Impact of a vancomycin loading dose on the achievement of target vancomycin exposure in the first 24 h and on the accompanying risk of nephrotoxicity in critically ill patients

Background: The advocated pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin, AUC/MIC >= 400 mg.h/L, may not be reached with a conventional fixed starting dose of 1000mg in critically ill patients, but increasing the dose may cause nephrotoxicity. Objectives: To evaluate the effect of a weight-based loading dose of 25 mg/kg vancomycin on PK/PD target attainment in the first 24 h (AUC(0-24)) in critically ill patients and to evaluate whether this increases the risk of acute kidney injury (AKI). Patients and methods: A prospective observational before/after study was performed in ICU patients, comparing the percentage of vancomycin courses with AUC(0-24)>= 400 mg.h/L and the incidence of AKI, defined as worsening of the risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE) score. The conventional dose group received 1000 mg of vancomycin as initial dose; the loading dose group received a weight-based loading dose of 25 mg/kg. A population PK model developed using non-linear mixed-effects modelling was used to estimate AUC(0-24) in all patients. Results: One hundred and four courses from 82 patients were included. With a loading dose, the percentage of courses achieving AUC(0-24)>= 400 mg.h/L increased significantly from 53.8% to 88.0% (P=0.0006). The percentage of patients with new-onset AKI was not significantly higher when receiving a 25 mg/kg loading dose (28.6% versus 37.8%; P=0.48). However, the risk of AKI was significantly higher in patients achieving AUC(0-24)>400 mg.h/L compared with patients achieving AUC<400 mg.h/L (39.0% versus 14.8%; P=0.031). Conclusions: A weight-based loading dose of 25 mg/kg vancomycin led to significantly more patients achieving AUC(0-24)>= 400 mg.h/L without increased risk of AKI. However, some harm cannot be ruled out since higher exposure was associated with increased risk of AKI.