Mycobacteria have caused epic diseases: 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 abscessus has now been called a new “antibiotic” nightmare because of its tenacity, lack of response to combination antibiotics, and a nearly universal propensity to develop acquired drug resistance. Mycobacterium avium-intracellulare (or MAC) infection continues to be difficult to treat, mainly due to three natural barriers:
Cell wall. Mycobacterium, from the Greek mycos, refers to mycobacteria’s waxy appearance, which is 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 76–90 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, ABC permeases comprise a full 2.5% of the genome of Mycobacterium tuberculosis.
Location in host. 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 defined by their rate of growth on agar as rapid and slow growers (see list in Table 60–1). 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. Recent evidence suggests that in countries such as the U.S., M. abscessus now accounts for 80% of rapid growers from the respiratory system (Griffith et al., 2007). The pharmacology of drugs developed against slow growers is discussed in this chapter. However, rapid growers tend to be treated with antibiotics used to treat nonmycobacteria, such as macrolides, aminoglycosides, quinolones, and -lactams, whose pharmacology is discussed in Chapters 56, 57, 58, 59.
Table 60–1Pathogenic Mycobacterial Slow and Rapid Growers (Runyon Classification)