a mycobacterial enzyme that functions as an enoyl-acyl carrier protein (enoyl-ACP) reductase.92,93 InhA is required for the synthesis of very-long-chain lipids, mycolic acids (containing between ...

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