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

Table 54–2
Algorithm for Dose Reduction of Aminoglycosides
Based on Calculated Creatinine Clearance
CREATININE
CLEARANCE % OF MAXIMUM FREQUENCY
(mL/min) DAILY DOSE* OF DOSING
100 100
75 75 Every 24 hours
50 50
25 25
20 80
10 60 Every 48 hours
<10 40
*The maximum adult daily dose for amikacin, kanamycin, and
streptomycin is 15 mg/kg; for gentamicin and tobramycin, 5.5
mg/kg; and for netilmicin, 6.5 mg/kg.
dialysis has bacterial peritonitis, a therapeutic concentration of the
aminoglycoside probably will not be achieved in the peritoneal fluid
because the ratio of the concentration in plasma to that in peritoneal
fluid may be 10:1 (Smithivas et al., 1971). Thus, it is recommended
that antibiotic be added to the dialysate to achieve concentrations
equal to those desired in plasma.
Aminoglycosides can be inactivated by various penicillins in
vitro and thus should not be admixed in solution. Some reports indicate
that this inactivation may occur in vivo in patients with endstage
renal failure (Blair et al., 1982), thus making monitoring of
aminoglycoside plasma concentrations even more necessary in such
patients. Amikacin appears to be the aminoglycoside least affected
by this interaction, and penicillins with more nonrenal elimination
(such as piperacillin) may be less prone to cause this interaction.
Although excretion of aminoglycosides is similar in adults
and children >6 months of age, half-lives of the drugs may be prolonged
significantly in the newborn: 8-11 hours in the first week of
life in newborns weighing <2 kg and ~5 hours in those weighing
>2 kg (Yow, 1977). Thus, it is critically important to monitor plasma
concentrations of aminoglycosides during treatment of neonates
(Philips et al., 1982). For unknown reasons, aminoglycoside clearances
are increased and half-lives are reduced in patients with cystic
fibrosis compared to subjects without cystic fibrosis, after
controlling for age and weight (Mann et al., 1985). Larger doses of
aminoglycosides may likewise be required in burn patients because
of more rapid drug clearance, possibly because of drug loss through
burn tissue.
Dosing. Recommended doses of individual aminoglycosides in the
treatment of specific infections are given in later sections of this
chapter. Historically, aminoglycosides have been administered as
two or three equally divided doses, based on the short t 1/2
of the
drugs. However, studies of the pharmacokinetic/pharmacodynamic
properties of aminoglycosides demonstrate that administering
higher doses at extended intervals (typically once daily in patients
with normal renal function) is likely to be at least equally efficacious
and potentially less toxic than administration of divided doses.
35
30
every 8h
every 24h
25
Threshold
20
15
10
5
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Hours
Figure 54–3. Plasma concentrations (μg/mL) after administration
of 5.1 mg/kg of gentamicin intravenously to a hypothetical
patient either as a single dose (every 24h) or as three divided
doses (every 8h). The threshold for toxicity has been chosen to
correspond to a plasma concentration of 2 μg/mL, the maximum
recommended. The high-dose, extended-interval (once-daily)
regimen produces a 3-fold higher plasma concentration, which
enhances efficacy that otherwise might be compromised due to
prolonged sub-MIC concentrations later in the dosing interval
compared with the every-8-hours regimen. The once-daily regimen
provides a 12-hour period during which plasma concentrations
are below the threshold for toxicity, thereby minimizing
the toxicity that otherwise might result from the high plasma
concentrations early on. The every-8-hours regimen, in contrast,
provides only a brief period during which plasma concentrations
are below the threshold for toxicity.
μg/mL
A comparison of this high-dose, extended-interval dosing method to
traditional divided-dose methods is illustrated in Figure 54–3.
Because of the post-antibiotic effect of aminoglycosides, good therapeutic
response can be attained even when concentrations of aminoglycosides
fall below inhibitory concentrations for a substantial
fraction of the dosing interval. High-dose, extended-interval dosing
schemes for aminoglycosides may also reduce the characteristic otoand
nephrotoxicity of these drugs. This diminished toxicity is probably
due to a threshold effect from accumulation of drug in the inner
ear or in the kidney. More drug accumulates with higher plasma concentrations,
particularly at trough, and with prolonged periods of
exposure. Net elimination of aminoglycoside from these organs
occurs more slowly when plasma concentrations are relatively high.
High-dose, extended-interval regimens, despite the higher peak concentration,
provide a longer period when concentrations fall below the
threshold for toxicity than does a multiple-dose regimen (12 hours
versus <3 hours total in the example shown in Figure 54–3), potentially
accounting for the lower toxicity of this approach.
Numerous studies and meta-analyses demonstrate that administration
of the total dose once daily is associated with less nephrotoxicity
and is just as effective as multiple-dose regimens (Bailey et al.,
1997; Buijk et al., 2002). Extended-interval dosing also costs less and
is administered more easily. For these reasons, high-dose, extendedinterval
administration of aminoglycosides is the preferred means of
administering aminoglycosides for most indications and patient
populations. Although the use of extended-interval dosing has been
controversial in pregnancy, neonatal, and pediatric infections
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CHAPTER 54
AMINOGLYCOSIDES