Impact of area under the concentration–time curve to minimum inhibitory concentration ratio on vancomycin treatment outcomes in methicillin-resistant Staphylococcus aureus bacteraemia
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.
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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
References (31)
- et al.
Area under the concentration–time curve to minimum inhibitory concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant Staphylococcus aureus bacteraemia
Int J Antimicrob Agents
(2014) - et al.
Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices
Chest
(2006) - et al.
Impact of source of infection and vancomycin AUC0–24/MICBMD targets on treatment failure in patients with methicillin-resistant Staphylococcus aureus bacteraemia
Clin Microbiol Infect
(2014) - et al.
A new method of classifying prognostic comorbidity in longitudinal studies: development and validation
J Chronic Dis
(1987) - et al.
Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus-associated septic shock
Int J Antimicrob Agents
(2013) - et al.
High vancomycin minimum inhibitory concentration and clinical outcomes in adults with methicillin-resistant Staphylococcus aureus infections: a meta-analysis
Int J Infect Dis
(2013) - et al.
Characteristics of invasive Staphylococcus aureus infections in three regions of Korea, 2009–2011: a multi-center cohort study
BMC Infect Dis
(2013) - et al.
The burden of nosocomial Staphylococcus aureus bloodstream infection in South Korea: a prospective hospital-based nationwide study
BMC Infect Dis
(2014) - et al.
Predictors of mortality in Staphylococcus aureus bacteremia
Clin Microbiol Rev
(2012) - et al.
Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough?
Clin Infect Dis
(2014)
Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections
Clin Pharmacokinet
The pharmacokinetic and pharmacodynamic properties of vancomycin
Clin Infect Dis
Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets
Clin Infect Dis
Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization
Antimicrob Agents Chemother
Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists
Am J Health Syst Pharm
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