vancomycin in infected surgical intensive care unit patients. They assumed and documented
that theVdof vancomycin was essentially that of total body water, or 0.6 L/kg. While the linear
regression forVdfor vancomycin did cluster about 0.6 L/kg, the variability was quite high
with anR^2 for the relationship only being 0.15. In selected cases, theVdwas so high that it
actually exceed the theoretical maximum of 1.0 L/kg, reflecting probably tissue binding the
antibiotic. Pharmacokinetic dosing required a 20% increase in the predicted dose of
vancomycin, but a 50% increase in the interval between doses reflected a longerT1/2than
expected. In a more recent study, Va ́zquez et al. (15) note that 3 g of vancomycin was required
every 24 hours to effectively treat patients in septic shock, but also noted that the adverse
pharmacokinetic profile of the patients quickly reverted to normal when the infection was
receding and that risks of toxicity can quickly evolve.
Vancomycin pharmacodynamics in burn patients has been noted to be quite variable.
Rybak et al. (16) noted thatVdwas quite variable, but only averaged about 10% more than
control patients or intravenous drug abusers. Vancomycin clearance was 143 mL/min in the
burn patient which was more than twice as great as that seen in control patients (68 mL/min).
Vancomycin patients required larger and more frequent doses of the drug to achieve
satisfactory peaks and troughs during therapy. The hyperdynamic circulation of the burn
patient with normal kidney function was thought to be the basis for accelerated drug clearance.
Garrelts and Peterie (17) made similar observations with respect to a reducedT1/2in burn
patients receiving vancomycin.
b-Lactam Antibiotics
Studies of the cephalosporin antibiotics have been limited with many of the commonly used
drugs (e.g., cefazolin) not having been studied in trauma or febrile states. Virtually all have
been in the third-generation group of cephalosporins. Van Dalen and Vree (18) studiedVdand
T1/2in critically ill patients after the administration of ceftriaxone, the most commonly
employed third-generation cephalosporin. They identified that the pharmacokinetics patterns
were very similar to the aminoglycosides with an expanded Vdand wide inter-patient
variability withT1/2. They concluded that unique nomograms needed to be developed to
permit dosing of ceftriaxone that was consistent with each patient’s unique severity of disease
profile. Yet another study demonstrated similar findings with a 90% increase inVdand that
drug clearance was increased in patients with normal renal function (19). Patients with
diminished renal function demonstrated a very prolongedT1/2and posed a serious problem of
potential drug accumulation.
Hanes et al. (20) studied ceftazidime in critically ill trauma patients. They identified that
theVdwent from 0.210.03 L/kg in healthy volunteers to 0.320.14 L/kg in the trauma
patients. It was felt that the large dose of the antibiotic (2 g every eight hours) overcame the
pharmacokinetic changes in that only 8% of patients had subtherapeutic serum concentrations
beneath the MIC. Dailly et al. (21) studied ceftazidime in burn patients that were not in the
acute post-injury phase and noted an increasedVdbut also identified lower clearance of the
drug. They suggested that the expandedVdcould serve as a reservoir for the drug and result
in slow return to the circulation, which would explain the reduced clearance. Gomez et al. (22)
noted a significantly increasedVd and an increased T1/2,, but antibiotic clearance and
bioavailability (i.e., “area under the curve”) were not changed. Angus et al. (23) studied
intermittent versus continuous infusion of ceftazidime in septic patients and concluded that
every eight hour dosing of the drug left the patient at-risk for subtherapeutic concentrations
because of the increasedVd. They concluded that continuous infusion would prove to use less
total drug and would ensure reliable therapeutic drug concentrations.
Cefepime is a commonly used antibiotic especially later in the trauma patient’s course
when fever and nosocomial infection are significant issues. Bonapace et al. (24) studied
12 patients with burns (average of 36% total body surface) with suspected or documented
infection and found a reduction in concentrations due to increasedVdbut that doses of 1 g
every 8 hours, and 2 g every 12 hours resulted in blood concentrations above the MICs of
organisms likely to be targeted by this drug. Lipman et al. (25) studied 10 patients that were
critically ill with sepsis and found that 80% of trough levels were beneath the MIC 50 for
Pseudomonas aeruginosa. Kieft et al. (26) studied cefepime in patients with the septic syndrome
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