Supplementary Material for: Optimal Meropenem Dosing Regimens in Patients undergoing Continuous Renal Replacement Therapy: Systematic review and Monte Carlo simulations

Introduction The optimal meropenem dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) based on pharmacokinetic and pharmacodynamic concepts are not well established. This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving CRRT and (2) to define the optimal meropenem dosing regimens in these populations via Monte Carlo simulations. Methods We used Medical Subject Headings (MeSH) of “meropenem”, “continuous renal replacement therapy” and “pharmacokinetics” or related terms to identify studies for systematic review. A one-compartment pharmacokinetic model was conducted to predict meropenem levels for the initial 48 hours of therapy. The pharmacodynamic (PD) targets were 40% of free drug above a threshold of 1 times the minimum inhibitory concentration (MIC) (40% fT >MIC), 4 times the MIC (40% fT > 4MIC), and an additional target of free drug level above 1 times MIC 100% of the time (fT> MIC). The dose that achieved at least 90% of the probability of target attainment (PTA) was defined as an optimal dose. Results Twenty-one articles were included for our systematic review. The necessary pharmacokinetic parameters such as volume of distribution and CRRT clearance were cited in 90.5 and 71.4% of articles, respectively. None of the published studies reported completed necessary parameters. A regimen of 750 mg q 8 hours was found to be the optimal dose for predilution-CVVH and CVVHD modality using two effluent rates (25 and 35 mL/kg/h) which achieved the PD target of 40% fT > 4MIC. Conclusion None of the published studies showed the necessary pharmacokinetic parameters. Pharmacodynamic target significantly contributed to meropenem dosage regimens in these patients. Differing effluent rates and types of CRRT shared similar dosing regimens. Clinical validation of the recommendation is suggested.