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

1530 In general, organisms are considered susceptible to
clarithromycin and azithromycin at MICs ≤2 μg/mL.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Clarithromycin and azithromycin have some activity
against H. influenzae, with MIC breakpoints of ≤8 μg/mL and
≤4 μg/mL, respectively. However, these agents are not drugs of
choice for documented H. influenzae infections because of their
lesser activity compared to β-lactams or fluoroquinolones.
Clarithromycin is slightly more potent than erythromycin against
sensitive strains of streptococci and staphylococci, and has modest
activity against H. influenzae and N. gonorrhoeae.
Azithromycin generally is less active than erythromycin against
gram-positive organisms and slightly more active than either
erythromycin or clarithromycin against H. influenzae and
Campylobacter spp. Clarithromycin and azithromycin have good
activity against M. catarrhalis, Chlamydia spp., L. pneumophila,
B. burgdorferi, Mycoplasma pneumoniae, and H. pylori.
Azithromycin and clarithromycin have enhanced activity against
M. avium-intracellulare, as well as against some protozoa (e.g.,
Toxoplasma gondii, Cryptosporidium, and Plasmodium spp.).
Clarithromycin has good activity against Mycobacterium leprae.
Telithromycin’s spectrum of activity is similar to
clarithromycin and azithromycin. MIC breakpoints for
telithromycin are ≤0.25 μg/mL for S. aureus, ≤1 μg/mL
for S. pneumoniae, and ≤4 μg/mL for H. influenzae.
Telithromycin’s ability to withstand many macrolide
resistance mechanisms increases its activity against
macrolide-resistant S. pneumoniae and S. aureus.
Mechanism of Action. Macrolide antibiotics are bacteriostatic agents
that inhibit protein synthesis by binding reversibly to 50S ribosomal
subunits of sensitive microorganisms (Figure 55–3), at or very near
the site that binds chloramphenicol (Figure 55–2). Erythromycin
does not inhibit peptide bond formation per se but rather inhibits the
translocation step wherein a newly synthesized peptidyl tRNA molecule
moves from the acceptor site on the ribosome to the peptidyl
donor site. Gram-positive bacteria accumulate ~100 times more
erythromycin than do gram-negative bacteria. Cells are considerably
more permeable to the unionized form of the drug, which probably
explains the increased antimicrobial activity at alkaline pH.
Ketolides and macrolides have the same ribosomal target site. The
principal difference between the two is that structural modifications
within ketolides neutralize the common resistance mechanisms that
make macrolides ineffective (Nilius and Ma, 2002).
Resistance to Macrolides and Ketolides. Resistance
to macrolides usually results from one of four
mechanisms:
• drug efflux by an active pump mechanism (encoded
by mrsA, mefA, or mefE in staphylococci, group A
streptococci, or S. pneumoniae, respectively)
• ribosomal protection by inducible or constitutive
production of methylase enzymes, mediated by
expression of ermA, ermB, and ermC, which modify
the ribosomal target and decrease drug binding
Nascent
polypeptide
chain
P site
Macrolides
tRNA
50S
30S
A site
Transferase
site
mRNA
template
Figure 55–3. Inhibition of bacterial protein synthesis by the
macrolide antibiotics erythromycin, clarithromycin, and azithromycin.
Macrolide antibiotics are bacteriostatic agents that inhibit protein
synthesis by binding reversibly to the 50S ribosomal subunits of
sensitive organisms. Erythromycin appears to inhibit the translocation
step such that the nascent peptide chain temporarily residing at
the A site of the transferase reaction fails to move to the P, or donor,
site. Alternatively, macrolides may bind and cause a conformational
change that terminates protein synthesis by indirectly interfering
with transpeptidation and translocation. See Figure 55–1 and its legend
for additional information.
• macrolide hydrolysis by esterases produced by
Enterobacteriaceae (Lina et al., 1999; Nakajima, 1999)
• chromosomal mutations that alter a 50S ribosomal
protein (found in B. subtilis, Campylobacter spp.,
mycobacteria, and gram-positive cocci)
The MLS B
(macrolide-lincosamide-streptogramin B) phenotype
is conferred by erm genes, which encode methylases that modify
the macrolide binding of the ribosome. Because macrolides,
lincosamides, and type B streptogramins share the same ribosomal
binding site, constitutive expression of erm confers cross-resistance
to all three drug classes. If resistance is due to inducible expression
of erm, there is resistance to the macrolides, which are inducers of
erm, but not to lincosamides and streptogramin B, which are not
inducers. Cross-resistance can still occur if constitutive mutants are
selected by exposure to lincosamides or streptogramin B. Effluxmediated
resistance to macrolides may not result in cross-resistance
to lincosamides or streptogramin B because they are structurally dissimilar
to macrolides and are not substrates of the macrolide pump.
Introduction of the 3-keto function converts a methylaseinducing
macrolide into a noninducing ketolide. This moiety also
prevents drug efflux, probably because it generates a less-desirable
substrate. The carbamate substitution at C11-C12 enhances binding
to the ribosomal target site, even when the site is methylated, by
introducing an extra interaction of the ketolide with the ribosome.
Inducible and constitutive methylase-producing strains of S. pneumoniae
are therefore susceptible to telithromycin. However, constitutive
methylase-producing strains of S. aureus and S. pyogenes are
telithromycin resistant because the strength of the ketolide interaction
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