Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens

Abstract

Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m² would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.

Fig. 1.

Diagnostic plots for the final population pharmacokinetic covariate model. (Left) Observed concentrations versus the population predicted concentrations (r² = 0.07). (Right) Observed concentrations versus the individual predicted concentrations (r² = 0.60). The nonlinear regression line of fit is shown by the solid black line, and the line of x = y is the gray dotted line.

Fig. 2.

The effect of loading dose on rapid attainment of target vancomycin concentrations. Different weight-based doses are simulated for a critically ill patient with a creatinine clearance of 100 ml/min/1.73 m², followed by administration as a 35-mg/kg/day continuous infusion.

Fig. 3.

The effect of creatinine clearance on vancomycin concentrations administered by continuous infusion (35 mg/kg per day after 35-mg/kg loading dose).

Fig. 4.

The effect of different doses (mg/kg) on vancomycin concentrations administered by continuous infusion after a 35-mg/kg loading dose in a patient with a creatinine clearance of 100 ml/min/1.73 m².