Chapter 56: Antituberculous Medications

HISTORY AND EPIDEMIOLOGY

Approximately one-third of the total population of the world, or 2 billion ­people, are infected with Mycobacterium tuberculosis. An estimated 10.4 million new cases of disease are diagnosed annually.¹⁶⁹ In 2010, 1.45 million deaths were reported; of which approximately 0.35 million were attributed to HIV-associated tuberculosis. In 2014, the incidence of TB in the United States was the lowest recorded (9,412 new cases) since the inception of national reporting in 1953, but in 2015, the number increased to 9557, after declining annually for more than 20 years.^25,134 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 decreased the prevalence rate in the United States and worldwide.¹¹⁵ In 2006, 20% of Mycobacterium tuberculosis isolates were resistant to at least isoniazid and rifampin, called multidrug-resistant tuberculosis (MDR-TB), and 2% were identified as highly resistant extensively drug-resistant tuberculosis (XDR-TB), with resistance to many additional drugs—defined as all fluoroquinolones, and at least one of 3 injectable drugs (capreomycin, kanamycin, and amikacin).^9,24 Between 1993 and 2015, 73 cases of XDR-TB were reported in the United States.²⁶

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.⁹ The use of multiple drugs in regimens against MDR-TB and XDR-TB results in significant adverse drug effects, approximately 40%, and this increases to approximately 70% in treatment against coinfection with human immunodeficiency virus (HIV). These reactions include hepatotoxicity, peripheral neuropathy, arthralgias, rash, anemia, and require discontinuation of therapy if severe. These effects are greatest in the first weeks of therapy, often are irreversible, and potentially fatal.⁹⁷

ISONIAZID

Pharmacology

Isoniazid (INH, or isonicotinic hydrazide) is structurally related to nicotinic acid (niacin, or vitamin B₃), nicotinamide adenosine dinucleotide (NAD), and pyridoxine (vitamin B₆) (Fig. 56–1). The pyridine ring is essential for antituberculous activity. Isoniazid itself does not have direct antibacterial activity. It is a prodrug that undergoes metabolic activation by KatG, a catalase peroxidase in M. tuberculosis that ...