Vancomycin dosing in chronic high-flux haemodialysis: a systematic review

Highlights

• There is uncertainty surrounding vancomycin dosing in high-flux haemodialysis (HD).

• There are fewer pre-HD concentrations <15 mg/L with weight-based dosing (WBD).

• Larger high-quality studies with a focus on WBD are required.

• More studies reporting the AUC/MIC ratio and clinical outcomes are needed.

Abstract

The aim of this study was to systematically evaluate whether non-weight-based dosing (non-WBD) or weight-based dosing (WBD) of vancomycin leads to a higher proportion of patients achieving the pharmacokinetic/pharmacodynamic target. Studies from January 1985 to February 2017 were identified through Cochrane, MEDLINE and Embase databases. Those conducted in adults with end-stage renal disease receiving high-flux haemodialysis (HD) and intravenous vancomycin were included. The primary outcome was the proportion of patients with a pre-HD vancomycin concentration of 15–20 mg/L and/or an area under the concentration–time curve/minimum inhibitory concentration (AUC/MIC) ratio ≥400. Of the 3948 studies screened, 5 met the inclusion criteria. The proportion of patients with pre-HD concentrations between 15–20 mg/L were 35% (non-WBD) and 13% (WBD) post-loading dose. During maintenance dosing, the proportion of patients with pre-HD concentrations between 15–20 mg/L were 37% (non-WBD) and 50–67% (WBD). The proportion of pre-HD concentrations <15 mg/L was greater in the non-WBD group post-loading dose but was similar between the non-WBD and WBD group during maintenance dosing. One study reported that all patients had an AUC/MIC ≥ 400 for micro-organisms with an MIC ≤ 1 mg/L for weight-based maintenance dosing. The limited data suggest that WBD may be preferential as there was a smaller proportion of pre-HD concentrations falling below 15 mg/L. However, larger well-designed studies of higher quality are required to provide guidance for vancomycin dosing in the high-flux HD setting. Future research should focus on reporting AUC/MIC ratios and exploring clinical outcomes in this patient population.

Introduction

Vancomycin is an antibiotic that is often prescribed for infections caused by methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic is predominantly renally cleared, and in patients with end-stage renal disease (ESRD) clearance is reduced. Many patients with ESRD will require renal replacement therapy, which includes haemodialysis (HD). However, to complicate matters, vancomycin is readily cleared by high-flux dialysers (haemodialysis filters) [1], [2], [3], [4], [5], [6]. This drastically affects the amount of vancomycin available in the body to treat an infection. If therapeutic serum concentrations of vancomycin are not reached, the risk of antimicrobial resistance in bacterial pathogens may increase [7].

To determine an optimal dosage regimen for an antibiotic, the pharmacokinetic/pharmacodynamic (PK/PD) parameter specific to the antibiotic should be considered. The PK/PD parameter that correlates best with outcomes for vancomycin is the ratio between the 24-h area under the concentration–time curve to the minimum inhibitory concentration (i.e. AUC/MIC) [8]. To date, the Infectious Diseases Society of America (IDSA) has recommended an AUC/MIC ratio of ≥400 for vancomycin, with a serum trough concentration of 15–20 mg/L as a surrogate measure for micro-organisms with an MIC of ≤1 mg/L [9]. The quality of evidence and the strength of this recommendation is Level III (evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees) and grade B (moderate quality of evidence to support recommendation for use), respectively [9]. In the HD setting, pre-HD vancomycin concentrations are often obtained in place of a trough concentration owing to the rebound of plasma concentrations observed immediately post-HD. This allows for vancomycin to be dosed during or immediately after HD.

Studies investigating vancomycin dosing in high-flux HD have often focused on either non-weight-based dosing (non-WBD) or weight-based dosing (WBD) strategies. However, it is still unclear whether non-WBD or WBD strategies for vancomycin will result in a higher proportion of patients within the nominal PK/PD target for vancomycin in the high-flux HD setting. A systematic review of the current evidence available for vancomycin dosing in patients receiving HD was conducted in order to address this knowledge gap and, where possible, to examine the clinical outcomes of the two types of dosing strategies.