Impact of Molecular Epidemiology and Reduced Susceptibility to Glycopeptides and Daptomycin on Outcomes of Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia

RESEARCH ARTICLE Impact of Molecular Epidemiology and Reduced Susceptibility to Glycopeptides and Daptomycin on Outcomes of Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia a11111 Hao-Yuan Lee1,2,3, Chyi-Liang Chen2,3, Shu-Ying Liu4, Yu-Shan Yan3,4, Chee-Jen Chang1, Cheng-Hsun Chiu1,2,3* 1 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan, 2 Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan, 3 Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan, 4 Department of Molecular Biotechnology, Da-Yeh University, Changhua, Taiwan OPEN ACCESS Citation: Lee H-Y, Chen C-L, Liu S-Y, Yan Y-S, Chang C-J, Chiu C-H (2015) Impact of Molecular Epidemiology and Reduced Susceptibility to Glycopeptides and Daptomycin on Outcomes of Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia. PLoS ONE 10(8): e0136171. doi:10.1371/journal.pone.0136171 Editor: Axel Cloeckaert, Institut National de la Recherche Agronomique, FRANCE * Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia was associated with high mortality, but the risk factors associated with mortality remain controversial. Received: June 2, 2015 Methods Accepted: July 30, 2015 A retrospective cohort study was designed. All patients with MRSA bacteremia admitted were screened and collected for their clinical presentations and laboratory characteristics. Minimum inhibitory concentration (MIC) and staphylococcal cassette chromosome mec (SCCmec) type of bacterial isolates were determined. Risk factors for mortality were analyzed. Published: August 21, 2015 Copyright: © 2015 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by grants from Ministry of Science and Technology, Executive Yuan, Taiwan (97-2314-B-182A-019-MY3 and 102-2314-B182A-023) and Chang Gung Memorial Hospital, Taiwan (CMRPG390702, CMRPG490052, CMRPG4C0031 and CMRPG3E0481). Competing Interests: The authors have declared that no competing interests exist. Results Most MRSA isolates from the 189 enrolled patients showed reduced susceptibility to antibiotics, including MIC of vancomycin  1.5 mg/L (79.9%), teicoplanin  2 mg/L (86.2%), daptomycin  0.38 mg/L (73.0%) and linezolid  1.5 mg/L (64.0%). MRSA with vancomycin MIC  1.5 mg/L and inappropriate initial therapy were the two most important risk factors for mortality (both P < 0.05; odds ratio = 7.88 and 6.78). Hospital-associated MRSA (HAMRSA), carrying SCCmec type I, II, or III, was associated with reduced susceptibility to vancomycin, teicoplanin or daptomycin and also with higher attributable mortality (all P < 0.05). Creeping vancomycin MIC was linked to higher MIC of teicoplanin and daptomycin (both P < 0.001), but not linezolid (P = 0.759). PLOS ONE | DOI:10.1371/journal.pone.0136171 August 21, 2015 1 / 14 Factors Influencing the Outcome of MRSA Bacteremia Conclusions Giving empirical broad-spectrum antibiotics for at least 5 days to treat catheter-related infections, pneumonia, soft tissue infection and other infections was the most important risk factor for acquiring subsequent HA-MRSA infection. Choice of effective anti-MRSA agents for treating MRSA bacteremia should be based on MIC of vancomycin, teicoplanin and daptomycin. Initiation of an effective anti-MRSA agent without elevated MIC in 2 days is crucial for reducing mortality. Introduction Staphylococcus aureus bacteremia was associated with high risk of mortality, longer hospital stay, and increased costs for patients and the health care system than bacteraemia due to other bacterial pathogens [1,2]. Vancomycin is still the drug widely used for treating methicillin-resistant S. aureus (MRSA) infections, but several studies have reported a creeping tendency for vancomycin minimum inhibitory concentration (MIC) within the susceptible range ( 2 mg/L) [3]. Clinical treatment failure was found in association with creeping vancomycin MIC in some studies, but others showed no correlation [4, 5]. These findings should be considered when interpreting vancomycin susceptibility and in determining whether alternative antistaphylococcal agents are necessary for patients infected by MRSA with elevated but susceptible vancomycin MIC values. Furthermore, a higher teicoplanin MIC (> 1.5 mg/L) has been proved to predict an unfavourable outcome and higher mortality rate among teicoplanin-treated MRSA bacteraemic patients [6]. However, there are no studies to assess whether the outcome is associated with MICs of other alternative antistaphylococcal agents, such as daptomycin and linezolid. The molecular classification system of MRSA is based on the staphylococcal cassette chromosome mec (SCCmec) [7]. The association of molecular epidemiology of SCCmec types with vancomycin MIC was found in previous studies [8–10]. A significant association between SCCmec II and elevated vancomycin MIC was reported before [8]. The higher vancomycin MIC was associated with specific clonal complexes (CCs) and hospital-associated MRSA, as described in previous studies [10, 11]. Risk factors associated with mortality, such as SCCmec types, inappropriate initial therapy, MIC of antistaphylococcal agents, hospital- or community-associated MRSA, and disease severity were reported in earlier studies but remained incomplete and controversial [12, 13]. The present study tried to fill the gap by applying backward root analysis to survey, step by step, the independent risk factors associated with mortality due to MRSA bacteremia. We analyzed clinical characteristics, microbiological features, and final outcomes of bacteremic patients stratified by both SCCmec types and the antimicrbial MICs of the isolates. Materials and Methods Ethics statement and inclusion criteria This study was approved by the Institutional Review Board of the Chang Gung Memorial Hospital which waived the requirement of informed consent (approval reference number 1003588B). Medical records were reviewed for all admitted patients with  1 positive blood culture for S. aureus and symptoms and signs of infection. For patients with multiple episodes of bacteremia, only the first episode was included. Patients with incomplete medical records, younger than 18 years of age, or with polymicrobial infection were excluded. PLOS ONE | DOI:10.1371/journal.pone.0136171 August 21, 2015 2 / 14 Factors Influencing the Outcome of MRSA Bacteremia Antimicrobial susceptibility testing and vancomycin-heteroresistant S. aureus screeni (...truncated)