Abstract
OBJECTIVE: The study aimed to evaluate and compare the pharmacokinetic/pharmacodynamic (PK/PD) exposure to vancomycin in the novel optimal two-step infusion (OTSI) vs. intermittent infusion (II) vs. continuous infusion (CI) mode, for MRSA bloodstream infections occurring in critical patients. METHODS: With PK/PD modeling and Monte Carlo simulations, the PK/PD exposure of 15 OTSI, 13 II, and 6 CI regimens for vancomycin, at 1, 2, 3, 4, 5, and 6 g daily dose, was evaluated. Using the Monte Carlo simulations, the vancomycin population PK parameters derived from critical patients, the PD parameter for MRSA isolates [i.e., minimum inhibitory concentration (MIC)], and the dosing parameters of these regimens were integrated into a robust mdel of vancomycin PK/PD index, defined as a ratio of the daily area under the curve (AUC(0-24)) to MIC (i.e., AUC(0-24)/MIC), to estimate the probability of target attainment (PTA) of these regimens against MRSA isolates with an MIC of 0.5, 1, 2, 4, and 8 mg/L in patients with varying renal function. The PTA at an AUC(0-24)/MIC ratio of >400, 400-600, and >600 was estimated. A regimen with a PTA of ≥90% at an AUC(0-24)/MIC ratio of 400-600, which is supposed to maximize both efficacy and safety, was considered optimal. RESULTS: At the same daily dose, almost only the OTSI regimens showed a PTA of ≥90% at an AUC(0-24)/MIC ratio of 400-600, and this profile seems evident especially in patients with creatinine clearance (CL(cr)) of ≥60 ml/min and for isolates with an MIC of ≤2 mg/L. However, for patients with CL(cr) of <60 ml/min and for isolates with an MIC of ≥4 mg/L, the II regimens often displayed a higher or even ≥90% PTA at an AUC(0-24)/MIC ratio of >400 and of >600. The CI regimens frequently afforded a reduced PTA at an AUC(0-24)/MIC ratio of >400 and of >600, regardless of CL(cr) and MIC. CONCLUSIONS: The data indicated that the OTSI regimens allowed preferred PK/PD exposure in terms of both efficacy and safety, and thus should be focused more on, especially in patients with CL(cr) of ≥60 ml/min and for isolates with an MIC of ≤2 mg/L.