Abstract
There is controversy over whether traditional intermittent bolus dosing or continuous infusion of beta-lactam antibiotics is preferable in critically ill patients. No significant difference between these two dosing strategies in terms of patient outcomes has been shown yet. This is despite compelling in vitro and in vivo pharmacokinetic/pharmacodynamic (PK/PD) data. A lack of significance in clinical outcome studies may be due to several methodological flaws potentially masking the benefits of continuous infusion observed in preclinical studies. In this review, we explore the methodological shortcomings of the published clinical studies and describe the criteria that should be considered for performing a definitive clinical trial. We found that most trials utilized inconsistent antibiotic doses and recruited only small numbers of heterogeneous patient groups. The results of these trials suggest that continuous infusion of beta-lactam antibiotics may have variable efficacy in different patient groups. Patients who may benefit from continuous infusion are critically ill patients with a high level of illness severity. Thus, future trials should test the potential clinical advantages of continuous infusion in this patient population. To further ascertain whether benefits of continuous infusion in critically ill patients do exist, a large-scale, prospective, multinational trial with a robust design is required.
Highlights
The mortality rate of severe sepsis and septic shock in critically ill patients remains high despite recent therapeutic advances
Ill patients with severe sepsis are more likely to benefit from continuous infusion (CI), because they commonly develop severe pathophysiological changes, which may reduce effective antibiotic exposure [95]
Conclusions numerous pharmacokinetic/ pharmacodynamic (PK/PD) data from various in vitro and in vivo experimental studies favor the use of continuous infusion, the current clinical data are less convincing and insufficient to instigate a global shift from conventional bolus dosing
Summary
The mortality rate of severe sepsis and septic shock in critically ill patients remains high despite recent therapeutic advances. This limitation has been highlighted in the two most recent meta-analyses and has been proposed as one of the contributing reasons why clinical differences between CI and IB of beta-lactams have not been found This notion is supported by one randomized, clinical trial [87] and two retrospective, observational studies [45,96], which were conducted in critically ill patients infected with gram-negative organisms. Methodology concerns and the proposed characteristics of an “ideal” trial Several reviews have suggested the importance of designing and conducting a methodologically sound clinical trial in the investigation of CI versus IB antibiotic administration benefits in critically ill patients [29,38,39,40] These recommendations cannot be overemphasized due to frequent reports of low methodological quality clinical studies. PK/PD analysis should evaluate the relative ability of IB to achieve a Cmin greater than 4 x MIC of the offending pathogen for 40-70% of the dosing interval while for CI, a Css greater than 4 x MIC
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