Pharmacokinetic and Pharmacodynamic Efficacies of Continuous versus Intermittent Administration of Meropenem in Patients with Severe Sepsis and Septic Shock: A Prospective Randomized Pilot Study

Background: The antibiotic meropenem is commonly administered in patients with severe sepsis and septic shock. We compared the pharmacokinetic, clinical, and bacteriological efficacies of continuous infusion of meropenem versus intermittent administration in such patients. Methods: Patients admitted to the Intensive Care Unit (ICU) with severe sepsis or septic shock who received meropenem were randomly assigned to either the continuous (n = 25) or intermittent groups (n = 25). The continuous group received a loading dose of 0.5 g of meropenem followed by a continuous infusion of 3 g/day; the intermittent group received an initial dose of 1.5 g followed by 1 g for every 8 h. Clinical success, microbiological eradication, superinfection, ICU mortality, length of ICU stay, and duration of meropenem treatment were assessed. Serial plasma meropenem concentrations for the first and third dosing periods (steady state) were also measured. Results: Clinical success was similar in both the continuous (64%) and intermittent (56%) groups (P = 0.564); the rates of microbiological eradication and superinfection (81.8% vs. 66.7% [P = 0.255] and 4% vs. 16% [P = 0.157], respectively) showed improvement in the continuous group. The duration of meropenem treatment was significantly shorter in the continuous group (7.6 vs. 9.4 days; P = 0.035), where a better steady-state concentration was also achieved. Peak and trough concentrations were significantly different between the continuous and intermittent groups both in the first (Cmax: 19.8 mg/L vs. 51.8 mg/L, P = 0.000; Cmin: 11.2 mg/L vs. 0.5 mg/L, P = 0.000) and third dosing periods (Cmax: 12.5 mg/L vs. 46.4 mg/L, P = 0.000; Cmin: 11.4 mg/L vs. 0.6 mg/L, P = 0.000). For medium-susceptibility pathogens, continuous infusion concentrations above the minimal inhibitory concentration were 100%, which was better than that in the intermittent group. Conclusions: Continuous infusion of meropenem provides significantly shorter treatment duration and a tendency for superior bacteriological efficacy than intermittent administration. Continuous infusion may be more optimal against intermediate-susceptibility pathogens.