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

1542 because these modalities clear vancomycin efficiently. Because there
is so much variation in how well vancomycin is dialyzed with different
membranes, it is recommended that blood levels be monitored to
decide how frequently the drug needs to be administered to maintain
therapeutic concentrations.
Skin/Soft-Tissue and Bone/Joint Infections. Vancomycin is frequently
used in the empirical and definitive treatment of skin/softtissue
and bone/joint infections, where gram-positive organisms
including MRSA are the leading pathogens.
Respiratory Tract Infections. Vancomycin is employed for the treatment
of pneumonia when MRSA is suspected, either because of
healthcare-associated acquisition or in patients with communityacquired
pneumonia with risk factors for staphylococcal infection
(e.g., influenza). Because vancomycin penetration into lung tissue
is relatively low, aggressive dosing (targeting trough levels of 15-20
μg/mL) is generally recommended.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
CNS Infections. Because of vancomycin’s excellent activity against
Streptococcus pneumoniae, it is a key component in the initial empirical
treatment of community-acquired bacterial meningitis in locations
where penicillin-resistant Streptococcus pneumoniae is
common (Tunkel et al., 2004). Penetration of vancomycin across
inflamed meningitis is modest to poor; thus aggressive dosing is typically
warranted. Vancomycin is also used to treat nosocomial
meningitis, usually associated with neurosurgical procedures and
often caused by staphylococci. Intraventricular administration of
vancomycin (via a shunt or reservoir) has been necessary in a few
cases of CNS infections due to susceptible microorganisms that did
not respond to intravenous therapy alone.
Endocarditis and Vascular Catheter Infections. Vancomycin is standard
therapy for staphylococcal endocarditis when the isolate is
methicillin resistant or patients have a severe penicillin allergy
(Baddour et al., 2005). Administration of an adjunctive aminoglycoside
is no longer recommended unless there is a prosthetic valve.
Vancomycin is an effective alternative for the treatment of endocarditis
caused by viridans streptococci in patients who are allergic
to penicillin. In combination with an aminoglycoside, it may be used
for enterococcal endocarditis in patients with serious penicillin
allergy or for isolates that are not susceptible to penicillins.
Vancomycin is commonly used for the treatment of vascular
catheter infections due to gram-positive organisms, such as staphylococci,
viridans streptococci, Corynebacterium spp, and Bacillus spp. In
situations when removal of the catheter is not desired, adjunctive treatment
with vancomycin as an “antibiotic lock” may aid in salvaging the
catheter. In this procedure, a concentrated solution of vancomycin is
instilled into the catheter hub and allowed to dwell for variable amounts
of time when the catheter is not in use (Carratala, 2002).
Other Infections. Vancomycin can be administered orally to patients
with pseudomembranous colitis due to C. difficile, and it may be
more efficacious than metronidazole in patients with severe disease.
The dose for adults is 125-250 mg every 6 hours; the total daily dose
for children is 40 mg/kg, given in three to four divided doses.
Commercially available capsules can be used for this purpose, or the
intravenous formulation can be administered orally with or without
compounding into a more palatable oral solution.
The standard dose of teicoplanin in adults is 3-6 mg/kg per
day, with higher dosages possible for treatment of serious staphylococcal
infections. Once-daily dosing is possible for the treatment of
most infections because of the prolonged serum elimination halflife.
As with vancomycin, teicoplanin doses must be adjusted in
patients with renal insufficiency. For functionally anephric patients,
administration once weekly has been appropriate, but serum drug
concentrations should be monitored to determine that the therapeutic
range has been maintained (e.g., trough concentration of
15-20 μg/mL). Oral teicoplanin has also been studied for the treatment
of C. difficile disease, at a dose of 100 mg twice daily.
Untoward Effects. Among the hypersensitivity reactions produced by
vancomycin and teicoplanin are macular skin rashes and anaphylaxis.
Phlebitis and pain at the site of intravenous injection are relatively
uncommon. Chills, rash, and fever may occur. Rapid
intravenous infusion of vancomycin may cause erythematous or
urticarial reactions, flushing, tachycardia, and hypotension. The
extreme flushing that can occur is sometimes called “red-neck” or
“red-man” syndrome. This is not an allergic reaction but a direct
toxic effect of vancomycin on mast cells, causing them to release
histamine. This reaction is generally not observed with teicoplanin.
Auditory impairment, sometimes permanent, may follow the
use of vancomycin or teicoplanin. Ototoxicity is associated with excessively
high concentrations of these drugs in plasma (60-100 μg/mL of
vancomycin). Nephrotoxicity, formerly very problematic due to the
impurities in earlier formulations of vancomycin, has become less
common with modern formulations at standard dosages. However,
the more aggressive dosing regimens recently advocated have been
demonstrated to increase nephrotoxicity risk. In a recent observational
study, nephrotoxicity occurred in 33% of patients with initial
vancomycin trough concentrations of >20 μg/mL, compared to 5%
among patients with trough concentrations of <10 μg/mL (Lodise
et al., 2009). Thus, careful dosing and monitoring of vancomycin is
necessary to balance the risks and benefits. Additionally, caution
should be exercised when ototoxic or nephrotoxic drugs, such as
aminoglycosides, are administered concurrently with vancomycin.
LIPOPEPTIDES (DAPTOMYCIN)
Daptomycin (CUBICIN) is a cyclic lipopeptide antibiotic
derived from Streptomyces roseosporus. Discovered
>25 years ago, its clinical development has been
resumed in response to increasing need for bactericidal
antibiotics effective against vancomycin-resistant grampositive
bacteria (Carpenter and Chambers, 2004;
Eisenstein and Tally, 2006).
HO 2 C
HO
O
HN
HN
HO 2 C
HN
O
NH
O
O
O
H
N
O
N
H
HO 2 C
O
O
O
O
NH 2
NH
N
H
O
HN
H
N
O
O
H
N
O
CO 2 H
NH 2
DAPTOMYCIN
CONH 2
O
N
H
H
N
N
H
O
(CH 2 ) 8 CH 3