and identified nearly a doubling of theVdand a prolongedT1/2. They indicated that 2 g every
12 hours still resulted in adequate trough concentrations for expected MICs of pathogens, but
also noted a widely variable pharmacokinetic profile in their patients, especially in the elderly.
The pharmacokinetics of aztreonam were studied in 28 critically ill, mostly trauma
patients, with gram-negative infections (27). TheVdwas nearly doubled over anticipated
values for this study population. The patients were a relatively young group (age¼35 years)
and received 2 g of aztreonam every six hours. Trough levels were above the MICs of likely
pathogens, despite the increase in Vd. The larger dose of aztreonam was the likely reason that
adverse effects were not seen from the increase inVd. McKindley et al. (28) similarly identified
increasedVdin trauma patients with pneumonia, but also identified prolongation of theT1/2.
Carbapenems
The carbapenem antibiotics are a subgroup of theb-lactams that are commonly used to treat
the most difficult of infected trauma patients, especially with hospital-acquired bacteria. The
data with imipenem have been quite variable. Boucher et al. (29) found that averageVdwas
comparable to controls in patients with burns, but did note the highly variable observations in
the burn group. Dailly et al. (30) noted increasedVdand increased imipenem clearance rates in
burn patients. McKindley et al. (26) also noted increasedVdand noted significantly lower
plasma concentrations in trauma patients with pneumonia, while Belzberg et al. (31) noted
very unpredictableVdandT1/2in critically ill patients and noted that very highVdand low
serum concentrations may contribute to treatment failures in this population of patients. Fish
et al. (32) made the unique observation of the efficient clearance of imipenem by continuous
venovenous hemofiltration and have indicated that this variable in addition to pharmacoki-
netic changes may be an additional reason to increase antibiotic administration. Similar
pharmacokinetic observations were made with meropenem (33).VdandT1/2tended to be
similar to normal adult measurements in surgical patients with intraabdominal infection and
other surgical infections.
In a comparative trial of imipenem and meropenem, Novelli et al. (34) found differences
in the two drugs. Following a standardized infusion of 1 g., they found a higher peak
concentration and area-under-the-serum concentration–time curve with imipenem, while the
Vdwas higher for meropenem.
Profound changes in ertapenem pharmacokinetics have been reported in critically ill
patients. Burkhardt et al. (35) treated 17 patients with ventilator-associated pneumonia. They
found that theVdof ertapenem nearly doubled, and that peak concentration– and the area-
under-the-serum concentration–time curve were dramatically reduced. Of interest, theT1/2
was minimally changed. Ertapenem is a highly protein-bound drug (85% to 95%) and they
associated these changes with the decline in the serum albumin of the patients. However, acute
declines in serum proteins are certainly markers of the severity of infection, and the changes in
ertapenem pharmacokinetics are still likely to be consequences of the systemic manifestations
of severe infection.
Quinolones
While specific data in the trauma patient are not available, the quinolone group of antibiotics
appear to follow a different pattern of pharmacokinetic change in the critically ill patient and
can be anticipated to have a different pattern in the injured patient as well. Lipman et al. (36)
studied 18 critically ill patients at several days into the patients’ treatment with ciprofloxacin.
While normal volunteers will have aVd¼1.8 L/kg and aT1/2will be four to five hours,
adverse changes were not seen in severely infected patients treated with ciprofloxacin. TheVd
was 1.2 to 1.4 L/kg andT1/2was 3.2 to 3.9 hours. Peak and trough concentrations did not
appear to be influenced by the septic state. These observations with ciprofloxacin were
confirmed in patients with intraabdominal infection (37). A single study has identified selected
patients where high MIC requirements may not be uniformly achieved in critically ill patients,
and recommended 1200 mg daily to ensure optimal concentrations (38).
Studies with levofloxacin in patients with critical illness (39) and with ventilator-
associated pneumonia (40) have similarly demonstrated no adverse changes in pharmacoki-
netic profiles. A single levofloxacin study identified pharmacokinetic changes that may have
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