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

1540 Antimicrobial Activity. Vancomycin possesses activity against a broad
spectrum of gram-positive bacteria (Table 55–2). Strains are considered
susceptible at MICs of ≤2 μg/mL for S. aureus, ≤4 μg/mL for
S. epidermidis, and ≤1 μg/mL for streptococci. Bacillus spp., including
B. anthracis, are inhibited by ≤2 μg/mL. Corynebacterium spp.
(diphtheroids) are inhibited by <0.04-3.1 μg/mL of vancomycin; most
species of Actinomyces, by 5-10 μg/mL; and Clostridium spp., by
0.39-6 μg/mL. Essentially all species of gram-negative bacilli and
mycobacteria are resistant to vancomycin.
Teicoplanin is active against methicillin-susceptible and
methicillin-resistant staphylococci, which typically have MICs of
<4 μg/mL. The MICs for Listeria monocytogenes, Corynebacterium
spp., Clostridium spp., and anaerobic gram-positive cocci range from
0.25-2 μg/mL. Nonviridans and viridans streptococci, S. pneumoniae,
and enterococci are inhibited by concentrations ranging
from 0.01-1 μg/mL. Some strains of staphylococci, coagulase
positive and coagulase negative, as well as enterococci and other
organisms that are intrinsically resistant to vancomycin (i.e.,
Lactobacillus spp. and Leuconostoc spp.), are resistant to
teicoplanin.
Mechanism of Action. Vancomycin and teicoplanin inhibit the synthesis
of the cell wall in sensitive bacteria by binding with high affinity
to the D-alanyl-D-alanine terminus of cell wall precursor units
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
A. Polymerization
(NAM–NAG) n
LCP–NAM–NAG
(Figure 55–4). Because of their large molecular size, they are unable
to penetrate the outer membrane of gram-negative bacteria.
Glycopeptides are generally bactericidal against susceptible
strains, except for enterococci. The activity of glycopeptides is best
predicted by the ratio of the total drug exposure (area under the curve
[AUC]) of glycopeptide to minimum inhibitory concentration (MIC)
of the infecting organism. This AUC-to-MIC ratio is established as
being predictive of organism killing and cure in in vitro and animal
models, and in some limited clinical data (Rybak, 2006). An AUCto-MIC
ratio of 400 was predictive of efficacy in patients with
MRSA pneumonia (Moise-Broder et al., 2004). One implication of
the potential importance of this parameter is that increases in organism
MIC, even below the cutoff for susceptibility, can make achieving
this target ratio difficult without substantial dosage increases.
Thus, although an isolate of S. aureus with an MIC of 2 μg/mL
would be considered susceptible, it would be difficult to achieve an
AUC-to-MIC ratio of 400 at standard doses. The validity and target
value of this parameter requires confirmation in further clinical studies
with a variety of organisms and infections. The potential contribution
to toxicity of using higher doses to achieve these target values
also requires consideration (see later in the chapter).
Resistance to Glycopeptides. Strains of enterococci once were uniformly
susceptible to glycopeptides. Glycopeptide-resistant strains
(NAM–NAG) n
NAM–NAG
+
Vancomycin
transglycosylases
LCP
B. Crosslinking
(NAM–NAG) n
(NAM–NAG) n
(NAM–NAG) n
β-Lactam
agents
(NAM–NAG) n
transpeptidases
KEY
L–Alanine
D–Glutamate
L–Lysine
D–Alanine
Glycine
NAM = N–Acetylmuramic acid
NAG = N–Acetylglucosamine
LCP = Lipid carrier bactoprenol
cell wall
Figure 55–4. Inhibition of bacterial cell wall synthesis: vancomycin and β-lactam agents. Vancomycin inhibits the polymerization or
transglycosylase reaction (A) by binding to the D-alanyl-D-alanine terminus of the cell wall precursor unit attached to its lipid carrier
and blocks linkage to the glycopeptide polymer (indicated by the subscript n). These (NAM–NAG) n
peptidoglycan polymers are
located within the cell wall. Van A-type resistance is due to expression of enzymes that modify cell wall precursor by substituting a
terminal D-lactate for D-alanine, reducing vancomycin binding affinity by 1000 times. β-Lactam antibiotics inhibit the cross-linking
or transpeptidase reaction (B) that links glycopeptide polymer chains by formation of a cross-bridge with the stem peptide (the five
glycines in this example) of one chain, displacing the terminal D-alanine of an adjacent chain. See also Figure 53–3.