significance for pathogens with high MIC breakpoints (41). The observation that the quinolone
group of antibiotics have very largeVdthat exceeds total body water means that increases in
extracellular water volume have little impact. This potentially constitutes an advantage for this
group of antibiotics in the febrile, critically ill patient, and perhaps in the trauma patient as
well.
Linezolid
A significant number of reports have identified treatment failures for both methicillin-sensitive
and methicillin-resistantStaphylococcus aureus(MSSA and MRSA) infections from treatment
with vancomycin (42–45). This has led to considerable interest in the identification of
alternative antibiotic treatment for both community-associated and hospital-acquired staph-
ylococcal infections. Linezolid is the first of a new class of oxazolidinone antibiotics that
appears to have a particular role in the treatment of MRSA infections. TheVdof this drug in
patients and normal volunteers has been at 0.6 to 1.0 L/kg, which like the quinolones is a Vd
that exceeds total body water.T1/2has been reported from four to seven hours. Whitehouse
et al. (46) reported linezolid pharmacokinetics on 28 patients with gram-positive infections in
the intensive care unit. They found aVd ¼ 0.63 L/kg and T1/2 ¼ 2.6 hours. Trough
concentrations were adequate for the treatment of susceptible organisms. Of note, no
modification was necessary for either renal or hepatic dysfunction. The combined observations
of the quinolones and linezolid suggest that antibiotics withVdthat exceed total body water are
less likely to be adversely affected by physiologic changes of injury, critical illness, and sepsis.
MANAGEMENT OF PHARMACOKINETIC CHANGES
As clinical evidence has demonstrated that the pathophysiological changes of severe injury,
fever, and the human septic response adversely affect the functional concentrations of
antibiotics, modifications in how antibiotics are dosed and the frequency of administration has
become the focus of new strategies. Traditional pharmacokinetic dosing could be employed,
where peak and trough measurements permit the clinician to adjust the total dose, the dosing
interval, or both. This becomes a biological titration where doses are empirically modified and
remeasurement is undertaken to assess favorable changes in subsequent peak/trough
concentrations. This has been a traditional way of managing aminoglycosides and in some
cases vancomycin use. Most clinical pharmacokinetic dosing has been geared to avoid toxicity
and only secondarily to the maintenance of therapeutic concentrations.b-Lactams, fluoroqui-
nolones, and other antibiotics that have a favorable therapeutic ratio are not commonly
pharmacokinetically dosed, and most clinical laboratories do not have the analytical methods
for measurement. Measurement of these nontoxic agents will be an expense that most will not
be willing to accept.
Increase the Dose/Frequency of the Drug
One strategy to overcome the reduction in antibiotic concentrations in the febrile, trauma
patient is to either increase the dose or shorten the dosing interval. Figure 3 illustrates the
potential benefit of increasing the dose. Doubling of the intravenous dose actually adds only
one half-life to the duration of the drug concentration above the target concentration for the
MIC. It does give a high peak concentration, which may be of value for antibiotics like the
aminoglycosides that are concentration-dependent and have a sustained post-antibiotic
effect (47). Another strategy is to shorten the dosing interval. For example, a q6h drug might be
shortened to give the same dose to q4h to reduce the interval of subtherapeutic concentration.
Increasing the dose or shortening the dosing interval can only be entertained when the
antibiotic being used has a favorable therapeutic ratio. The rate of clearance of the drug and the
Vdare dynamic processes, and very high concentrations of the antibiotic can be the result
when dosing is increased in a patient with rapidly resolving pathophysiological hemody-
namics of the systemic inflammatory response.
Continuous Antibiotic Infusion
Antibiotic infusions are commonly given as 30 to 60 minute infusions. This results in the rapid
spike in antibiotic concentration in serum that is identified in Figure 1. A very large amount of
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