Impact of area under the concentration–time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia

https://doi.org/10.1016/j.ijantimicag.2015.09.010Get rights and content

Highlights

  • We prospectively evaluated vancomycin AUC24/MIC and treatment outcomes in MRSA bacteraemia.

  • AUC24 was estimated by a Bayesian approach using individual vancomycin concentrations.

  • Low AUC24/MIC was independently associated with treatment failure.

  • Outcomes may be improved by adjusting the ratio of individualised AUC24/MIC to >400.

Abstract

There have been few clinical studies on the association between the vancomycin 24-h area under the concentration–time curve (AUC24) to minimum inhibitory concentration (MIC) ratio and vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus (MRSA) infections. To examine this association and to establish a suitable cut-off value for AUC24/MIC, a multicentre prospective observational study was conducted in patients with MRSA bacteraemia. Data were collected on all patients aged ≥18 years with MRSA bacteraemia treated with vancomycin for ≥72 h without dialysis. The MIC was determined by broth microdilution (BMD) and Etest. Treatment failure was defined as (i) 30-day mortality, (ii) persistent bacteraemia (≥7 days) and (iii) recurrence (≤30 days after completion of therapy). AUC24 was estimated by a Bayesian approach based on individual vancomycin concentrations. The AUC24/MIC cut-off value for differentiating treatment success and failure was calculated by Classification and Regression Tree (CART) analysis. In total, 117 patients were enrolled, among which vancomycin treatment failure occurred in 38 (32.5%). In univariate analysis, high vancomycin MIC and low trough levels were unrelated to treatment outcomes. In the CART analysis, low vancomycin AUC24/MIC [<392.7 (BMD) and <397.2 (Etest)] was associated with treatment failure. In multivariate analysis, low AUC24/MIC was a risk factor for treatment failure [adjusted odds ratio (aOR) = 3.50, 95% confidence interval (CI) 1.39–8.82 by BMD; aOR = 5.61, 95% CI 2.07–15.24 by Etest]. AUC24/MIC is associated with vancomycin treatment outcomes in MRSA bacteraemia, and seeking individualised AUC24/MIC ratios above target (>400) may improve treatment outcomes.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) infection is an important disease with high mortality rates and substantial cost to the healthcare system [1], [2]. The 30-day all-cause mortality rate of MRSA bacteraemia exceeds 30% and has not changed for two decades [3]. Although vancomycin remains the treatment of choice, there are concerns about its suboptimal efficacy and the optimal dosing strategy [4], [5]. Clinical studies have shown an association between treatment outcome and the ratio of the vancomycin 24-h area under the concentration–time curve (AUC24) to minimum inhibitory concentration (MIC) [6], [7], [8], [9], [10]. Based on those studies, the Infectious Diseases Society of America (IDSA) and the American Society of Health-System Pharmacists (ASHP) guidelines recommend that vancomycin trough levels should reach 15–20 mg/L for optimal antibiotic exposure (AUC24/MIC > 400) in serious MRSA infections such as bacteraemia [11]. In most previous studies, workers did not follow these new target trough levels. This was because of their retrospective nature and the long study periods involved (usually over 5 years) [5], [8], [9], [12], [13]. Vancomycin AUC24 was usually estimated by a simple formula based on daily vancomycin dose and creatinine clearance in previous studies [8], [9], [12], [13].

In the present study, the association between vancomycin AUC24/MIC and treatment outcomes was examined in a multicentre prospective cohort study with a predefined sample size providing adequate statistical power. The optimal cut-off value of AUC24/MIC in these patients was established by performing a Bayesian estimation based on individual AUC24 and measuring the MIC by both broth microdilution (BMD) and Etest in a clinical setting, according to the recent vancomycin dosing guidelines.

Section snippets

Study population

This prospective cohort study was conducted at Seoul National University Bundang Hospital (a 900-bed tertiary hospital in Seongnam) and Seoul National University Hospital (a 1300-bed tertiary hospital in Seoul). All adult patients (aged ≥18 years) with first MRSA bacteraemia during the study period were screened. Patients who fulfilled the following criteria were excluded: (i) polymicrobial bacteraemia; (ii) immediate transfer to another hospital; (iii) absence of data on treatment outcome;

Clinical characteristics

A total of 296 patients with MRSA bacteraemia were identified between 1 December 2010 and 31 December 2012. Of these, 117 cases were included in the study. Patients who fulfilled the following criteria were excluded: polymicrobial bacteraemia (n = 18 patients); immediate transfer to another hospital (n = 8); no data on treatment outcome (n = 12); died within 72 h after index culture (n = 17); received renal replacement therapy (n = 59); received vancomycin for <72 h (n = 31); did not receive vancomycin

Discussion

In this study, we showed that low initial steady-state vancomycin AUC24/MIC was an independent risk factor for treatment failure in MRSA bacteraemia. This result was obtained by two methods of measuring MIC and was also consistent with past clinical studies. The two methods gave AUC24/MIC cut-off values of 392.7 (BMD) and 397.2 (Etest), similar to those reported previously [4], [5], [6], [8], [9], [12], [21]. In this study, both methods of measuring MIC were used, and AUC values were estimated

Acknowledgments

The authors express their gratitude to Hye Yun Shin and Jung In Park for their active participation in screening and case recording for MRSA bacteraemia. The authors are very grateful to Jeong Eun Cho and Yun Jung Choi for their microbiological laboratory work. The authors also thank the Medical Research Collaborating Center at Seoul National University Bundang Hospital (Seongnam, South Korea) for their help with statistical analyses, and express their gratitude to Prof. Julian D. Gross

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