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

1512 (Knoderer et al., 2003; Rastogi et al., 2002), data from meta-analyses
now support this mode of administration in appropriately selected
patients from these populations (Contopoulos-Ioannidis et al., 2004;
Nestaas et al., 2005; Ward and Theiler, 2008). One key exception to
the use of extended-interval dosing is for aminoglycoside use as combination
therapy with a cell wall–active agent in the treatment of
gram-positive infections, such as endocarditis. In these infections,
administration of multiple daily doses (with a lower total daily dose)
is preferred because data documenting equivalent safety and efficacy
of extended-interval dosing are inadequate. Although schemes exist
for adjusting dosages of aminoglycosides dosed by extended-interval
methods in patients with significant renal dysfunction (i.e., creatinine
clearance <25 mL/minute), some clinicians prefer to use the traditional
multiple-dose regimen in such patients.
Nomograms may be helpful in selecting initial doses, but
variability in aminoglycoside clearance among patients is too great
for these to be relied on for more than a few days (Bartal et al.,
2003). If it is anticipated that the patient will be treated with an
aminoglycoside for >3-4 days, then plasma concentrations should
be monitored to avoid drug accumulation. Whether extended-interval
or multiple-daily dosing is chosen, the dose must be adjusted for
patients with creatinine clearances of <80-100 mL/minute (Table
54–2), and plasma concentrations must be monitored. Determination
of the concentration of drug in plasma is an essential guide to the
proper administration of aminoglycosides. In patients with lifethreatening
systemic infections, aminoglycoside concentrations
should be determined several times per week (more frequently if
renal function is changing) and should be determined within 24-48
hours of a change in dosage. The size of the individual dose, the
interval between doses, or both can be altered based on the results of
monitoring of drug levels in plasma. Methods for calculation of
dosage are described in Appendix II. There are obvious difficulties
in using any of these approaches for ill patients with rapidly changing
renal function. In addition, even when known factors are taken
into consideration, concentrations of aminoglycosides achieved in
plasma after a given dose vary widely among patients. If the extracellular
volume is expanded, the volume of distribution is increased,
and concentrations will be reduced.
For twice- or thrice-daily dosing regimens, both peak and
trough plasma concentrations are determined. The trough sample is
obtained just before a dose, and the peak sample is obtained 60 minutes
after intramuscular injection or 30 minutes after an intravenous infusion
given over 30 minutes. The peak concentration documents that the dose
produces therapeutic concentrations, generally accepted to be 4-10
μg/mL for gentamicin, netilmicin, and tobramycin and 15-30 μg/mL
for amikacin and streptomycin. The trough concentration is used to
avoid toxicity by monitoring for accumulation of drug. Trough concentrations
should be <1-2 μg/mL for gentamicin, netilmicin, and
tobramycin and <10 μg/mL for amikacin and streptomycin.
Monitoring of aminoglycoside plasma concentrations also is
important when using an extended-interval dosing regimen, although
peak concentrations are not determined routinely (these will be three
to four times higher than the peak achieved with a multiple-dailydosing
regimen). Several approaches may be used to determine that
drug is being cleared and not accumulating.
The most accurate method for monitoring plasma levels for
dose adjustment is to measure the concentration in two plasma samples
drawn several hours apart (e.g., at 2 and 12 hours after a dose).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
The clearance then can be calculated and the dose adjusted to achieve
the desired target range.
Another approach relies on nomograms to target a range of
concentrations in a sample obtained earlier in the dosing interval.
For example, if the plasma concentration from a sample obtained
8 hours after a dose of gentamicin is between 1.5 and 6 μg/mL, then
the concentration at 18 hours will be <1 μg/mL (Chambers et al.,
1998). Target ranges of 1-1.5 μg/mL for gentamicin at 18 hours for
patients with creatinine clearances >50 mL/min and 1-2.5 μg/mL
for those with clearances <50 mL/min also have been used. This
method also tends to be inaccurate, particularly when conditions that
alter aminoglycoside clearance are present (Bartal et al., 2003;
Toschlog et al., 2003).
The simplest method is to obtain a trough sample 24 hours
after dosing and adjust the dose to achieve the recommended plasma
concentration, (e.g., <1-2 μg/mL in the case of gentamicin or
tobramycin). This approach probably is the least desirable. An undetectable
trough concentration could reflect grossly inadequate dosing
in patients who clear the drug rapidly with prolonged periods
(perhaps well over half the dosing interval) during which concentrations
are subtherapeutic. In contrast, a 24-hour trough concentration
target of 1-2 μg/mL actually would increase aminoglycoside exposure
compared with a multiple-daily-dosing regimen (Barclay et al.,
1999), which defeats the goal of providing a washout with concentrations
of 0-1 μg/mL between 18 and 24 hours after a dose.
Untoward Effects
All aminoglycosides have the potential to produce
reversible and irreversible vestibular, cochlear, and
renal toxicity. These side effects complicate the use of
these compounds and make their proper administration
difficult.
Ototoxicity. Vestibular and auditory dysfunction can follow
the administration of any of the aminoglycosides,
and ototoxicity may become a dose-limiting adverse
effect. Aminoglycoside induced ototoxicity results in
irreversible, bilateral high-frequency hearing loss and
temporary vestibular hypofunction. Degeneration of hair
cells and neurons in the cochlea correlates with the loss
of hearing. With increasing dosage and prolonged exposure,
damage progresses from the base of the cochlea,
where high-frequency sounds are processed, to the apex,
which is necessary for the perception of low frequencies.
Although these histological changes correlate with
the ability of the cochlea to generate an action potential in
response to sound, the biochemical mechanism for ototoxicity
is poorly understood. Early changes induced
by aminoglycosides in experimental ototoxicity are
reversible by Ca 2+ . Once sensory cells are lost, however,
regeneration does not occur; retrograde degeneration of
the auditory nerve follows, resulting in irreversible hearing
loss.
Aminoglycosides may interfere with the active
transport system essential for the maintenance of the