DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Chemotherapy of Tuberculosis,
Mycobacterium Avium Complex
Disease, and Leprosy
Tawanda Gumbo
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.
History. The first successful drug for treating TB was para-amino
salicylic acid (PAS), developed by Lehman in 1943. A more dramatic
success came when Waksman and Schatz developed streptomycin.
Further efforts led to development of thiacetazone by
Domagk in 1946, isoniazid at Squibb, Hoffman La Roche, and Bayer
in 1952, pyrazinamide by Kushner and colleagues in 1952, and
rifamycins by Sensi and Margalith in 1957. Ethambutol was discovered
at Lederle Laboratories in 1961. As might be anticipated, the use
all of these drugs presents problems of drug resistance, adverse events,
and drug interactions. Therefore, newer classes of agents are being
developed. Moxifloxacin, PA-824, and TMC-207 have reached
advanced clinical testing.
ANTI-MYCOBACTERIAL DRUGS
Rifamycins: Rifampin,
Rifapentine, and Rifabutin
Rifampin or rifampicin (RIFADIN; RIMACTANE, others),
rifapentine (PRIFTIN), and rifabutin (MYCOBUTIN) are
important in treatment of mycobacterial diseases.
Chemistry. Rifamycins are macrocyclic antibiotics characterized by
a chromophoric naphthohydroquinone group that is spanned by a