Vancomycin-Variable Enterococcus faecium:
            <i>In Vivo</i>
            Emergence of Vancomycin Resistance in a Vancomycin-Susceptible Isolate

Coburn, Bryan; Low, Donald E.; Patel, Samir N.; Poutanen, Susan M.; Shahinas, Dea; Eshaghi, Alireza; Willey, Barbara M.; McGeer, Allison

doi:10.1128/jcm.03579-13

Cited by 27 publications

(27 citation statements)

References 10 publications

(14 reference statements)

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“…However, none of the isolates contained the orf1, orf2, vanR, or vanS gene. On the basis of these results, it was confirmed that the patient was infected with the recently discovered VVE isolate (1,2). With respect to the two colonized patients, one of the ICU patients was colonized with a strain identical to the index patient's VVE when PFGE analysis was performed and the other patient was colonized with a strain genetically closely related to the index patient's VVE, thus demonstrating transmission among patients (Fig.…”

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confidence: 53%

“…However, this may have been due to poor source control, given that the isolate was still susceptible to vancomycin on a repeat blood culture. A patient colonized with this organism was recently described, and it was shown in that case that the isolate became resistant to vancomycin in vivo over time during vancomycin therapy (1). A recent study reported that exposure of VVE strains to vancomycin in vitro leads to the development of vancomycin resistance by the constitutive expression of vanHAXYZ gene clusters (10).…”

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confidence: 99%

“…Rectal swabs obtained during the point prevalence screening were tested directly with GeneXpert vanA/vanB PCR (Cepheid). Standard methodology was used to isolate E. faecium in culture and confirm the VVE phenotype and genotype (1). VVE was isolated from the rectal swabs of two patients during the first ICU point prevalence screening, and these were included with three blood culture isolates from the case patient for analysis.…”

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confidence: 99%

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Vancomycin-Variable Enterococcal Bacteremia

et al. 2015

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Vancomycin-Variable Enterococcal Bacteremia

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“…As such, the clinical utility of vancomycin in these cases remains unknown. However, as described in the accompanying paper (24), a recent observation in a 69-year-old patient colonized with VVE showed that subsequent vancomycin exposure resulted in development of vancomycin resistance, with a MIC of 256 g/ml in vivo. Further research involving both in vitro and in vivo studies with animal models are needed to determine whether vancomycin exposure induces resistance in these strains.…”

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confidence: 99%

Outbreak of Vancomycin-Susceptible Enterococcus faecium Containing the Wild-Type vanA Gene

Szakacs¹,

Kalan

McConnell³

et al. 2014

J Clin Microbiol

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e Accurate detection of vancomycin-resistant enterococci (VRE) is essential in preventing transmission in health care settings. Chromogenic media are widely used for screening VRE because of fast turnaround times (TAT) and high sensitivity. We report an outbreak of Enterococcus faecium bearing vanA yet susceptible to vancomycin (vancomycin-variable Enterococcus [VVE]). Between October 2009 to March 2011, clinical and screening specimens (n ‫؍‬ 14,747) were screened for VRE using VRE-selective medium and/or PCR. VVE isolates were genotyped to determine relatedness. Plasmids from these isolates were characterized by sequencing. Overall, 52 VVE isolates were identified, comprising 15% of all VRE isolates identified. Isolates demonstrated growth on Brilliance VRE agar (Oxoid) at 24 h of incubation but did not grow on brain heart infusion agar with 6 g/ml vancomycin (Oxoid) or bile esculin azide agar with 6 g/ml vancomycin (Oxoid) and were susceptible to vancomycin. Genotyping of 20 randomly selected VVE isolates revealed that 15/20 were identical, while 5 were highly related. PCR of the VVE transposon confirmed the presence of vanHAXY gene cluster; however, vanS (sensor) and vanR (regulator) genes were absent. The outbreak was controlled through routine infection control measures. We report an emergence of a fit strain of E. faecium containing vanA yet susceptible to vancomycin. Whether this new strain represents VRE has yet to be determined; however, unique testing procedures are required for reliable identification of VVE. Vancomycin-resistant enterococcus (VRE) colonization and infection are increasingly common in both hospital and outpatient settings. Since the initial discovery of VRE during the 1980s in the United Kingdom and France, it has spread to many countries throughout the world (1, 2). In Canada, there has been a small but steady increase in rates of detection of VRE from 0.37 case per 1,000 patient admissions in 1999 to 1.32 in 2005 (3). VRE infection rates increased from 0.02 to 0.05 case per 1,000 admitted patients. Six different types of glycopeptide resistance (vanA, vanB, vanC, vanD, vanE, and vanG) have been described, of which the vanA-and vanB-mediated types are clinically significant in enterococci. Typically, vanA-mediated vancomycin resistance is found in Enterococcus faecium. VRE resistance in vanA-bearing isolates is mediated by the group of genes vanR, vanS, vanH, vanA, and vanX, which are usually carried on the Tn1546 transposon. The expression of these genes leads to replacement of the C-terminal D-Ala residue with D-Lac during cell wall synthesis, thus modifying the vancomycin-binding target. The transposon is often contained on plasmids, making it easy to transfer among enterococcal strains. Historically, there has been little sequence variation in this gene cluster (4).Various studies have shown that infections caused by VRE lead to longer hospital stays, higher mortality, and significantly higher cost than infections caused by vancomycin-susceptible enterococci (5). Therefore, ac...

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“…As a result, they have spread globally, and VRE remains an important drug-resistant pathogen in many clinical settings (1). Consequently, VRE colonization in patients is monitored in clinical microbiology laboratories by screening rectal swab specimens on selective chromogenic medium and by PCR detection of vanA/vanB (7).Because VanA-and VanB-type VRE are linked to the presence of the vanHAX genes, we were intrigued by the recent identification of strains of vancomycin-susceptible enterococci (VSE) determined by susceptibility testing from Ontario, Canada, which nevertheless were positive for the vanHAX genes, as assessed by PCR (8,9). A similar phenomenon has been described in which genetic alterations in plasmid pS177 give rise to vanA-positive enterococcal isolates that are susceptible to vancomycin (VSE) …”

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Vancomycin-Variable Enterococci Can Give Rise to Constitutive Resistance during Antibiotic Therapy

Thaker

Kalan

Waglechner

et al. 2015

Antimicrob Agents Chemother

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e Vancomycin-resistant enterococci (VRE) are notorious clinical pathogens restricting the use of glycopeptide antibiotics in the clinic setting. Routine surveillance to detect VRE isolated from patients relies on PCR bioassays and chromogenic agar-based test methods. In recent years, we and others have reported the emergence of enterococcal strains harboring a "silent" copy of vancomycin resistance genes that confer a vancomycin-susceptible phenotype (vancomycin-susceptible enterococci [VSE]) and thus escape detection using drug sensitivity screening tests. Alarmingly, these strains are able to convert to a resistance phenotype (VSE¡VRE) during antibiotic treatment, severely compromising the success of therapy. Such strains have been termed vancomycin-variable enterococci (VVE). We have investigated the molecular mechanisms leading to the restoration of resistance in VVE isolates through the whole-genome sequencing of resistant isolates, measurement of resistance gene expression, and quantification of the accumulation of drug-resistant peptidoglycan precursors. The results demonstrate that VVE strains can revert to a VRE phenotype through the constitutive expression of the vancomycin resistance cassette. This is accomplished through a variety of changes in the DNA region upstream of the resistance genes that includes both a deletion of a likely transcription inhibitory secondary structure and the introduction of a new unregulated promoter. The VSE¡VRE transition of VVE can occur in patients during the course of antibiotic therapy, resulting in treatment failure. These VVE strains therefore pose a new challenge to the current regimen of diagnostic tests used for VRE detection in the clinic setting. Fig. 1) (5). VanX is a dipeptidase that removes the D-Ala-D-Ala that continues to be generated by the constitutively expressed chromosomal cell wall biosynthesis machinery. VanH supplies D-Lac by the biochemical reduction of pyruvate, while VanA is an ATP-dependent ligase that synthesizes the ester D-Ala-D-Lac. This depsipeptide is then incorporated into intracellular cell wall precursor biosynthesis, which supplies the reagents required for extracellular peptidoglycan synthesis, which is necessary for cell division and growth.The expression of the vanHAX three-gene cassette is controlled by the two-component regulatory system VanRS, in which VanR is a response regulator and VanS is an integral membrane histidine kinase that recognizes the presence of vancomycin (by direct binding in the case of VanS B [3,6]). The autophosphorylation of VanS and transfer of the phosphate to a VanR aspartyl side chain generates the induction-competent version of VanR that binds to elements upstream of vanH, inducing the expression of vanHAX, which results in resistance (Fig. 1). The vanRS and vanHAX genes have been found on a number of mobile genetic elements, including plasmids and transposons, such as Tn1546. As a result, they have spread globally, and VRE remains an important drug-resistant pathogen in many clinical settings (1). Co...

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Vancomycin-Variable Enterococcus faecium: In Vivo Emergence of Vancomycin Resistance in a Vancomycin-Susceptible Isolate

Cited by 27 publications

References 10 publications

Vancomycin-Variable Enterococcal Bacteremia

Vancomycin-Variable Enterococcal Bacteremia

Outbreak of Vancomycin-Susceptible Enterococcus faecium Containing the Wild-Type vanA Gene

Vancomycin-Variable Enterococci Can Give Rise to Constitutive Resistance during Antibiotic Therapy

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