Model-informed identification of optimised dosing strategies for meropenem in critically ill patients receiving...

An increasing number of critically ill patients receive slow extended daily dialysis (SLEDD) due to their pathophysiology while suffering from sepsis, necessitating effective and safe antibiotic therapy. Although SLEDD reduces meropenem exposure and increases treatment failure risk, effective and safe dosing regimens are unclear. We aimed to identify optimised meropenem dosing strategies for critically ill SLEDD patients through population pharmacokinetic (PK) modelling and PK/pharmacodynamic (PD)-based probability of target attainment (PTA) analysis.

Clinical data from a prospective study involving critically ill SLEDD patients receiving meropenem were monitored through routine therapeutic drug monitoring. A total of 178 blood samples from 13 patients (median 14 samples per patient) were analysed. A PK model was developed and utilised to evaluate 24 clinically relevant dosing regimens during SLEDD therapy (7-h on-SLEDD periods q24h) in PTA analyses. The PK/PD target window of minimum meropenem concentration between 8 mg/L (P. aeruginosa; R-breakpoint) and 44.45 mg/L (toxicity threshold) was used.

A one-compartment PK model with linear elimination and total clearance (CL) split into renal (CL_REN; 45%) and SLEDD-associated (55%) CL well characterised the SLEDD data. Creatinine clearance (urine-collected; CLCR_urine) was identified as significant factor on CL_REN. Continuous infusions, specifically 2 g q24h for CLCR_urine 0-25 mL/min and 3 g q24h for CLCR_urine 25-40 mL/min, showed the highest PTA being effective and safe during SLEDD therapy. A comprehensive dosing nomogram was developed.

Our easy-to-use dosing nomogram presents a promising tool in optimising meropenem dosing regimens for critically ill SLEDD patients considering their kidney function in clinical practice.

Clinicaltrials.gov NCT03985605. Registered 14 June 2019. https://classic.

gov/ct2/show/study/NCT03985605.