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

of enterococci, primarily Enterococcus faecium, have emerged as
major nosocomial pathogens in hospitals in the U.S. Vancomycin
resistance determinants in E. faecium and E. faecalis are located on
a transposon that is part of a conjugative plasmid, rendering it readily
transferable among enterococci and, potentially, other grampositive
bacteria. These strains typically are resistant to multiple
antibiotics, including streptomycin, gentamicin, and ampicillin,
effectively eliminating these as alternative therapeutic agents.
Resistance to streptomycin and gentamicin is of special concern
because the combination of an aminoglycoside with a cell-wallsynthesis
inhibitor is the only reliably bactericidal regimen for
treatment of enterococcal endocarditis.
Enterococcal resistance to glycopeptides is the result of alteration
of the D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-
D-serine (Arias et al., 2000), which bind glycopeptides poorly, due to
the lack of a critical site for hydrogen bonding. Several enzymes
within the van gene cluster are required for this target alteration to
occur. Several phenotypes of resistance to glycopeptides have been
described. The Van A phenotype confers inducible resistance to
teicoplanin and vancomycin in E. faecium and E. faecalis. The Van B
phenotype, which tends to be a lower level of resistance, also has been
identified in E. faecium and E. faecalis. The trait is inducible by vancomycin
but not teicoplanin, and consequently, many strains remain
susceptible to teicoplanin. The Van C phenotype, the least important
clinically and least well characterized, confers resistance only to vancomycin,
is constitutive, and is present in no species of enterococci
other than E. faecalis and E. faecium. Van D and Van E gene clusters
also have been identified, and presumably others will follow.
S. aureus and coagulase-negative staphylococci may
express reduced or “intermediate” susceptibility to vancomycin
(MIC, 4-8 μg/mL) (Garrett et al., 1999; Hiramatsu et al., 1997;
Smith et al., 1999) or high-level resistance (MIC ≥16 μg/mL).
Intermediate resistance is associated with (and may be preceded
by) a heterogeneous phenotype in which a small proportion of cells
within the population (1 in 10 5 to 1 in 10 6 ) will grow in the presence
of vancomycin concentrations >4 μg/mL. The genetic and biochemical
basis of the intermediate phenotype is unknown. Intermediate
strains produce an abnormally thick cell wall, and resistance may be
due to false targets for vancomycin. Several genetic elements and
multiple mutations are involved, and many of the genes that have
been implicated encode enzymes of the cell-wall biosynthetic pathway
(Sieradzki and Tomasz, 1999; Sieradzki et al., 1999). Infections
caused by vancomycin-intermediate strains have failed to respond
to vancomycin clinically and in animal models (Climo et al., 1999;
Moore et al., 2003). Prior treatment courses and low vancomycin
levels may predispose patients to infection and treatment failure with
vancomycin-intermediate strains. These strains typically are resistant
to methicillin and multiple other antibiotics; their emergence is
a major concern because until recently vancomycin has been the only
antibiotic to which staphylococci were reliably susceptible.
The first high-level vancomycin-resistant S. aureus strain
(MIC ≥32 μg/mL) was isolated in June 2002 (Weigel et al., 2003).
This strain, like others that have subsequently been isolated, harbored
a conjugative plasmid into which the Van A transposon,
Tn1546, was integrated as a consequence of an interspecies horizontal
gene transfer from E. faecalis to a methicillin-resistant strain
of S. aureus. These isolates have been variably susceptible to
teicoplanin and the investigational lipoglycopeptides.
Absorption, Distribution, and Excretion
Absorption. Vancomycin is poorly absorbed after oral administration.
For parenteral therapy, the drug should be administered intravenously,
never intramuscularly. Teicoplanin can be administered safely
by intramuscular injection as well as intravenous administration.
Distribution. A single intravenous dose of 1 g in adults produces
plasma concentrations of 15-30 μg/mL 1 hour after a 1- to 2-hour
infusion. Approximately 30% of vancomycin is bound to plasma
protein. Vancomycin appears in various body fluids, including the
CSF when the meninges are inflamed (7-30%); bile; and pleural,
pericardial, synovial, and ascitic fluids. Teicoplanin is highly bound
by plasma proteins (90-95%).
Elimination. About 90% of an injected dose of vancomycin is
excreted by glomerular filtration. The drug has a serum elimination
t 1/2
of ~6 hours. The drug accumulates if renal function is impaired,
and dosage adjustments must be made under these circumstances.
The drug can be cleared rapidly from plasma with high-flux methods
of hemodialysis. In contrast to vancomycin, teicoplanin has an
extremely long serum elimination t 1/2
(up to 100 hours in patients
with normal renal function).
Therapeutic Uses and Dosage. Vancomycin and teicoplanin have
been used to treat a wide variety of infections, including
osteomyelitis and endocarditis, caused by methicillin-resistant and
methicillin-susceptible staphylococci, streptococci, and enterococci.
Teicoplanin has been found to be comparable to vancomycin in efficacy,
except for treatment failures from low doses used for such
serious infections as endocarditis. In general, recommendations for
teicoplanin follow those of vancomycin, except where noted later.
Although extensively studied for >10 years, teicoplanin has not yet
been licensed for use in the U.S.
Vancomycin hydrochloride (VANCOCIN, others) is marketed for
intravenous use as a sterile powder for solution. It should be diluted
and infused over at least a 60-minute period to avoid infusion-related
adverse reactions. The recommended dose of vancomycin for adults
is 30-45 mg/kg per day in 2-3 divided doses. The “therapeutic range”
for this agent is somewhat controversial. Current recommendations
call for monitoring serum trough concentrations (within 30 minutes
prior to a dose) at steady state, typically before the fourth dose of a
given dosage regimen. A minimum target trough serum concentration
of 10 μg/mL is recommended in the most recent consensus
guidelines (Rybak et al., 2009). For patients with more serious infections
(including endocarditis, osteomyelitis, meningitis, and MRSA
pneumonia), trough levels of 15-20 μg/mL are recommended.
General pediatric dosage ranges for vancomycin are as follows: for
newborns during the first week of life, 15 mg/kg initially, followed by
10 mg/kg every 12 hours; for infants 8-30 days old, 15 mg/kg followed
by 10 mg/kg every 8 hours; for older infants (>30 days) and
children, 10-15 mg/kg every 6 hours (Frymoyer et al, 2009).
Alteration of dosage is required for patients with impaired
renal function. Serum drug concentrations may help guide dose
adjustment, but caution should be used in interpreting concentrations
in patients with rapidly changing renal function. In functionally
anephric patients and patients receiving dialysis with non-high-flux
membranes, administration of 1 g (~15 mg/kg) every 5-7 days typically
achieves adequate serum levels. In patients receiving intermittent
high-efficiency or high-flux dialysis, maintenance doses
administered after each dialysis session are typically required
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CHAPTER 55
PROTEIN SYNTHESIS INHIBITORS AND MISCELLANEOUS ANTIBACTERIAL AGENTS