Dosage Regimen Optimization of Ertapenem Against ESBL-Producing Enterobacterales Infection in Critically Ill Patients Using Monte Carlo Simulation

Abstract

Extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales infections are associated with high mortality rates. Ertapenem is recommended as one of the first-line drugs due to its efficacy against these pathogens. However, physiological changes in critically ill patients may influence drug pharmacokinetics. Thus, this study aims to optimize the ertapenem dosage regimen for critically ill patients in both efficacy and neurotoxicity. The previously reported population pharmacokinetic model and drug-albumin binding model were used for Monte Carlo simulation. A total of 10 ertapenem dosage regimens were performed in 10,000 simulated critically ill patients with varying degrees of renal function and serum albumin. A PTA of achieving 100% for time of free drug above the minimum inhibitory concentration (fT>MIC) was assessed for efficacy. A PTA of achieving a total drug ≥ 11.77 mg/L was determined for neurotoxicity. A usual recommended dosing of 1 g every 24 h can ensure a PTA > 80% for efficacy only in patients having a creatinine clearance of 30–59 mL/min with unlikely neurotoxic risk (a PTA < 2%). Moreover, the study highlights the need for an individualized ertapenem dosage regimen based on renal function in critically ill patients, as ertapenem in divided doses might be more optimal for both efficacy and safety compared to once daily dosing in patients with creatinine clearance ≥ 60 mL/min. Further randomized controlled trials are needed to confirm these dose recommendations.