Prevalence of vancomycin-variable Enterococcus faecium (VVE) among vanA-positive sterile site isolates and patient factors associated with VVE bacteremia

RESEARCH ARTICLE Prevalence of vancomycin-variable Enterococcus faecium (VVE) among vanApositive sterile site isolates and patient factors associated with VVE bacteremia Philipp Kohler1,2*, Alireza Eshaghi3, Hyunjin C. Kim1,4, Agron Plevneshi1, Karen Green1, Barbara M. Willey1, Allison McGeer1,4, Samir N. Patel3,4, for the Toronto Invasive Bacterial Diseases Network (TIBDN)¶ a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Microbiology Department, Mount Sinai Hospital, Toronto, Ontario, Canada, 2 Clinic for Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland, 3 Public Health Ontario, Public Health Ontario Laboratory, Toronto, Ontario, Canada, 4 Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada ¶ Membership of the Toronto Invasive Bacterial Diseases Network is provided in the Acknowledgments. * OPEN ACCESS Citation: Kohler P, Eshaghi A, Kim HC, Plevneshi A, Green K, Willey BM, et al. (2018) Prevalence of vancomycin-variable Enterococcus faecium (VVE) among vanA-positive sterile site isolates and patient factors associated with VVE bacteremia. PLoS ONE 13(3): e0193926. https://doi.org/ 10.1371/journal.pone.0193926 Editor: Daniela Flavia Hozbor, Universidad Nacional de la Plata, ARGENTINA Received: October 6, 2017 Accepted: February 21, 2018 Published: March 22, 2018 Copyright: © 2018 Kohler 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 data are either available from the Dryad Digital Repository (doi:10. 5061/dryad.8pt2c) or are shown in the paper (Table 4). Funding: This work was supported by the Swiss National Science Foundation Fellowship (158728 to P.K.), and internal funding from Public Health Ontario Laboratories and the Toronto Invasive Bacterial Diseases Network. The funders had no role in study design, data collection and analysis, Abstract Vancomycin-variable enterococci (VVE) are vanA-positive, vancomycin-susceptible enterococci with the ability to revert to a vancomycin-resistant phenotype on exposure to vancomycin. We sought to assess the prevalence of VVE and to determine clinical characteristics of patients infected with VVE. We prospectively collected Enterococcus faecium sterile site isolates from Toronto Invasive Bacterial Diseases Network hospitals from January 2015 to June 2016 and calculated VVE (defined as vanA-positive, vancomycin-susceptible isolates) prevalence among vanA-containing isolates. We performed chart reviews of VVE and vancomycin-resistant E. faecium (VRE) bacteremias identified from January 2012 to June 2016, and on a random sample of patients with bacteremia due to vanA/vanB-negative, vancomycinsusceptible enterococci (VSE) from January 2015 to June 2016. Clinical characteristics were compared and factors associated with mortality assessed. Because of the potential reversion from VVE to VRE, pulsed-field gel electrophoresis (PFGE) was performed for strains causing breakthrough bacteremia in order to identify relatedness among strains with different phenotypic resistance within the same patient. VVE comprised 47% (18/38) of vanA-positive isolates. The charts of 36 VRE, 25 VVE, and 79 VSE patients were reviewed. Central venous catheter associated bacteremia was more common in VVE (44%) and VRE patients (57%) than in VSE patients (28%) (P = 0.01). The Pitt bacteremia (OR 1.3, P = 0.002) and the Charlson score (OR 1.2, P = 0.008) were the only independent mortality predictors. PFGE of strains causing breakthrough bacteremia showed high within-patient clonality, irrespective of vanA-positivity or vancomycin-susceptibility. A substantial proportion of vanA-positive isolates are VVE and are therefore not detected with conventional selective culture methods. Bacteremia sources of patients with VVE are similar to those infected with VRE. We detected no association between VVE and 30-day mortality or breakthrough bacteremia. PLOS ONE | https://doi.org/10.1371/journal.pone.0193926 March 22, 2018 1 / 11 Prevalence of and patient factors associated with vancomycin-variable enterococci decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction VanA-positive enterococci with phenotypic susceptibility to vancomycin have been termed vancomycin-variable enterococci (VVE) and have been reported from Canada, South Korea, and Norway [1–5]. Molecular analyses have shown that VVE typically lack the vanS (sensor) and vanR (regulator) genes despite harbouring the vanHAX gene cassette [3, 6]. Because of their susceptibility to vancomycin, VVE escape the traditional detection methods for vancomycin-resistant enterococci (VRE), which might be associated with under-diagnosing and silent dissemination of VVE in healthcare facilities. Indeed, VVE have often been reported as clusters causing hospital outbreaks [3–5, 7]. Worryingly, both in vivo and in vitro data show that VVE have the ability to revert into vancomycin-resistant phenotypes upon vancomycin exposure [5, 6, 8]. The prevalence of VVE among vanA-positive enterococci has mostly been reported in single institution reports, but rarely on a multi-institutional or regional level [1, 3, 5, 6]. Despite the obvious challenges regarding diagnosis and infection control aspects of VVE, their clinical significance remains unknown. No data are available regarding risk profiles or outcomes of patients with VVE in comparison to VRE or vanA-negative vancomycin-susceptible enterococci (VSE). Whether patients infected with VVE can safely be treated with vancomycin or whether compounds active against VRE such as linezolid or daptomycin should be given, is not clear. This study aimed to assess the prevalence of VVE among vanA-positive Enterococcus faecium sterile-site isolates in patients hospitalized in south-central Ontario, to compare the clinical characteristics of patients with VVE, VRE and VSE bacteremia, and to determine factors associated with 30-day mortality. Due to the ability of VVE to revert into VRE under treatment with vancomycin, we also aimed to describe clinical and microbiology details of patients with breakthrough E. faecium bacteremia with regard to the underlying resistance patterns. Materials and methods Setting We prospectively collected all consecutive E. faecium (N = 372) isolates from sterile body sites (i.e. blood, ascites, pleural fluid) from microbiology laboratory members of the Toronto Invasive Bacterial Diseases Network (TIBDN) between January 2015 and June 2016 (prospective isolates). The TIBDN is a collaborative network of microbiology laboratories, infection-control practitioners, and public-health departments that performs population-based surveillance (...truncated)