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

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SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Table 56–1
Pathogenic Mycobacterial Rapid and Slow Growers
(Runyon Classification)
SLOW GROWERS
Runyon I: Photochromogens
Mycobacterium kansasii
Mycobacterium marinum
Runyon II: Scotochromogens
Mycobacterium scrofulaceum
Mycobacterium szulgai
Mycobacterium gordonae
Runyon III: Non-chromogens
Mycobacterium avium complex
Mycobacterium haemophilum
Mycobacterium xenopi
RAPID GROWERS
Runyon IV:
Mycobacterium fortuitum complex
Mycobacterium smegmatis group
Slow growers tend to be susceptible to antibiotics specifically developed
for Mycobacteria; rapid growers tend to be susceptible to
antibiotics also used against many other bacteria.
long aliphatic bridge, with an acetyl group at C25. Rifapentine and
rifabutin are derivatives of rifampin, whose structure is:
RIFAMPIN
Mechanism of Action. The mechanism of action for
rifamycins is typified by rifampin’s action against
M. tuberculosis. Rifampin enters bacilli in a concentration
dependent manner, achieving steady-state concentrations
within 15 minutes (Gumbo et al., 2007a).
Rifampin binds to the β subunit of DNA-dependent
RNA polymerase (rpoB) to form a stable drug–enzyme
complex. Drug binding suppresses chain formation in
RNA synthesis.
Antibacterial Activity. Rifampin inhibits the growth of most grampositive
bacteria as well as many gram-negative microorganisms
such as Escherichia coli, Pseudomonas, indole-positive and
indole-negative Proteus, and Klebsiella. Rifampin is very active
against Staphylococcus aureus and coagulase-negative staphylococci.
The drug also is highly active against Neisseria meningitidis
and Haemophilus influenzae. Rifampin inhibits the growth of
Legionella species in cell culture and in animal models.
Rifampin inhibits the growth of many M. tuberculosis clinical
isolates in vitro at concentrations of 0.06-0.25 mg/L (Heifets,
1991). Rifampin is also bactericidal against M. leprae. M. kansasii
is inhibited by 0.25-1 mg/L. Most strains of Mycobacterium scrofulaceum,
Mycobacterium intracellulare, and M. avium are suppressed
by concentrations of 4 mg/L. Mycobacterium fortuitum is highly
resistant to the drug. Rifapentine minimum inhibitory concentrations
(MICs) are similar to those of rifampin. Rifabutin inhibits the growth
of most MAC isolates at concentrations ranging from 0.25-1 mg/L.
Rifabutin also inhibits the growth of many strains of M. tuberculosis
at concentrations of ≤0.125 mg/L and in vitro has better MICs than
rifampin.
Bacterial Resistance. The prevalence of rifampin-resistant
isolates are 1 in every 10 7 to 10 8 bacilli. Microbial resistance
to rifampin is due to an alteration of the target of
this drug, rpoB, with resistance in 86% of cases due to
mutations at codons 526 and 531 of the rpoB gene
(Somoskovi et al., 2001). Rifamycin monoresistance
occurs at higher rates when patients with AIDS and
multi-cavitary TB are treated with either rifapentine or
rifabutin (Burman et al., 2006a).
Mutations in genes involved in DNA repair mechanisms will
impair the repair of multiple genes, which may lead to hyper-mutable
strains (Chapter 48). M. tuberculosis Beijing genotype clinical isolates
have been associated with higher rates of simultaneous rifampin
and isoniazid resistance associated with mutations in the repair genes
mut and ogt (Nouvel et al., 2006; Rad et al., 2003). Inducible or environment-dependent
mutators may be a more common phenomenon
than these stable mutator phenotypes (Warner and Mizrahi, 2006).
Antibiotics, endogenous oxidative and metabolic stressors lead to
DNA damage, which induces dnaE2. The induction is associated
with error-prone DNA repair. This leads to higher rates of rifampin
resistance (Boshoff et al., 2003).
Absorption, Distribution, and Excretion. After oral
administration, the rifamycins are absorbed to variable
extents (Table 56–2) (Burman et al., 2001). Food
decreases the rifampin C Pmax
by one third; a high-fat meal
increases the area under the curve (AUC) of rifapentine
by 50%. Food has no effect on rifabutin absorption. Thus
rifampin should be taken on an empty stomach, whereas
rifapentine should be taken with food, if possible.
Rifamycins are metabolized by microsomal B-esterases
and cholinesterases that remove the acetyl group at position 25,
resulting in 25-O-desacetyl rifamycins. Rifampin is also metabolized
by hydrolysis to 3-formyl rifampin, whereas rifapentine is
metabolized to 3-formyl rifapentine and 3-formyl-25-O-desacetylrifapentine.
A major pathway for rifabutin elimination is CYP3A.
Due to autoinduction, all three rifamycins reduce their own area