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[OPTIMIZING ANTIMICROBIAL PHARMACODYNAMICS: A GUIDE FOR YOUR STEWARDSHIP PROGRAM - Joseph L. Kuti, PharmD]
defined portion of the dosing interval (fT
>
MIC). Additionally,
antibiotics that have both concentration- and time-
dependent effects may observe killing that is associated with
the free drug area under the curve to MIC ratio (ƒAUC/MIC). A
summary of currently available antibiotic classes used in the
acute care setting and their respective pharmacodynamic
characteristics is provided in Table 1. At standard clinically
relevant doses, concentration-dependent antimicrobials
include the aminoglycosides, fluoroquinolones, and colistin.
Time-dependent antimicrobials include the
β
-lactams,
glycylcyclines, and vancomycin.
AMINOGLYCOSIDES
The
goal
when
dosing
concentration-dependent
antimicrobials is to achieve a total drug Cmax/MIC of
approximately 10 to 12 or a total AUC/MIC of 150, both
of which have been predictive of clinical success (6,7).
Total drug exposure targets are reasonable here because
the 3 currently available aminoglycosides (gentamicin,
tobramycin, and amikacin) have low protein binding. As a
result of pharmacodynamic studies, the traditional dosing
regimen of 1 to 1.5mg/kg (gentamicin and tobramycin) or
7.5mg/kg (amikacin) divided into two to three daily doses
has been largely replaced with high-dose, extended-
interval regimens to achieve higher peak concentrations,
resulting in improved clinical efficacy and, importantly,
fewer nephrotoxic events. Nicolau and colleagues evaluated
a once daily aminoglycoside dosing algorithm (7mg/kg daily,
referred to as the Hartford Nomogram) in over 2000 adult
patients and found a similar clinical response, but a reduced
incidence of nephrotoxicity compared with historical data
(1.2% vs. 3-5%) (8). In a simulation study, the probability of
day 7 temperature resolution and nephrotoxicity between
a once daily aminoglycoside regimen (10mg/kg every
24h) compared with a twice daily (5mg/kg every 12h)
dose was determined (9). At an MIC of 4mg/L (the current
susceptibility breakpoint for gram-negative bacteria), the
TABLE 1. SUMMARY OF ANTIBIOTICS THAT DISPLAY CONCENTRATION-DEPENDENT OR TIME-DEPENDENT KILLING
CHARACTERISTIC AND THE REQUISITE PHARMACODYNAMIC EXPOSURE
a
Denotes common exposures based on free (f) drug concentrations, unless otherwise noted.
b
Total drug exposure target.
ANTIBIOTIC CLASS
Antibiotic
KILLING CHARACTERISTIC PHARMACODYNAMIC PARAMETER
a
Aminoglycosides
Concentration Dependent
amikacin, gentamicin, tobramycin
f
C
max
/MIC
>
10–12 (Gram-negatives)
β
-lactams
Time Dependent
carbapenems
(doripenem, ertapenem,
imipenem, meropenem)
40%
f
T
>
MIC (bactericidal activity,
Gram-negatives)
cephalosporins
(e.g., ceftriaxone,
ceftazidime, cefepime)
50%-70%
f
T
>
MIC (bactericidal activity, Gram-
negatives)
penicillins
(e.g., oxacillin, ampicillin/
sulbactam, piperacillin/tazobactam)
50%
f
T
>
MIC (bactericidal activity,
Gram-negatives)
Fluoroquinolones
Concentration Dependent
ciprofloxacin, levofloxacin,
AUC/MIC
>
125 (Gram-negatives)
b
moxifloxacin
f
AUC/MIC
>
30–50 (Gram-positives)
Glycopeptides
Concentration and Time
Dependent
vancomycin
AUC/MIC
>
400
b
Glycylcycline
Time Dependent
tigecycline
Polymyxins
Concentration Dependent
f
AUC/MIC
>
12–48 (
Pseudomonas
and
polymyxin B, colistin (polymyxin E)
Acinetobacter
); corresponds with a Css
avg
of 1–4mg/L when MIC=1mg/L