Skip Navigation



JAC Advance Access published online on January 29, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn025
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
61/4/838    most recent
dkn025v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Song, J.-H.
Right arrow Articles by Lee, W. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Song, J.-H.
Right arrow Articles by Lee, W. G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Clinical implications of vancomycin-resistant Enterococcus faecium (VRE) with VanD phenotype and vanA genotype

Jae-Hoon Song1,2,*,{dagger}, Kwan Soo Ko2,3,{dagger}, Ji Yoeun Suh2,{dagger}, Won Sup Oh1, Cheol-In Kang1, Doo Ryeon Chung1, Kyong Ran Peck1, Nam Yong Lee4 and Wee Gyo Lee5

1 Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Asian-Pacific Research Foundation for Infectious Diseases (ARFID), Seoul, Korea 3 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea 4 Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Laboratory Medicine, Ajou University School of Medicine, Suwon, Korea

* Corresponding author. Tel: +82-2-3410-0320; Fax: +82-2-3410-0328; E-mail: jhsong{at}ansorp.org

Received 14 September 2007; returned 3 January 2008; revised 5 November 2007; accepted 4 January 2008


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
Objectives: To investigate the clinical implications of vancomycin-resistant Enterococcus faecium (VRE) with VanD phenotype and vanA genotype (VanD-vanA VRE).

Methods: We tested in vitro and in vivo efficacies of teicoplanin against VanD-vanA VRE strains. Change in teicoplanin MICs was monitored during incubation with teicoplanin. In vitro and in vivo time–kill assay and survival analysis using a mouse peritonitis model were performed.

Results: Teicoplanin MICs of VanD-vanA VRE strains increased to 128 mg/L within 48 h when they were cultured with 120 mg/L teicoplanin. In vitro and in vivo time–kill assay showed that VanD-vanA VRE strains were not eliminated by 120 mg/L teicoplanin in contrast to vancomycin-susceptible E. faecium and VanD-vanB strains. The survival rate of mice infected with VanD-vanA VRE strains treated with teicoplanin was comparable with that of untreated mice.

Conclusion: Data suggest that teicoplanin would fail in the treatment of VanD type VRE infections if the strains contained the vanA gene, which cannot be detected in the clinical microbiology laboratory.

Key Words: vancomycin-resistant enterococci , teicoplanin , VanD-vanA


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
Enterococci have become a clinical concern with the emergence of vancomycin-resistant Enterococcus faecium (VRE).1,2 The importance of VRE has increased due to limited treatment options and increased morbidity and mortality.3,4 VanA and VanB are the most common phenotypes among six phenotypes of glycopeptide resistance in enterococci.5 The VanA phenotype, which is encoded by the vanA gene, is characterized by acquired inducible and high-level resistance to vancomycin and teicoplanin. In contrast, the VanB phenotype is characterized by variable levels of vancomycin resistance, and susceptibility to teicoplanin, and is encoded by vanB.5,6

Recent studies reported VRE strains from Korea, Japan and Taiwan with incongruence between phenotype and genotype, which were susceptible to teicoplanin by in vitro test, despite the presence of the vanA gene.7–12 It has been suggested that point mutations in the sensor domain of the vanS gene in Tn1546-like element (or vanA operon)7,8,10 or impairment of accessory proteins VanY and VanZ9,11 would be the reason for the loss of teicoplanin resistance in these strains. Our recent report showed that 15% of VRE isolates from Korean hospitals were teicoplanin-susceptible or -intermediate in spite of the vanA gene,13 which is defined as VanD phenotype as in Naas et al.14 Because these strains are reported to be susceptible or intermediate to teicoplanin based on in vitro tests in the clinical microbiology laboratory, clinicians would use teicoplanin for the treatment of patients. However, clinical efficacy of teicoplanin against these VanD-vanA VRE strains has not been investigated. Given the increasing frequency of VanD-vanA VRE strains and the very limited therapeutic options for VRE infections, this would be an important issue in clinical practice. We report here on the in vitro and in vivo evaluation of teicoplanin against VRE strains with VanD phenotype and vanA genotype.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 Transparency declarations
 References
 
Bacterial strains and antimicrobial susceptibility testing

E. faecium strains used in this study were isolated from tertiary care hospitals in Korea (Samsung Medical Center, Kyungpook National University Hospital and Chungnam National University Hospital) (Table 1). Their genetic backgrounds were determined by multilocus sequence typing (MLST), as described elsewhere.9,15 The genotype for glycopeptide resistance was determined by the multiplex PCR method.16 They were tested for in vitro vancomycin and teicoplanin susceptibilities by evaluating MICs using the broth microdilution method according to the CLSI.17 Six strains showed VanD phenotype (i.e. vancomycin-resistant and teicoplanin-susceptible or -intermediate) with vanA gene. Although these six strains are classified as susceptible or intermediate to teicoplanin according to the CLSI,17 teicoplanin MICs of 8 and 16 mg/L could be classified as intermediate or even resistant, respectively, according to the European Committee on Antimicrobial Susceptibility Testing.18 As comparators, one strain with VanA phenotype and vanA genotype, one strain with VanB phenotype and vanB genotype, and one vancomycin-susceptible E. faecium (VSE) strain were tested. Enterococcus faecalis ATCC 29212 and Staphylococcus aureus ATCC 29213 strains were used as reference strains in vitro susceptibility testing.


View this table:
[in this window]
[in a new window]

  		Table 1. Characteristics of E. faecium strains used in this study

 
Genetic analysis of Tn1546-like element

Genetic variations among van gene cluster (Tn1546-like element) of VanD-vanA VRE strains were investigated by the PCR assay and sequencing as in previous studies.11,19 Briefly, overlapping PCR amplification of internal regions of Tn1546-like element was performed, and PCR fragments longer or shorter than that of the prototype vanA gene cluster of BM4147 were sequenced. The genetic structures of Tn1546-like elements of the strains after exposure to teicoplanin were also determined by PCR and sequencing of VanR, VanS, VanX and VanY genes.

MIC changes after exposure to teicoplanin

Changes in teicoplanin MICs after exposure to teicoplanin were determined for eight isolates of E. faecium (#18, #44, #88, 0-182, 06-12, 06-16, 07-16 and VSE-6800). Isolates were cultured in Mueller–Hinton broth containing 120 mg/L teicoplanin and were harvested after 2, 4, 6, 8, 12, 24, 48 and 72 h of culture. Teicoplanin MIC for each isolate was determined using the broth microdilution method according to the CLSI.17

In vitro time–kill assay

In vitro time–kill curves were determined for eight isolates of E. faecium (#18, #44, #88, 01-182, 06-12, 06-16, 07-16 and VSE-6800). Bacterial colonies were inoculated onto blood agar plates and were incubated at 37°C overnight. Each culture was suspended in saline solution (0.9% NaCl) and inoculated into freshly prepared Mueller–Hinton broth, which contained 4x MIC, 8x MIC and 120 mg/L teicoplanin, adjusted to a final concentration of 106 cfu/mL. Viable counts were evaluated at 4, 8, 12, 24, 48 and 72 h with shaking incubation at 37°C including antibiotic-free control. All time–kill curve experiments were performed at least three times and were averaged.

Establishment of mouse peritonitis model

To establish the mouse peritonitis model, 4- to 6-week-old female outbred ICR mice with a mean weight of 20 g were purchased from Orient Co. Ltd (Gyeonggi, Korea) and adapted to standardized environmental conditions (temperature, 24 ± 2°C and humidity, 55 ± 10%) for 1 week before the experiments. All animal procedures were performed in accordance with the institution’s guidelines for the humane handling, care and treatment of research animals. Mice were administered intraperitoneally with 1 mL of an overnight E. feacium culture suspended in saline solution (0.9% NaCl) containing 5% pig mucin (Sigma, St Louis, MO, USA) to a final cell density corresponding to the minimal lethal dose, which is shown in Table 2. If untreated, mice died by 48–72 h. A 0.3 mL dose of teicoplanin (40 mg/kg) was given subcutaneously to infected mice 3 h after infection. Mice were observed for 72 h following inoculation and the teicoplanin treatment. The concentration of teicoplanin was adjusted to 120 mg/L, which is the peak level of teicoplanin treatment in human serum based on previous experiments.20 When teicoplanin 40 mg/kg was injected into the mouse, the peak level of teicoplanin (120 mg/L) in mouse serum was achieved; teicoplanin concentrations were determined microbiologically by an agar-dilution method.


View this table:
[in this window]
[in a new window]

  		Table 2. Results of survival analysis

 
In vivo time–kill assay

The in vivo time–kill curves were determined by inoculating various enterococcal strains into mice in each teicoplanin treatment group. Mice were infected as in the mouse peritonitis model. Four enterococcal strains were used: VSE-6800, #18 (VanA-vanA), #44 (VanD-vanA) and #88 (VanB-vanB). Teicoplanin (40 mg/kg) was administered subcutaneously 3 h after infection to achieve the peak concentration of 120 mg/L. Untreated mice were used as controls. Blood samples were obtained from three infected mice by cardiac puncture at 0, 6, 12, 24, 48 and 72 h after treatment with teicoplanin. Samples were plated on blood agar with appropriate dilution for the determination of viable bacterial cell counts after overnight incubation in 5% CO2.

Survival analysis

Survival of mice was evaluated for five groups with different enterococcal strains: VSE-6800, #18 (VanA-vanA), #28 (VanD-vanA), #44 (VanD-vanA) and #88 (VanB-vanB). Five to 21 mice were prepared as described earlier for each strain and controls. As for in vivo time–kill growth curve determination, 40 mg/kg of teicoplanin was administered subcutaneously 3 h after infection and re-administered once a day. Untreated mice were used as controls. The cumulative per cent survival (%S) was estimated at 12, 24, 36, 48, 60 and 72 h after administration of teicoplanin. Evaluation of survival rate differences between the treatment group and the control group was performed using the Kaplan–Meier method. A P value of less than 0.05 was considered significant. SPSS for Windows (version 11.5 software package; SPSS Inc., Chicago, IL, USA) was used for the analysis.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 Transparency declarations
 References
 
Genetic analysis of Tn1546-like element of VRE strains

Genetic backgrounds of E. faecium isolates, which were determined using MLST, showed that they belonged to ST78 and its single locus variants (Table 1). ST78 is a single locus variant of ST17 and thus related to the internationally disseminated lineage, CC-17.9 Structures of Tn1546-like elements, which account for glycopeptide resistance of vanA genotype in Enterococcus species, are shown in Figure 1. All isolates except #28 and 06-12 showed different structures. This indicates that loss of teicoplanin resistance in VanD-vanA VRE strains did not occur by horizontal transfer of an impaired Tn1546-like element, but by independent deletion of vanY or vanZ associated with insertion of IS1216V. No point mutations in vanS were found in any strain, but an IS1216V element was inserted within vanS in strain 06-16.


Figure 1
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1. Structures of Tn1546-like elements of six VanD-vanA VRE isolates used in this study. The location of genes and the direction of transcription of normal Tn1546-like element of a strain BM4147 are shown at the top. Grey arrows represent IS elements. Dashed arrows are genes with interruption by IS elements. The positions of IS insertion sites are shown at the corresponding sites.

 
MIC changes after exposure to teicoplanin

Teicoplanin MICs did not change significantly in enterococcal strains with congruent phenotype and genotype. VSE and VanB-vanB VRE strains retained susceptibility to teicoplanin (MICs, both 1 mg/L) after exposure to 120 mg/L teicoplanin. Exposure to teicoplanin resulted in only a 2-fold increase in MIC, from 64 to 128 mg/L, in VanA-vanA VRE strain. However, significant increases in teicoplanin MICs were observed in VanD-vanA VRE strains after exposure to teicoplanin. Within 48 h of exposure to 120 mg/L teicoplanin, teicoplanin MICs increased from 4–16 to 128 mg/L. This suggests that VanD-vanA VRE strains could acquire high-level resistance to teicoplanin, if they are exposed to teicoplanin, or that teicoplanin leads to the selection of the mutants. The acquired teicoplanin resistance was preserved after removal of the selective pressure of teicoplanin.

In vitro time–kill analysis

The in vitro time–kill curve showed that the growth of VSE and VanB-vanB VRE strains was inhibited by more than 2 logs by 120 mg/L teicoplanin, whereas VanD-vanA and VanA-vanA VRE strains were not inhibited by this concentration of teicoplanin (Figure 2). Although a VanA-vanA strain was inhibited by 8x MIC of teicoplanin (512 mg/L), this concentration is more than four times the achievable peak concentration (120 mg/L) in humans.


Figure 2
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2. The results of in vitro time–kill analysis in E. faecium isolates. Open diamonds, 0x MIC; open squares, 4x MIC; open triangles, 8x MIC; open circles, 120 mg/L.

 
In vivo time–kill analysis

The results of in vivo growth curve experiments were demonstrated in Figure 3. In vivo time–kill analysis showed that all mice infected with E. faecium strains died within 48 h and bacterial cell numbers did not decrease if they were not treated with teicoplanin. VSE and VanB-vanB VRE strains were eradicated by teicoplanin after 48 h of treatment, and the infected mice survived. However, VanA-vanA and VanD-vanA VRE strains were not eradicated from blood of the infected mice despite teicoplanin treatment. The mice infected with VanA-vanA or VanD-vanA VRE strains used in the in vivo time–kill experiments died within 48 h irrespective of treatment with teicoplanin.


Figure 3
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 3. The results of in vivo growth curve experiments. Filled marks indicated mice groups treated with teicoplanin and empty marks indicated control groups. In some strains, no values could be represented because all mice died.

 
Survival analysis

The Kaplan–Meier survival analysis showed that teicoplanin treatment has significantly increased the survival rate of the mice infected with VSE (P = 0.007) or VanB-vanB VRE strains (P = 0.001). However, the survival rate of mice infected with VanA-vanA or VanD-vanA VRE strains treated with 120 mg/L teicoplanin was comparable with that of untreated controls (Table 2).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 Transparency declarations
 References
 
In clinical practice, only a few antimicrobial agents can be used for the treatment of VRE infections, and these include quinupristin–dalfopristin, linezolid and teicoplanin. Teicoplanin could be one of the therapeutic options for teicoplanin-susceptible VRE infections either alone or in combination with clindamycin, rifampicin and ampicillin.4,21,22 However, because it has been also described that VanS(B) gene mutations mediate constitutive or teicoplanin-inducible expression of resistance,23 combination therapy with teicoplanin and aminoglycopeptides is more highly recommended. In a surveillance study in Korean hospitals, 15.3% of VRE isolates showed teicoplanin susceptibility despite vanA genotype.13 Most of them are thought to emerge sporadically to date due to the different structure of Tn1546-like elements. However, it is possible that VanD-vanA VRE strains disseminate clonally both between and within hospitals because they belong to the same clonal complex, CC-78. A nosocomial outbreak VRE showing susceptibility or intermediate resistance to teicoplanin associated with vanA genotype was reported in a French hospital.14

Because VanD-vanA VRE strains showed phenotypic susceptibility to teicoplanin by in vitro tests, teicoplanin could be selected for use in the clinical practice. Data from this study, however, suggested that teicoplanin therapy will fail if VanB- or VanD-type VRE strains contain the vanA gene. According to our in vitro time–kill assay, teicoplanin was not active against VanD-vanA VRE strains. These strains also acquired high-level resistance after exposure to teicoplanin without any structural change in the Tn1546-like element, which was determined by PCR and sequencing of VanR, VanS, VanX and VanY genes. In a mouse peritonitis model, teicoplanin failed to eradicate VanD-vanA VRE strains. These results are consistent with the previous studies using a rabbit endocarditis model, in which VanD-type E. faecium with a vanD glycopeptide resistance operon was not cured by teicoplanin and in vivo emergence of teicoplanin-resistant mutants in VanB-type E. faecalis occurred during teicoplanin treatment.24,25

VanD-vanA VRE strains may contain heterogeneous populations consisting of VanA-vanA and vancomycin-susceptible or VanB-vanB cells. Recently, Naas et al.14 showed that the low teicoplanin MIC for VRE strains with the vanA gene is due to insertion of IS16 in the vanY gene, resulting in heterogeneous expression of vancomycin resistance. Heterogeneous expression of vancomycin resistance resulted from heterogeneous E. faecium populations, which consisted of susceptible and highly resistant cells. In our study, no heterogeneous colonies showing teicoplanin and vancomycin resistances were detected, when they were tested using teicoplanin and vancomycin Etest strips (AB Biodisk, Solna, Sweden). In these strains, vanB gene could not be amplified by multiplex PCR assay for the genotyping of glycopeptide resistance. In addition, genetic structures of Tn1546-like elements determined from colonies, which survived after exposure to teicoplanin, did not change. Thus, the VanD-vanA VRE strains included in our study may not contain heterogeneous populations.

Although the results in this study may be strain-dependent, data from the current study suggest that phenotypic characteristics based on in vitro susceptibility tests in VRE isolates cannot be the sole guide to the selection of antimicrobial agents in clinical practice. Genotypic characteristics of glycopeptide resistance in enterococci should also be considered in the treatment of VRE infection. Generally, however, genotyping of VRE strains is not routinely performed in most clinical microbiology laboratories. Given these in vitro and in vivo data about VanD-vanA VRE strains, genotyping for glycopeptide resistance would be required in the hospitals where VanD-vanA VRE strains emerge.

In summary, we showed that teicoplanin was not effective against VanD-vanA VRE strains both in vitro and in vivo, despite its phenotypic susceptibility to teicoplanin. When teicoplanin is considered to treat severe VanD-type VRE infections, genotyping of glycopeptide resistance is warranted.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
Transparency declarations
 References
 
This study was partly supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2005-015-E00195) and the Korean Food and Drug Administration (KFDA).


   Transparency declarations
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 Transparency declarations
References
 
None to declare.


   Footnotes
 
{dagger} J.-H. Song, K. S. Ko and J. Y. Suh contributed to this study equally. Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 Transparency declarations
 References
 
1 . Bonten MJM, Willems R, Weinstein RA. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis (2001) 1:314–25.[CrossRef][Medline]

2 . Harbarth S, Cosgrove S, Carmeil Y. Effects of antibiotics on nosocomial epidemiology of vancomycin-resistant enterococci. Antimicrob Agents Chemother (2002) 46:1619–28.[Free Full Text]

3 . Lodise TP, McKinnon PS, Tam VH, et al. Clinical outcomes for patients with bacteremia caused by vancomycin-resistant Enterococcus in a level 1 trauma center. Clin Infect Dis (2002) 34:922–9.[CrossRef][Web of Science][Medline]

4 . Malathum K, Murray BE. Vancomycin-resistant enterococci: recent advances in genetics, epidemiology and therapeutic options. Drug Resist Updat (1999) 2:224–43.[CrossRef][Web of Science][Medline]

5 . Woodford N. Epidemiology of the genetic elements responsible for acquired glycopeptide resistance in enterococci. Microb Drug Resist (2001) 7:229–34.[CrossRef][Web of Science][Medline]

6 . Cetinkaya Y, Falk P, Mayhal CG. Vancomycin-resistant enterococci. Clin Microbiol Rev (2000) 13:686–707.[Abstract/Free Full Text]

7 . Eom JS, Hwang IS, Hwang BY, et al. Emergence of vanA genotype vancomycin-resistant enterococci with low or moderate levels of teicoplanin resistance in Korea. J Clin Microbiol (2004) 42:1785–6.[Abstract/Free Full Text]

8 . Hashimoto Y, Tanimoto K, Ozawa Y, et al. Amino acid substitutions in the VanS sensor of the VanA-type vancomycin-resistant Enterococcus strains result in high-level vancomycin resistance and low level teicoplanin resistance. FEMS Microbiol Lett (2000) 185:247–54.[CrossRef][Web of Science][Medline]

9 . Ko KS, Baek JY, Lee JY, et al. Molecular characterization of vancomycin-resistant Enterococcus faecium isolates from Korea. J Clin Microbiol (2005) 43:2303–6.[Abstract/Free Full Text]

10 . Lauderdale TL, McDonald LC, Shiau YR, et al. Vancomycin-resistant enterococci from humans and retail chickens in Taiwan with unique VanB phenotype–vanA genotype incongruence. Antimicrob Agents Chemother (2002) 46:525–7.[Abstract/Free Full Text]

11 . Lee WG, Huh JY, Cho SR, et al. Reduction in glycopeptide resistance in vancomycin-resistant enterococci as a result of vanA cluster rearrangements. Antimicrob Agents Chemother (2004) 48:1379–81.[Abstract/Free Full Text]

12 . Oh WS, Ko KS, Song JH, et al. High rate of resistance to quinupristin–dalfopristin in Enterococcus faecium clinical isolates from Korea. Antimicrob Agents Chemother (2005) 49:5176–8.[Abstract/Free Full Text]

13 . Song JH, Ko KS, Oh WS, et al. High frequency of vancomycin-resistant Enterococcus faecium isolates with VanB phenotype and vanA genotype in Korean hospitals. Diagn Microbiol Infect Dis (2006) 56:410–06.

14 . Naas T, Fortineau N, Sanaoudj R, et al. First nosocomial outbreak of vancomycin-resistant Enterococcus faecium expressing a VanD-like phenotype associated with a vanA genotype. J Clin Microbiol (2005) 43:3642–9.[Abstract/Free Full Text]

15 . Homan WL, Tribe D, Poznanski S, et al. Multilocus sequence typing scheme for Enterococcus faecium. J Clin Microbiol (2002) 40:1963–71.[Abstract/Free Full Text]

16 . Bell JM, Paton JC, Turnidge J. Emergence of vancomycin-resistant enterococci in Australia: phenotype and genotype characteristics of isolates. J Clin Microbiol (1998) 36:2187–90.[Abstract/Free Full Text]

17 . Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Fifteenth Informational Supplement M100-S16. (2006) Wayne, PA: CLSI.

18 . European Committee on Antimicrobial Susceptibility Testing (EUCAST). European Antimicrobial MIC Breakpoints Through EUCAST and the National Breakpoint Committees. (2004) Basel: EUCAST. http://www.srga.org/eucastwt/bpsetting.htm (15 November 2007, date last accessed).

19 . Huh JY, Lee WG, Lee K, et al. Distribution of insertion sequences associated with Tn1546-like elements among Enterococcus faecium isolates from patients in Korea. J Clin Microbiol (2004) 42:1897–902.[Abstract/Free Full Text]

20 . Peetermans WE, Hoogeterp JJ, Hazekamp-van Dokkum AM, et al. Antistaphylococcal activities of teicoplanin and vancomycin in vitro and in an experimental infection. Antimicrob Agents Chemother (1990) 34:1869–74.[Abstract/Free Full Text]

21 . Linden PK. Treatment options for vancomycin-resistant enterococcal infections. Drugs (2002) 62:425–41.[CrossRef][Web of Science][Medline]

22 . Losonsky GA, Wolf A, Schwalbe RS, et al. Successful treatment of meningitis due to multiply resistant Enterococcus faecium with a combination of intrathecal teicoplanin and intravenous antimicrobial agents. Clin Infect Dis (1994) 19:163–5.[Web of Science][Medline]

23 . Baptista M, Depardieu F, Reynolds P, et al. Mutations leading to increased levels of resistance to glycopeptide antibiotics in VanB-type enterococci. Mol Microbiol (1997) 25:93–105.[CrossRef][Web of Science][Medline]

24 . Lefort A, Garry L, Depardieu F, et al. Influence of VanD type resistance on activities of glycopeptides in vitro and in experimental endocarditis due to Enterococcus faecium. Antimicrob Agents Chemother (2003) 47:3515–8.[Abstract/Free Full Text]

25 . Lefort A, Arthur M, Depardieu F, et al. Expression of glycopeptide-resistance gene in response to vancomycin and teicoplanin in the cardiac vegetations of rabbits infected with VanB-type Enterococcus faecalis. J Infect Dis (2004) 189:90–7.[CrossRef][Web of Science][Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
61/4/838    most recent
dkn025v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Song, J.-H.
Right arrow Articles by Lee, W. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Song, J.-H.
Right arrow Articles by Lee, W. G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?