Knowledge of theVdandT1/2allows the design of dose and dosage intervals for the
antibiotic. If our theoretical drug in Figure 1 was deemed to have toxicity at concentrations
above 80m/mL then it would be desirable to have the concentration below that threshold for
the treatment interval. Furthermore, the treatment interval between individual doses requires
an understanding of the rate of declining concentrations of the drug and the minimum
inhibitory concentration (MIC) of the drug against the likely pathogens to be encountered. If
the MIC for likely pathogens was 5m/mL, and theT1/2of our drug was two hours, then four
T1/2would give a drug plasma concentration of 6.25m/mL, which remains above the target
MIC. Thus, a rational configuration of the use of this drug would be a 1 g dose that was re-
dosed every eight hours. This theoretical design obviously assumes that maintenance of the
drug concentration must be above the MIC at all time intervals. The post-antibiotic effect is
seen where certain antibiotics (e.g., aminoglycosides) bind irreversibly to bacterial cell targets
(e.g., ribosomes), and the action of the antibiotic persists after the therapeutic concentration is
no longer present. Antibiotics with a significant post-antibiotic effect can have treatment
intervals that are greater than would be predicted by the above model. Nevertheless, the above
strategy is generally used for the design of the therapeutic application of drugs in clinical trials.
The design is derived from studies in healthy volunteers and clinical trials are generally
performed in patients without critical illness.
Biotransformation is the process by which the parent drug molecule is metabolized
following infusion. Some antibiotics require biotransformation to have antimicrobial activity
(e.g., clindamycin), others will have metabolism result in inactivity of the drug, while still
others may have both the parent drug and the metabolite with retained biological activity
(e.g., cefotaxime).
Biotransformation may occur via a number of pathways, although hepatic metabolism is
most common. It may occur within the gastrointestinal tract, the kidney epithelium, the lungs,
and even within the plasma itself. Hepatic biotransformation may result in the metabolite
being released within the blood, resulting commonly in attenuation of action and facilitation of
Figure 1 Illustrates the clearance curve of a theoretical antibiotic. The ordinate is the antibiotic concentration
expressed in log 10. The abscissa is time in hours. [A] represents the peak concentration after intravenous
administration. [B] represents the maximum concentration after full equilibration of the antibiotic with all body water
compartments to which that drug has access. [C] is the concentration of the antibiotic after oneT1/2. [D] is the
concentration after the secondT1/2. [E] is the time intercept when the concentration of the drug reaches the [MIC]
for the target organism that would be treated with the antibiotic being studied. [T 0 ] is the extrapolated concentration
of the drug assuming full equilibration of the entire administered dose and without any elimination. From [T 0 ] and
the dose of administration, theVdcan be calculated.Vdis a theoretical calculation that can be influenced by factors
other than the actual body water of drug distribution. Thus, this calculated variable may actually be greater than
total body water (>0.6 L/kg).Antibiotic Kinetics in the Multiple-System Trauma Patient 523