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The aminoglycoside antibiotics are widely used for the treatment
of severe gram-negative infections such as pneumonia or bacteremia,
often in combination with a β-lactam antibiotic.
Aminoglycosides are also used for gram-positive infections such
as infective endocarditis in combination with penicillins when antibiotic
synergy is required for optimal killing. Aminoglycoside antibiotics
available in the United States that are in common use include gentamicin,
tobramycin, netilmicin, and amikacin.
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Aminoglycoside antibiotics are bactericidal, and the drugs exhibit
concentration-dependent bacterial killing.1 Antibiotics
with concentration-dependent killing characteristically kill bacteria
at a faster rate when drug concentrations are higher. Also, aminoglycosides
have a concentration-dependent postantibiotic effect. The postantibiotic effect
is the phenomenon of continued bacterial killing even though serum
concentrations have fallen below the minimum inhibitory concentration
(MIC). Because the postantibiotic effect is concentration-dependent
for the aminoglycosides, higher drug concentrations lead to a longer
postantibiotic effect. The mechanisms of action for aminoglycosides
are binding to the 30S ribosomal subunit inhibiting protein synthesis
and misreading of mRNA causing dysfunctional protein production.
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The MIC for susceptible bacteria is higher for amikacin than
it is for the other aminoglycosides. Because the pharmacokinetics
is similar for all these drugs, higher doses of amikacin are needed
to treat infections. The conventional method of dosing aminoglycoside
antibiotics is to administer multiple daily doses (usually every
8 hours).2 In order to take advantage of concentration-dependent
bacterial killing and the postantibiotic effect, extended-interval
(usually the total daily dose given once per day) aminoglycoside
administration is also a dosing option.3 Because of these
two different methods of dosage administration, it is important
to identify which is being used when discussing serum concentration
monitoring.
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Aminoglycoside antibiotics are given as short-term (1/2–1
hour) infusions. If a 1-hour infusion is used, maximum end of infusion “peak” concentrations
are measured when the infusion is completed (Figure 4-1). If a 1/2-hour
infusion is used, serum concentrations exhibit a distribution phase
so that drug in the blood and in the tissues are not yet in equilibrium.
Because of this, a 1/2-hour waiting period
is allowed for distribution to finish if a 1/2-hour
infusion is used before peak concentrations are measured. Therapeutic
steady-state peak concentrations for gentamicin, tobramycin, and
netilmicin are generally 5–10 μg/mL
for gram-negative infections. Infection sites with more susceptible
bacteria, such as intra-abdominal infections usually can be treated
with steady-state peak concentrations at the lower end of this range
(typically 5–7 μg/mL). Infection
sites that are difficult to penetrate and with bacteria that have
higher MIC values, such as pseudomonal pneumonia usually require
steady-state peak concentrations in the higher end of the range
(typically 8–10 μg/mL). When
gentamicin, tobramycin, or netilmicin are used synergistically with
penicillins or other antibiotics for the treatment of gram-positive
infections such as infective endocarditis steady-state peak concentrations
of 3–5 μg/mL are often times
adequate. Therapeutic peak concentrations ...