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

which are more likely to be a problem in patients with hepatic insufficiency
and may be due to accumulation of metabolites, are managed
by reducing the infusion frequency to every 12 hours.
Drug Interactions. Quinupristin/dalfopristin inhibits CYP3A4. The concomitant
administration of other CYP3A4 substrates (Chapter 6) with
quinupristin/dalfopristin may raise blood pressure and/or result in significant
toxicity. Examples include antihistamines (e.g., azelastine and
clemastine); some anticonvulsants (e.g., fosphenytoin and felbamate),
macrolide antibiotics; some fluoroquinolones (e.g., moxifloxacin) and
ketoconazole; some antimalarials (e.g., chloroquine, mefloquine, and
quinine); some antidepressants (e.g., fluoxetine, imipramine, venlafaxine);
some antipsychotics (e.g., haloperidol, risperidone, and quetiapine);
tacrolimus; and doxepin. Appropriate caution and monitoring are
recommended for drugs in which the toxic therapeutic window is narrow
or for drugs that prolong the QTc interval.
OXAZOLIDINONES (LINEZOLID)
Linezolid (ZYVOX) is a synthetic antimicrobial agent of
the oxazolidinone class (Clemett and Markham, 2000;
Diekema and Jones, 2000; Hamel et al., 2000). Several
other oxazolidinones are in clinical development.
O
N
F
Antimicrobial Activity. Linezolid is active against gram-positive
organisms including staphylococci, streptococci, enterococci, grampositive
anaerobic cocci, and gram-positive rods such as
Corynebacterium spp. and Listeria monocytogenes (Table 55–2). It
has poor activity against most gram-negative aerobic or anaerobic
bacteria. It is bacteriostatic against enterococci and staphylococci
and bactericidal against streptococci. Breakpoints for susceptibility
are ≤4 μg/mL for staphylococci and ≤2 μg/mL for enterococci and
streptococci. Mycobacterium tuberculosis is moderately susceptible,
with MICs of 2 μg/mL.
Mechanism of Action and Resistance to Oxazolidinones. Linezolid
inhibits protein synthesis by binding to the P site of the 50S ribosomal
subunit and preventing formation of the larger ribosomal-fMet-tRNA
complex that initiates protein synthesis. Because of its unique mechanism
of action, linezolid is active against strains that are resistant to multiple
other agents, including penicillin-resistant strains of S. pneumoniae;
methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant
strains of staphylococci; and vancomycin-resistant strains of enterococci.
Resistance in enterococci and staphylococci is due to point
mutations of the 23S rRNA (Wilson et al., 2003). Because multiple
copies of 23S rRNA genes are present in bacteria, resistance generally
requires mutations in two or more copies.
Absorption, Distribution, and Excretion. Linezolid is well absorbed
after oral administration and may be administered without regard to
food. With oral bioavailability approaching 100%, dosing for oral and
intravenous preparations is the same. Peak serum concentrations average
13 μg/mL 1-2 hours after a single 600-mg dose in adults and
~20 μg/mL at steady state with dosing every 12 hours. The t 1/2
is
N
O
LINEZOLID
O
N
H
O
C
CH3
~4-6 hours. Linezolid is 30% protein-bound and distributes widely
to well-perfused tissues, with a 0.6-0.7 L/kg volume of distribution.
Linezolid is broken down by nonenzymatic oxidation to
aminoethoxyacetic acid and hydroxyethyl glycine derivatives.
Approximately 80% of the dose of linezolid appears in the urine,
30% as active compound and 50% as the two primary oxidation
products. Ten percent of the administered dose appears as oxidation
products in feces. Although serum concentrations and t 1/2
of the parent
compound are not appreciably altered by renal insufficiency, oxidation
products accumulate in renal insufficiency, with half-lives
increasing by ~50-100%. The clinical significance of this is
unknown, and no dose adjustment in renal insufficiency is currently
recommended. Linezolid and its breakdown products are eliminated
by dialysis; therefore the drug should be administered after
hemodialysis. One case report noted sustained therapeutic concentrations
of linezolid in peritoneal dialysis fluid with oral administration
of 600 mg of linezolid twice daily (DePestel et al., 2003).
Therapeutic Uses and Dosage. Linezolid is FDA approved for treatment
of infections caused by vancomycin-resistant E. faecium; nosocomial
pneumonia caused by methicillin-susceptible and resistant
strains of S. aureus; community-acquired pneumonia caused by
penicillin-susceptible strains of S. pneumoniae; complicated skin
and skin structure infections caused by streptococci and methicillinsusceptible
and -resistant strains of S. aureus; and uncomplicated
skin and skin-structure infections (Clemett and Markham, 2000).
Linezolid is bacteriostatic for staphylococci and enterococci; it
should not be first-line therapy for treatment of suspected endocarditis,
although there are reports of cure of endocarditis with linezolid
in salvage situations (Falagas et al., 2006).
Infections Due to Vancomycin-resistant E. faecium. In noncomparative
studies, linezolid (600 mg twice daily) has had clinical and
microbiological cure rates in the range of 85-90% in treatment of a
variety of infections (soft tissue, urinary tract, and bacteremia)
caused by vancomycin-resistant E. faecium.
Skin and Soft-Tissue Infections. Efficacy of linezolid was similar to
that of either oxacillin or vancomycin for complicated and uncomplicated
skin and skin-structure infections, most microbiologically
documented cases are caused by S. aureus. Linezolid, 600 mg twice
daily (with or without aztreonam), was as effective as ampicillin/
sulbactam (with or without vancomycin or aztreonam) for the management
of diabetic foot infections. A 400-mg twice-daily dosage
regimen is recommended only for treatment of uncomplicated skin
and skin-structure infections.
Respiratory Tract Infections. In randomized, comparative studies,
cure rates with linezolid (~60%) were similar to those with vancomycin
for nosocomial pneumonia caused by methicillin-resistant
or methicillin-susceptible S. aureus (Rubinstein et al., 2001;
Wunderink et al., 2003a). A post hoc analysis suggested that linezolid
may be superior to vancomycin for nosocomial pneumonia
caused by methicillin-resistant S. aureus, but this needs to be confirmed
in a prospective randomized trial (Wunderink et al., 2003b).
Linezolid also may be an effective alternative for patients with MRSA
infections who are failing vancomycin therapy or whose isolates have
reduced susceptibility to vancomycin (Howden et al., 2004).
Linezolid should be reserved as an alternative agent for treatment
of infections caused by multiple-drug-resistant strains. It
should not be used when other agents are likely to be effective (e.g.,
community-acquired pneumonia, even though it has the indication).
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CHAPTER 55
PROTEIN SYNTHESIS INHIBITORS AND MISCELLANEOUS ANTIBACTERIAL AGENTS