Pharmacokinetic/Pharmacodynamic Target Attainment of Vancomycin, at Three Reported Infusion Modes, for Methicillin-Resistant Staphylococcus aureus (MRSA) Bloodstream Infections in Critically Ill Patients: Focus on Novel Infusion Mode

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.

Keywords: continuous infusion; intermittent infusion; methicillin-resistant Staphylococcus aureus; optimal infusion; pharmacokinetic/pharmacodynamic; vancomycin.

Figure 1

Three infusion modes of vancomycin. (A) OTSI, optimal two-step infusion; “□”, loading-rate rapid infusion (LRRI) phase in OTSI mode; “◇”, low-rate continuous infusion (LRCI) phase in OTSI mode; “○”, elimination phase in OTSI mode. (B) II, intermittent infusion; τ, dosing interval; and (C) CI, continuous infusion. “↓”, start of the dose; AUC, area under the curve; C, drug concentration; C _trough, trough concentration.

Figure 2

PTA values of 34 dosage regimens for various MICs and CL _cr at various AUC_0–24/MIC targets. AUC_0–24, daily area under the curve; MIC, minimum inhibitory concentration; AUC_0–24/MIC, ratio of daily area under the curve to minimum inhibitory concentration; CL _cr, creatinine clearance; LRRI, loading-rate rapid infusion in OTSI mode; LRCI, low-rate continuous infusion in OTSI mode.