of drug elimination. It can be anticipated thatT1/2will be reduced. Subsequent organ failure
from the ravages of sustained sepsis results in impairment of drug elimination and
prolongation ofT1/2.
Severe injury results in the infiltration of the soft tissues with neutrophils and monocytes
as part of the phagocytic phase of the inflammatory response. Proinflammatory cytokine
signals are released from the phagocytic cells, from activated mast cells, and from other cell
populations. The circulation of these proinflammatory signals leads to a febrile response with
or without infection. The febrile response is associated with systemic hypermetabolism and
autonomic and neuroendocrine changes that further amplify the systemic dyshomeostasis.
Pro-inflammatory signaling up-regulates the synthesis of acute-phase reactants and down-
regulates the synthesis of albumen, which further impacts the restoration of oncotic pressure
and predictable drug pharmacokinetics. The summed effects of injury, fever, and the sequela
of systemic inflammation result in pathophysiologic alterations (Table 1) that compromise the
effectiveness of antibiotic therapy because of suboptimal dosing.
CLINICAL DATA
The discussion to this point has focused upon the theoretical argument that pathophysiologic
changes of multiple injury, fever, and systemic inflammation will have on antibiotic
pharmacokinetics. A review of the literature identifies a paucity of clinical studies in the
Figure 2 Illustrates the influence upon the
clearance curve of the theoretical antibiotic
in Figure 1 of an increase in extracellular
and/or intracellular water in a trauma patient
that has fever secondary to invasive infec-
tion. The peak concentration [A*] and the
equilibrated peak concentration [B*] are less
than those concentrations observed under
normal circumstances. The [T* 0 ] is reduced
because of the increase inVd. In this model,
theT1/2has not changed, but the time point
where the drug concentration [E*] intercepts
the [MIC] is 1.5 hours sooner (illustrated
by the arrow) than would ordinarily be the
case [E].Table 1 Pathophysiologic Changes of the Systemic Inflammatory Response that is Triggered by Injury, Fever,
and Sepsis
Pathophysiologic change Theoretical pharmacokinetic effect
Increase in extracellular water Increased volume of distribution; reduced peak concentration;
reduction in AUC
Increased intracellular water Increased volume of distribution; reduced peak concentration;
reduction in AUC
Change in vascular permeability Reduction in serum proteins; adverse effects upon highly
protein-bound drugs
Elevated cardiac output Increased hepatic and renal perfusion; reduction in biological
elimination half-life
Reduction in vascular resistance Reduced hepatic and renal perfusion, reduced drug clearance
Systemic inflammatory response syndrome Endothelial damage, reduced microcirculatory flow, hepatic and
renal dysfunction, and increased half-life and drug clearance
Each of the pathophysiologic parameters has a theoretical impact upon antibiotic pharmacokinetics.
Abbreviation: AUC, area under the curve.
Antibiotic Kinetics in the Multiple-System Trauma Patient 525