Can population pharmacokinetic modelling guide vancomycin dosing during continuous renal replacement therapy in critically ill patients?

Treatment of resistant bacteria such as meticillin-resistant Staphylococcus aureus (MRSA) relies on achieving adequate antibiotic concentrations at the site of infection. Strategies to attain such targets in septic critically ill patients receiving renal replacement therapy (RRT) are uncommon but could be useful for increasing the likelihood of therapeutic dosing. The aim of this study was to conduct a population pharmacokinetic (PK) analysis in septic patients undergoing continuous RRT and to determine which parameters were associated with inadequate vancomycin concentrations. In total, 81 patients with 199 blood samples were included in the study. All patients received vancomycin dosing according to the local protocol, which included a weight-based loading dose followed by continuous infusion. The vancomycin concentration-time points were adequately described with a one-compartment model with zero order input. The median population PK estimate for vancomycin clearance (CL) was 2.9 L/h [interquartile range (IQR) 2.4-3.4 L/h] and for volume of distribution (Vd) was 0.8 L/kg (IQR 0.6-1.1 L/kg). The goodness-of-fit plots for the model were adequate. When covariates were tested, none were found to adequately explain changing vancomycin CL or Vd in the population PK model. In particular, the lack of correlation between CL and RRT settings was likely due to the multiple confounders known to influence antibiotic prescription in this setting. These data provide a cautionary tale of the challenges of describing pharmacokinetics in critically ill patients receiving RRT and highlights the need for a detailed, prospective, multicentre study to better inform dosing practice.