Dose optimization of meropenem for critically ill patients by pharmacokinetic/ pharmacodynamic simulation

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Recent pharmacokinetic/pharmacodynamic (PK/PD) studies revealed that prolonged infusion, especially continuous infusion could improve probability of target attainment (PTA) of meropenem. However, the implementation of continuous meropenem infusion in the clinical environment can be limited due to the solution’s instability, which results in a diminished effectiveness of the drug. The two-step infusion approach has been expected as a promising novel approach to address this issue. The aim of this study was to assess the probability of target attainment for finding the optimal dosage regimens of meropenem in critically ill patients. Monte Carlo simulation using Ehmann population pharmacokinetic model was performed to evaluate the following different intravenous infusion regimens including extended infusion (EI), continuous infusion (CI) and two-step infusion (TS) with three total daily doses (3g, 4.5g and 6g). The PK/PD target was defined as the probability of achieving a fractional time above the MIC of ≥ 98% on the first day of therapy. Subsequently, dosing regimens were suggested based on renal function which was estimated by the Cockcroft & Gault creatinine clearance (Clcr =10-30, 31-50, 51-70, 71-90, 91-130, and over 130 mL/min). Simulations also revealed that the 1000mg q8h EI regimen is suitable to reach MICs of 1 mg/L, regardless of the patient’s renal function. For higher MICs and up to 16 mg/L, continuous infusion therapy with a loading dose of 0.5 g and a maintenance dose of 3 g to 6 g per day should be considered in clinical practice. The two-step infusion approach did not demonstrate superior PTA compared to extended infusion therapy and was significantly lower than that of continuous infusion at the same dosage level.