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

• To provide synergistic bacterial killing.
• To prevent the emergence of resistance to the individual
agents.
The first rationale is the most common justification
for the use of combination therapy in infections such
as healthcare-associated pneumonia or sepsis, where
multidrug-resistant gram-negative organisms such as
P. aeruginosa, Enterobacter, Klebsiella, and Serratia
may be causative and the consequences of failing to provide
initially active therapy are dire (Dupont et al., 2001).
This approach leverages the high levels of coverage that
aminoglycosides continue to provide against this organism.
The use of aminoglycosides to achieve synergistic
bacterial killing and improve microbiological eradication
and clinical response is most well established for the
treatment of endocarditis due to gram-positive organisms,
most importantly Enterococcus. Clinical data do
not support the use of combination therapy for synergistic
killing of gram-negative organisms, with the possible
exceptions of serious P. aeruginosa infections (Paul et
al., 2003, 2004; Safdar et al., 2004). With the exception
of mycobacterial infections, the use of aminoglycosides
to prevent the emergence of resistance is not supported
by clinical data, despite establishment as an in vitro phenomenon
(Bliziotis et al., 2005).
Gentamicin
The typical recommended intramuscular or intravenous dose of
gentamicin sulfate when used for the treatment of known or suspected
gram-negative organisms as a single agent or in combination
therapy for adults with normal renal function is 5-7 mg/kg
daily given over 30-60 minutes. For patients with renal dysfunction,
the interval may be extended. For patients who are not candidates
for extended-interval dosing, a typical dosing regimen for
gram-negative coverage is a loading dose of 2 mg/kg and then
3-5 mg/kg per day, one-third given every 8 hours when administered
as a multiple-daily-dosing regimen. Dosages at the upper
end of this range may be required to achieve therapeutic levels for
trauma or burn patients, those with septic shock, patients with cystic
fibrosis, and others in whom drug clearance is more rapid or
volume of distribution is larger than normal. Several dosage
schedules have been suggested for newborns and infants: 3 mg/kg
once daily for preterm newborns <35 weeks of gestation (Hansen
et al., 2003; Rastogi et al., 2002); 4 mg/kg once daily for newborns
>35 weeks of gestation; 5 mg/kg daily in two divided doses
for neonates with severe infections; and 2-2.5 mg/kg every 8 hours
for children up to 2 years of age. Peak plasma concentrations
range from 4-10 mg/mL (dosing: 1.7 mg/kg every 8 hours) and
16-24 mg/ mL (dosing: 5.1 mg/kg once daily). It should be emphasized
that the recommended doses of gentamicin do not always
yield desired concentrations. Periodic determinations of the
plasma concentration of aminoglycosides are recommended
strongly, especially in seriously ill patients, to confirm that drug
concentrations are in the desired range (see earlier sections on
dosing for more details).
Urinary Tract Infections. Aminoglycosides usually are not indicated
for the treatment of uncomplicated urinary tract infections, although
a single intramuscular dose of gentamicin (5 mg/kg) has been effective
in uncomplicated infections of the lower urinary tract. However,
as strains of E. coli have acquired resistance to β-lactams, trimethoprimsulfamethoxazole,
and fluoroquinolones, use of aminoglycosides
may increase. In the seriously ill patient with pyelonephritis, an
aminoglycoside alone or in combination with a β-lactam antibiotic
offers broad and effective initial coverage. Once the microorganism
is isolated and its sensitivities to antibiotics are determined, the
aminoglycoside should be discontinued if the infecting microorganism
is sensitive to less toxic antibiotics.
Pneumonia. The organisms that cause community-acquired pneumonia
are susceptible to broad-spectrum β-lactam antibiotics,
macrolides, or a fluoroquinolone, and usually it is not necessary to
add an aminoglycoside. Therapy with an aminoglycoside alone is
likely to be ineffective; therapeutic concentrations are difficult to
achieve owing to relatively poor penetration of drug into inflamed
tissues and the associated conditions of low O 2
tension and low pH—
both of which interfere with aminoglycoside antibacterial activity.
Aminoglycosides are ineffective for the treatment of pneumonia due
to anaerobes or S. pneumoniae, which are common causes of community-acquired
pneumonia. They should not be considered as effective
single-drug therapy for any aerobic gram-positive cocci
(including S. aureus or streptococci), the microorganisms commonly
responsible for suppurative pneumonia or lung abscess. An aminoglycoside
in combination with a β-lactam antibiotic is recommended
as standard therapy for hospital-acquired pneumonia in which a
multiple-drug-resistant gram-negative aerobe is a likely causative
agent (American Thoracic Society, 2005). Once it is established that
the β-lactam is active against the causative agent, there is generally
no benefit from continuing the aminoglycoside. Patients presenting
with pulmonary exacerbations of cystic fibrosis often receive aminoglycosides
as a component of therapy. Due to the altered pharmacokinetics
of aminoglycosides in cystic fibrosis patients, higher daily
doses (up to 10 mg/kg/day) may be necessary.
Meningitis. Availability of third-generation cephalosporins, especially
cefotaxime and ceftriaxone, has reduced the need for treatment
with aminoglycosides in most cases of meningitis, except for
infections caused by gram-negative organisms resistant to β-lactam
antibiotics (e.g., species of Pseudomonas and Acinetobacter). If therapy
with an aminoglycoside is necessary, in adults, 5 mg of a preservative-free
formulation of gentamicin (or equivalent dose of another
aminoglycoside) is administered directly intrathecally or intraventricularly
once daily (Barnes et al., 2003).
Peritonitis Associated with Peritoneal Dialysis. Patients who develop
peritonitis as a result of peritoneal dialysis may be treated with
aminoglycoside diluted into the dialysis fluid to a concentration of
4-8 mg/L for gentamicin, netilmicin, or tobramycin or 6-12 mg/L
for amikacin. Intravenous or intramuscular administration of drug
is unnecessary because serum and peritoneal fluid will equilibrate
rapidly.
Bacterial Endocarditis. “Synergistic” or low-dose gentamicin (3 mg/kg
per day in three divided doses) in combination with a penicillin or
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CHAPTER 54
AMINOGLYCOSIDES