virtues of this delivery method (61,62), but evidence to show consistently superior outcomes
have been lacking. Studies have suffered from small number of patients and an absence of
consistent severity in the study populations. Because the continuous infusion technique adds
an additional therapeutic imposition at the bedside in the intensive care unit, additional
evidence is necessary to validate the utility of this method.
Prolonged Antibiotic Infusion
A compromise position between conventional intermittent and continuous infusion is the
concept of prolonged or extended infusion of antibiotics. As was noted in Figure 1, intermittent
infusion results in a peak concentration and the peak is in part dictated by the rapidity with
which the drug is infused. After equilibration, elimination begins consistent with theT1/2of
the drug. If the infusion is extended over three hours instead of 30 minutes, then the peak
concentration will be somewhat diminished, but the rate of total drug elimination will also be
delayed. Prolonged administration affords an extended period of time for the drug to have
therapeutic concentrations (Fig. 4). This extension of therapeutic concentrations has the
potential for use under circumstances of adverseVd changes in febrile, multiple-trauma
patients. Studies with carbapenems (63,64) and piperacillin-tazobactam (65,66) have shown
favorable pharmacokinetic profiles with prolonged infusion, but clinical evidence that
compares this method with conventional antibiotic administration strategies are needed.
SUMMARY
The actual number of studies that have examined the febrile multiple-trauma patients is few,
and conclusions about pharmacokinetic changes in this population must be extrapolated at this
time from studies of intensive care unit patients, septic patients, burn patients, and others with
critical illness. It is clear that more clinical studies are needed and that alternative
administration strategies should be explored to improve clinical outcomes. However, it is
clear that antibiotic concentrations are adversely affected for most drugs as the injured and
septic patient progressively accumulates “third space” volume. The quinolones and perhaps
linezolid are exceptions. Clearance of antibiotics appear to be highly variable and clearly are
influenced by drug concentration changes, cardiac output changes and their influence upon
Table 3 Selection of Studies where Continuous Infusion of Antibiotics Was Compared with Intermittent Infusion
Authors Antibiotic(s) Type of infection
Patients
continuous/
intermittentAdembri et al. (48) Linezolid Septic patients 8/8
Angus et al. (23) Ceftazidime Septic melioidosis 10/11
Bodey et al. (49) Cefamandoleþ
carbenicillin
Fever of unknown origin/neutropenia 74/92Buijk et al. (50) Ceftazidime ICU patients 12/6
Feld et al. (51) Tobramycinþ
cefamandole
Septic granulocytopenia 30/46Feld et al. (52) Sisomicin Infections in neutropenia 60/61
Georges et al. (53) Cefepime Critically ill 26/24
Hanes et al. (20) Ceftazidime Nosocomial pneumonia (trauma patients) 17/14
Lau et al. (54) Piperacillinþ
tazobactam
Intra-abdominal infection 130/132McNabb et al. (55) Ceftazidime Nosocomial pneumonia 17/18
Roberts et al. (56) Ceftriaxone Critically ill 29/28
Sakka et al. (57) Imipenem Nosocomial pneumonia 10/10
Van Zanten et al. (58) Cefotaxime Exacerbation chronic lung disease 47/46
Wysocki et al. (59) Vancomycin Severe staphylococcal infections 61/58
Many of the studies are not powered with sufficient patients to give an assessment of outcomes. Numerous
different drugs have been studied. A prospective, randomized trial with a large population of well-stratified patients
is needed to answer the question of continuous infusion of antibiotics as a superior treatment strategy.
Abbreviation: ICU, intensive care unit.
532 Fry