Combination of pharmacokinetic and pathogen susceptibility information to optimize meropenem treatment of gram-negative infections in critically ill patients.

Background: Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients. This study aimed to develop a meropenem dosing algorithm for the treatment of gram-negative infections based on intensive care unit (ICU)-specific resistance data. Methods: Antimicrobial susceptibility testing of gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital. Based on the observed minimal inhibitory concentration (MIC) distribution, stochastic simulations (n=1000) of an evaluated pharmacokinetic meropenem model and a defined pharmacokinetic/pharmacodynamic target (100%T>4xMIC while minimum concentrations <44.5 mg/L), dosing recommendations for patients with varying renal function were derived: Pathogen-specific MIC distributions were used to calculate the cumulative fraction of response (CFR) and the overall MIC distribution was used to calculate the local pathogen-independent mean fraction of response (LPIFR) for the investigated dosing regimens. A CFR/LPIFR >90% was considered adequate. Results: The observed MIC distribution significantly differed from the EUCAST database. Based on the 6520 MIC values included, a three-level dosing algorithm was developed. If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacter baumannii or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function. In all other cases dosing needs to be adjusted based on renal function. Conclusion: ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings. (250 words).