elimination via the kidney. Hepatic metabolism may result in the inactivated metabolite being
eliminated within the bile.
Clearly, abnormalities within the organ responsible for biotransformation will affect
the process. Intrinsic hepatic disease from cirrhosis will alter hepatic biotransformation. The
cytochrome P-450 system requires molecular oxygen, so poor perfusion or oxygenation of the
liver from any cause will impact hepatic metabolism of specific drugs. Cytochrome P-450 may
be induced by other drugs or be competitively inhibited. Drug interaction becomes yet another
variable to influence concentration.
Excretion of the antibiotic occurs with or without biotransformation. Some drugs are
eliminated unchanged by the kidney into the urine, or excreted by the liver into the bile. The
rate of elimination of the unchanged drug directly affects theT1/2. Excretion of unchanged
drug via the biliary tract, which in turn can be reabsorbed, may create an enterohepatic
circulation that results in prolonged drug presence in the patient. When either the intact drug
or metabolic product is dependent on a specific organ system for elimination, intrinsic disease
becomes an important variable in the overall pharmacokinetic profile.
PATHOPHYSIOLOGY OF INJURY AND FEVER
The extreme model to characterize abnormal pharmacokinetics for any drug used in patient
care would be in the febrile, multiple-system injury patient. Extensive torso and extremity
injuries result in soft tissue injuries that activate the human systemic inflammatory response.
This systemic inflammatory response requires extensive volume resuscitation for maintenance
of intravascular volume and tissue perfusion. Extensive tissue injury also results in tissue
contamination. Blunt chest trauma requires intubation and prolonged ventilator support, and
exposure of the lung to environmental contamination. The injuries lead to prolonged
incapacitation and recumbence. The patients are immunosuppressed from the extensive
injuries, transfusions, and protein-calorie malnutrition. Following the injury itself, infection
becomes the second wave of activation of systemic inflammation. Infection becomes a
complication at the sites of injury, at the surgical sites of therapeutic interventions, and as
nosocomial complications at sites remote from the injuries. Fever and hypermetabolism are
common and add an additional compounding variable at a time when antimicrobial treatment
is most important in the patient’s outcome. Antibiotics are invariably used in the febrile,
multiple-injury patient, but they are dosed and re-dosed using the model of the healthy
volunteer initially employed in the development of the drug. Are antibiotics dosed in
accordance with the pathophysiologic changes of the injury and febrile state?
Extensive tissue injury and invasive soft-tissue infection share the common consequence
of activating local and systemic inflammatory pathways. The initiator events of human
inflammation include (i) activation of the coagulation cascade, (ii) activation of platelets,
(iii) activation of mast cells, (iv) activation of the bradykinin pathway, and (v) activation of the
complement cascade. The immediate consequence of the activation of these five initiator events
is the vasoactive phase of acute inflammation. The release of both nitric oxide–dependent
(bradykinin) and independent (histamine) pathways result in relaxation of vascular smooth
muscle, vasodilation of the microcirculation, increased vascular capacitance, increased
vascular permeability, and extensive movement of plasma proteins and fluid into the
interstitial space (i.e., edema). The expansion of intravascular capacitance and the loss of
oncotic pressure mean that theVdfor many drugs will be expanded. Shock, injury, and altered
tissue perfusion have been associated with the loss of membrane polarization, and the shift of
sodium and water into the intracellular space. At a theoretical level, there is abundant reason
to anticipate that the conventional dosing of antibiotics may be inadequate in these
circumstances (Fig. 2).
The vascular changes in activation of the inflammatory cascade also result in the
relaxation of arteriolar smooth muscle and a reduction in systemic vascular resistance. The
reduction in systemic vascular resistance becomes a functional reduction in left ventricular
afterload, which combined with an appropriate preload resuscitation of the severely injured
patient leads to an increase in cardiac index. The hyperdynamic circulation of the multiple-
trauma patients leads to the “flow” phase of the postresuscitative patient. Increased perfusion
of the kidney and liver results in acceleration of excretory functions and potential enhancement
524 Fry