Vancomycin pharmacokinetic and pharmacodynamic models for critically ill patients with post-sternotomy mediastinitis.

Abstract

Vancomycin is commonly used to treat serious methicillin-resistant staphylococcal infections, especially post-sternotomy mediastinitis (PSM). However, information on pharmacokinetics and pharmacodynamics in intensive care unit (ICU) patients remains scarce. We conducted vancomycin pharmacokinetic-pharmacodynamic modeling for ICU patients with PSM. This cohort study included 30 consecutive patients who received multiple vancomycin doses during primary closed drainage of PSM with Redon catheters, targeting serum drug trough concentrations of 25-35mg/L, and generating 359 serum vancomycin concentration-time values for analysis. Population pharmacodynamics served to describe the withdrawal of Redon catheters, i.e., the probability of in-ICU cure. Vancomycin pharmacokinetics corresponded to a two-compartment open model with first-order elimination kinetics. Mean [between-subject variability] population estimates were 1.91 (men)/1.25 (women) [0.28] L/h for vancomycin elimination, with intercompartmental clearance of 5.71 [1.01]L/h, and respective central and peripheral distribution volumes of 21.9 and 68 [0.53]L. Vancomycin clearance increased with body weight and declined with severity at ICU admission and serum creatinine (SCr), thereby allowing the prediction of the vancomycin plateau. Intercompartmental clearance decreased with diabetes mellitus (-70%). The probability of withdrawing all Redon catheters (patient cured) was dependent only on the area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) exposures ratio in plasma. Neither preoperative factors, antistaphylococcal co-treatments, nor the initial number of Redon catheters significantly influenced this probability. The AUC/MIC exposures ratio had no significant effect on SCr levels. These modeling analysis results identified five clinically relevant covariates that influenced vancomycin pharmacokinetics and might achieve better individualization of vancomycin dosing for methicillin-resistant staphylococcal PSM in ICU patients.