DOSE OPTIMIZATION
A working knowledge of antimicrobial pharmacokinetics and pharmacodynamics is required
for appropriate antimicrobial selection and dosing within an ICU. Simply put, pharmacoki-
netics may be defined as “how the body affects the administered drug” and pharmacody-
namics can be viewed as “how the administered drug affects the body.”
Pharmacokinetic analysis involves four elements: absorption, distribution, metabolism,
and elimination (ADME), each of which is typically altered in the critically ill. Collectively,
such alterations influence serum and tissue drug concentrations, time to maximum
concentrations, volumes of distribution, and serum half-lives. Impaired gastrointestinal
motility and incompatibilities with enteral nutrition result in unreliable drug bioavailability
following oral administration, and therefore intravenous (IV) routes for antibiotic adminis-
tration should be used initially. Studies demonstrate that timely and appropriate conversion to
oral route of administration can reduce length of stay, costs, and potential complications due to
IV access (25–27). Changes in drug distribution may be observed as a consequence of fluid
shifts, shifts in blood flow, and altered protein binding. Shifts in blood flow may also interfere
with drug metabolism and renal function. Renal elimination serves as the primary route of
elimination for many antibiotics, and renal insufficiency is often observed in the critically ill;
therefore, dose adjustments should be performed and reassessed periodically in this patient
population. Careful attention to dosing is crucial during continuous renal replacement therapy
(CRRT) and hemodialysis (28).
From the minimum inhibitory concentration (MIC) against a specified microorganism,
the peak serum level after a dose (Cmax), and the magnitude and duration of serum levels
over time after a dose (area under the curve, or AUC), we can derive three key relationships:
Cmax/MIC (the “kill ratio”); T>MIC (the amount of time during which the serum level
exceeds the MIC after a dose); and AUC/MIC (the relationship between the magnitude and
duration of serum levels and the MIC). These relationships, and also tissue distributions at
target sites, affect dosing strategies.
Two important pharmacodynamic factors influencing antimicrobial efficacy include
(i) the duration of time that target sites are exposed to the administered antimicrobial and
(ii) the drug concentration achieved at these sites. On the basis of these factors, patterns of
antimicrobial activity are defined as “time dependent” or “concentration dependent.” For
example, theb-lactam class exhibits time-dependent bacterial killing, and as a result, many
clinicians use continuous or prolonged infusions in an effort to decrease peak concentrations
and maintain appropriate drug concentrations for longer durations of time. A study
investigated the impact of infusion times of doripenem on target attainment (T>MIC 40%
for carbapenems) for various MIC values. Prolonged infusions, using the same daily dose,
were effective in achieving target attainment in organisms with increased MICs (29).
For concentration-dependent agents, dosing strategies can be optimized by administer-
ing increased doses such that increases inCmaxand AUC are achieved. The aminoglycosides
are concentration-dependent killers (Cmax/MIC ratio of 8 to 10) and dose optimization can be
achieved with extended-interval dosing of these agents while reducing potential for
nephrotoxicity (30,31). More recently, the standard dose of levofloxacin, for most indications,
has increased from 500 to 750 mg once daily in an effort to elevateCmaxand AUC values with
this concentration-dependent anti-infective.
An understanding of pharmacokinetic and pharmacodynamic (PK/PD) parameters, the
importance of target attainment, and awareness of the changes among PK/PD parameters in
the critically ill are crucial for dose optimization and should be incorporated into antimicrobial
guideline development in ICUs.
DRUG THERAPY
Vancomycin is a bactericidal glycopeptide that treats most gram-positive pathogens including
MRSA. In spite of tons of vancomycin being used in clinical settings, there are only seven
reported cases of vancomycin-resistantS. aureus(VRSA). However, over the last few years
there have been accumulating data that the usefulness of this drug is steadily decreasing. In a
recent practice statement in Clinical Infectious Diseases, the authors even go so far as to say
that vancomycin is obsolete, although most clinicians feel this is a premature generalization
(32). The steadily increasing MICs (the “MIC creep”) for MRSA and clinical failure with MIC
Selection of Antibiotics in Critical Care 493