subsequent use of the drug. The clear objective of pharmacokinetic assessment is to provide
antibiotic concentrations, which will ensure activity against the likely pathogens that are
consistent with quantitative susceptibility information. A second objective is to maintain
antibiotic concentrations within the nontoxic concentrations. In the process of drug develop-
ment, antibiotics are studied in healthy, normal volunteers. Even in phase 3 prospective,
randomized trials, the severity of illness that is evaluated with a new antibiotic product is not
extreme. Witness the fact that phase 3 trials of peritonitis customarily are studying largely
perforative appendicitis patients. The studies are geared to have few, if any, deaths, and
obviously the studies are aimed at having no differences in the clinical outcomes. Only when
new antibiotics are approved for use is there a meaningful trial of the drug in a critically ill
population.
Absorption of antibiotics that will be used in the multiple-system trauma patient will be
nearly 100% since all are given intravenously. This results in rapid distribution of the drug
throughout the body water compartments to which it will have access. Intramuscular antibiotic
administration would generally not be prudent in the trauma patient because severe soft tissue
injury, shock, and expanded interstitial water volume would make systemic uptake less
dependable. Oral antibiotics have generally not had a place in trauma patients during
hospitalization since many will have nasogastric tubes in place or may have post-injury
gastrointestinal ileus. The favorable bioavailability of quinolones, linezolid, and perhaps others
in development may result in some reevaluation of the use of oral antibiotics in hospitalized
trauma patients. Utilization of the gastrointestinal tract for nutritional support has been very
effective in many trauma patients, and the intestinal tract may evolve as a route for the
administration of antibiotics.
The distribution of the antibiotic after administration becomes a critically important
issue. Each antibiotic has a unique volume of body water that it accesses following intravenous
administration. The physiochemical properties of the drug that govern the distribution in the
patient include the electrical charge of the molecule in solution, its solubility, its movement
through cell membranes of different tissues, its lipophobic or lipophilic character, and whether
metabolism is a requirement for elimination from the body. The distribution of the drug in
body water is further modified by its degree of protein binding, since highly bound drugs will
functionally be restricted in the extracellular water volume.
Unique features of the patient will also affect the distribution of the antibiotic and
accordingly its concentration in serum at any point in time. Cardiac output, regional blood
flow, and the volumes of intravenous fluids that are administered will change elimination and
distribution. The route of drug elimination may be adversely affected by either preexisting or
acquired abnormalities of renal or hepatic function. Disease processes affecting protein
concentrations in plasma will particularly impact the drug that is highly protein bound.
In Figure 1, the concentrations of a hypothetical antibiotic in the serum of a patient are
illustrated after intravenous administration. A rapid peak concentration is achieved that is
largely dictated by the rate of infusion. The distribution of the drug throughout the various
compartments and tissues that are accessed result in an equilibrium concentration, and from
that point, the elimination of the drug proceeds in a consistent fashion. A semilogarithm plot is
used for the concentration at each time point and this yields a linear configuration to the
elimination plot. Extrapolation of the semilogarithm elimination plot to time-zero permits
calculation of the volume of distribution (Vd) of the drug in this specific set of clinical
circumstances. The volume of distribution equals the total dose of drug given (D) divided by
the time-zero theoretical concentration (T 0 ), orD/(T 0 )¼Vd. Thus, 1 g of an antibiotic (1 10
6
mg)
with an extrapolated (T 0 )¼ 50 m/mL results in aVd¼20,000 m, or 20 L. In an 80-kg patient,
this would customarily be expressed at 0.25 L/kg.
The linear configuration of drug elimination over time permits calculation of the
biological elimination half-life (T1/2). The T1/2 is the period of time required for the
equilibrated plasma concentration of the drug to decline by 50%. The expectation is that
the plasma concentration reflects the dynamic processes of equilibration of the central pool
(i.e., plasma) with the multiple different pools and compartments in which the drug is present.
Antibiotics are generally considered to have a singleT1/2that describes elimination of the
drug, but some may have a secondT1/2that describes clearance at low concentrations.
522 Fry