Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study

Stephan Braune,Claudia Langebrake,Oliver Steinmetz,Michael Baehr,Stefan Kluge,Axel Nierhaus,Christina König,Jason A Roberts

doi:10.1186/s13054-018-1940-1

Abstract

BackgroundThe aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED).MethodsProspective population PK study on 19 septic patients treated with meropenem and receiving SLED for acute kidney injury. Serial blood samples for determination of meropenem concentrations were taken before, during and after SLED in up to three sessions per patient. Nonparametric population PK analysis with Monte Carlo simulations were used. Pharmacodynamic (PD) targets of 40% and 100% time above the minimal inhibitory concentration (f T > MIC) were used for probability of target attainment (PTA) and fractional target attainment (FTA) against Pseudomonas aeruginosa.ResultsA two-compartment linear population PK model was most appropriate with residual diuresis supported as significant covariate affecting meropenem clearance. In patients without residual diuresis the PTA for both targets (40% and 100% f T > MIC) and susceptible P. aeruginosa (MIC ≤ 2 mg/L) was > 95% for a dose of 0.5 g 8-hourly. In patients with a residual diuresis of 300 mL/d 1 g 12-hourly and 2 g 8-hourly would be required to achieve a PTA of > 95% and 93% for targets of 40% f T > MIC and 100% f T > MIC, respectively. A dose of 2 g 8-hourly would be able to achieve a FTA of 97% for 100% f T > MIC in patients with residual diuresis.ConclusionsWe found a relevant PK variability for meropenem in patients on SLED, which was significantly influenced by the degree of residual diuresis. As a result dosing recommendations for meropenem in patients on SLED to achieve adequate PD targets greatly vary. Therapeutic drug monitoring may help to further optimise individual dosing.Trial registrationClincialtrials.gov, NCT02287493.

Highlights

The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED)
These plots generally show that the probability of target attainment (PTA) decreases with a higher residual diuresis
Aiming for 100% f T > minimum inhibitory concentration (MIC) with a residual diuresis of 0 mL/d a dose of 1 g 12-hourly resulted in a sufficient PTA above 95%

Summary

Introduction

The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED). In the intensive care unit (ICU), up to 42% of septic patients develop acute kidney injury (AKI) with approximately 5% of all ICU patients requiring renal replacement therapy (RRT) [1, 2]. Because of their high mortality risk optimised antibiotic dosing in these. Meropenem is a broad-spectrum antibiotic agent commonly used in critically ill patients [5,6,7]. Recent studies suggest a target of 100% f T > MIC to be more appropriate for critically ill patients with severe sepsis [10,11,12]

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