Chapter 56: Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy

INTRODUCTION

Mycobacteria have caused epic diseases: Tuberculosis (TB) and leprosy have terrorized humankind since antiquity. Although the burden of leprosy has decreased, TB is still the most important infectious killer of humans. Mycobacterium avium-intracellulare (or Mycobacterium avium complex; MAC) infection continues to be difficult to treat.

Mycobacterium, from the Greek "mycos," refers to Mycobacteria's waxy appearance, which is due to the composition of their cell walls. More than 60% of the cell wall is lipid, mainly mycolic acids composed of 2-branched, 3-hydroxy fatty acids with chains made of 76-90 carbon atoms! This extraordinary shield prevents many pharmacological compounds from getting to the bacterial cell membrane or inside the cytosol.

A second layer of defense comes from an abundance of efflux pumps in the cell membrane. These transport proteins pump out potentially harmful chemicals from the bacterial cytoplasm back into the extracellular space and are responsible for the native resistance of mycobacteria to many standard antibiotics (Morris et al., 2005). As an example, ATP binding cassette (ABC) permeases comprise a full 2.5% of the genome of Mycobacterium tuberculosis.

A third barrier is the propensity of some of the bacilli to hide inside the patient's cells, thereby surrounding themselves with an extra physicochemical barrier that antimicrobial agents must cross to be effective.

Mycobacteria are separated into two groups, defined by their rate of growth on agar. A list of pathogenic rapid and slow growers is shown in Table 56–1. Rapid growers are visible to the naked eye within 7 days; slow growers are visible later. Slow growers tend to be susceptible to antibiotics specifically developed for Mycobacteria, whereas rapid growers tend to be also susceptible to antibiotics used against many other bacteria. The pharmacology of drugs developed against slow growers is discussed in this chapter.

The mechanisms of action of the anti-mycobacterial drugs are summarized in Figure 56–1. The mycobacterial mechanisms of resistance to these drugs are summarized in Figure 56–2. Pharmacokinetic parameters are presented in terms of Figure 48–1 and Equation 48–1.