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


Jason A Roberts 1 ,

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

Jason A Roberts et al. Antimicrob Agents Chemother. 2011 Jun.

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.

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Figures

Fig. 1.
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.
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.
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.
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.

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