Translating Pharmacokinetic-Pharmacodynamic Principles Into Improved Methodology for Clinical Trials That Compare Intermittent With Prolonged Infusion of Beta-Lactam Antibiotics.

Based on the fact that beta-lactam antibiotics demonstrate time-dependent killing, different dosing strategies have been implemented to increase the time that free (unbound) antibiotic concentrations remain above the minimal inhibitory concentration, including prolonged and continuous infusion. Multiple studies have been performed that compared continuous with traditional intermittent infusion to improve outcomes in patients with severe sepsis. These studies have yielded inconsistent results for patients, as measured by clinical response to treatment and mortality due to heterogeneity of included patients, pathogens, dosing strategies, and the absence of therapeutic drug monitoring. The Continuous Infusion versus Intermittent Administration of Meropenem in Critically Ill Patients and Beta-Lactam Infusion Group trials failed to show a difference in mortality between patients randomized to receive continuous or intermittent infusion of beta-lactam antibiotics deeper understanding of the pharmacokinetic and pharmacodynamic mechanisms that occur in critically ill patients should guide us in dose optimization and improvement in methodology for future clinical trials.