Translating PK-PD principles into improved methodology for clinical trials which compare intermittent with prolonged infusion of beta-lactam antibiotics

Abstract

Based on the fact that beta-lactam antibiotics demonstrate time-dependent killing, different dosing strategies have been implemented to increase the time that free (f) (unbound) antibiotic concentrations remain above the Minimal Inhibitory Concentration (MIC), 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 and/or septic shock. 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 (TDM). The MERCY and BLING III studies failed to show a difference in mortality between patients randomized to receive continuous and intermittent infusion of beta-lactam antibiotics.
 A deeper understanding of pharmacokinetic (PK) and pharmacodynamic (PD) mechanisms that occur in critically ill patients should guide us in dose optimization and improvement in methodology for future clinical trials.