Population pharmacokinetics and Monte Carlo dosing simulations of meropenem during the early phase of severe sepsis and septic shock in critically ill patients in intensive care units

Abstract

Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT>MIC) and 80% fT>MIC. The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 μg/ml, the PTAs of 40% fT>MIC following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 μg/ml in immunocompromised hosts, the PTAs of 80% fT>MIC following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the V of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.

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Figures

FIG 1

Basic goodness-of-fit plots. (A) Plot of observations versus population predictions. (B) Plot of observations versus individual predictions. (C) Plot of conditional weighted residuals versus time. (D) Plot of conditional weighted residuals versus individual predictions.

FIG 2

Probability of target attainment (PTA) for meropenem regimens achieving 40% fT>MIC (A) or 80% fT>MIC (B) at specific MICs during the early phase of severe sepsis and septic shock in 9 patients, after administration of a 1-h infusion of 0.5 g every 8 h (▲), a 4-h infusion of 0.5 g every 8 h (△), a 1-h infusion of 1 g every 8 h (■), a 4-h infusion of 1 g every 8 h (□), a 1-h infusion of 2 g every 8 h (●), or a 4-h infusion of 2 g every 8 h (○). Dashed lines, 90% PTA. fT>MIC, exposure time during which the free plasma drug concentration remains above the MIC.