Mycobacteria have caused epic diseases: Tuberculosis (TB) and leprosy have terrorized humankind since antiquity, and TB is thought to have killed one in seven of humans who have ever lived. Although the burden of leprosy has decreased, TB surpassed human immunodeficiency virus (HIV) as the leading infectious disease killer in 2014, and nontuberculous mycobacteria (NTM) are a growing threat in certain populations (Winthrop et al., 2020). Mycobacterium abscessus, a species of NTM, is especially devastating because of its tenacity, lack of response to combination antibiotics, and nearly universal propensity to develop acquired drug resistance. These distinct mycobacterial infections continue to be difficult to treat, owing mainly to three natural barriers:
Cell wall. Mycobacteria are waxy in appearance, due to the composition of the 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 to 90 carbon atoms. This extraordinary shield prevents many pharmacological compounds from getting to the bacterial cell membrane or inside the cytosol.
Efflux pumps. 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) transporters, a group of permeases that transport across membranes, comprise a full 2.5% of the genome of Mycobacterium tuberculosis (Braibant et al., 2000).
Location in host. Mycobacterial infections are intracellular and extracellular, with bacilli hiding both inside patients’ cells and within necrotic, avascular areas of the lung. Antimicrobials must therefore penetrate the intracellular compartments and into the lesions where mycobacteria reside to be effective.
Summarizing antimycobacterial therapeutics is challenging, but we have taken the approach in this chapter of (1) organizing agents into those developed specifically for TB (or NTM) treatment versus those repurposed for that indication and (2) summarizing therapies for TB versus other types of mycobacteria. In presenting pharmacotherapies for TB, we periodically refer to drug groups A, B, and C, as delineated by the World Health Organization (WHO). This classification is explained fully later in the chapter (see the section on Definitive Therapy of Drug-Resistant TB and Table 65–6).
The first-line drugs we use for TB treatment were developed expressly for that purpose (see History). In fact, the first randomized controlled trial with concealed allocation in human history was for the treatment of TB—streptomycin versus bed rest. We divide mycobacteria into tuberculous versus nontuberculous mycobacteria; additionally, we often categorize them by their rate of growth on agar—as rapid and slow growers (see list in Table 65–1). Rapid growers are visible to the naked eye within 7 days; slow growers are visible later. The pharmacology of drugs developed against slow growers is ...