Annals of Hematology

, Volume 98, Issue 3, pp 763–773 | Cite as

Bloodstream infections with vancomycin-resistant enterococci are associated with a decreased survival in patients with hematological diseases

  • Sarah WeberEmail author
  • Michael Hogardt
  • Claudia Reinheimer
  • Thomas A. Wichelhaus
  • Volkhard A. J. Kempf
  • Johanna Kessel
  • Sebastian Wolf
  • Hubert Serve
  • Björn Steffen
  • Sebastian Scheich
Original Article


Enterococcus species are commensals of the human gastrointestinal tract with the ability to cause invasive infections. For patients with hematological diseases, enterococcal bloodstream infections (BSI) constitute a serious clinical complication which may even be aggravated if the pathogen is vancomycin-resistant. Therefore, we analyzed the course of BSI due to vancomycin-susceptible enterococci (VSE) in comparison to vancomycin-resistant enterococci (VRE) on patient survival. In this retrospective single-center study, BSI were caused by VRE in 47 patients and by VSE in 43 patients. Baseline patient characteristics were similar in both groups. Concerning infection-related characteristics, an increased CRP value and an increased rate of prior colonization with multidrug-resistant organisms were detected in the VRE BSI group. More enterococcal invasive infections were found in the VSE group. The primary endpoint, overall survival (OS) at 30 days after BSI, was significantly lower in patients with VRE BSI compared to patients with VSE BSI (74.5% vs. 90.7%, p = 0.039). In a multivariate regression analysis, VRE BSI and a Charlson comorbidity index higher than 4 were independent factors associated with 30-day mortality. Moreover, we found that VRE with an additional teicoplanin resistance showed a trend towards an even lower OS.


Bloodstream infections Hematological diseases Multidrug-resistant organisms Vancomycin-resistant enterococci Survival 



The authors thank all the physicians, nurses, technicians, and other hospital staff involved in patient care and lab work.

Compliance with ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. For this type of study formal consent is not required.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

277_2019_3607_MOESM1_ESM.docx (18 kb)
Table S1 (DOCX 17 kb)


  1. 1.
    Agudelo Higuita NI, Huycke MM (2014) Enterococcal Disease, Epidemiology, and Implications for Treatment. In: Gilmore MS, Clewell DB, Ike Y, Shankar N (eds) Enterococci: from commensals to leading causes of drug resistant infection. BostonGoogle Scholar
  2. 2.
    Huycke MM, Sahm DF, Gilmore MS (1998) Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future. Emerg Infect Dis 4(2):239–249. CrossRefGoogle Scholar
  3. 3.
    Miller WR, Munita JM, Arias CA (2014) Mechanisms of antibiotic resistance in enterococci. Expert Rev Anti-Infect Ther 12(10):1221–1236. CrossRefGoogle Scholar
  4. 4.
    Ahmed MO, Baptiste KE (2018) Vancomycin-resistant enterococci: a review of antimicrobial resistance mechanisms and perspectives of human and animal health. Microb Drug Resist 24(5):590–606. CrossRefGoogle Scholar
  5. 5.
    Leclercq R, Derlot E, Duval J, Courvalin P (1988) Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 319(3):157–161. CrossRefGoogle Scholar
  6. 6.
    Uttley AH, Collins CH, Naidoo J, George RC (1988) Vancomycin-resistant enterococci. Lancet 1(8575–6):57–58CrossRefGoogle Scholar
  7. 7.
    Lee K, Jang SJ, Lee HJ, Ryoo N, Kim M, Hong SG, Chong Y, Korean Nationwide Surveillance of Antimicrobial Resistance G (2004) Increasing prevalence of vancomycin-resistant Enterococcus faecium, expanded-spectrum cephalosporin-resistant Klebsiella pneumoniae, and imipenem-resistant Pseudomonas aeruginosa in Korea: KONSAR study in 2001. J Korean Med Sci 19(1):8–14. CrossRefGoogle Scholar
  8. 8.
    Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK, National Healthcare Safety Network T, Participating National Healthcare Safety Network F (2008) NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol 29(11):996–1011. CrossRefGoogle Scholar
  9. 9.
    European Centre for Disease Prevention and Control. (Stockholm: ECDC) (2017) Antimicrobial resistance surveillance in Europe 2016. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net)Google Scholar
  10. 10.
    Robert Koch-Institut (2017) Eigenschaften, Häufigkeit und Verbreitung von Vancomycin-resistenten Enterokokken (VRE) in Deutschland - Update 2015/2016. Epidemiol Bull 47:519–530Google Scholar
  11. 11.
    Gastmeier P, Schroder C, Behnke M, Meyer E, Geffers C (2014) Dramatic increase in vancomycin-resistant enterococci in Germany. J Antimicrob Chemother 69(6):1660–1664. CrossRefGoogle Scholar
  12. 12.
    Donskey CJ (2004) The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens. Clin Infect Dis 39(2):219–226. CrossRefGoogle Scholar
  13. 13.
    Ubeda C, Taur Y, Jenq RR, Equinda MJ, Son T, Samstein M, Viale A, Socci ND, van den Brink MR, Kamboj M, Pamer EG (2010) Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest 120(12):4332–4341. CrossRefGoogle Scholar
  14. 14.
    Garsin DA, Frank KL, Silanpaa J, Ausubel FM, Hartke A, Shankar N, Murray BE (2014) Pathogenesis and models of Enterococcal infection. In: Gilmore MS, Clewell DB, Ike Y, Shankar N (eds) Enterococci: From Commensals to Leading Causes of Drug Resistant Infection. BostonGoogle Scholar
  15. 15.
    Alevizakos M, Gaitanidis A, Nasioudis D, Tori K, Flokas ME, Mylonakis E (2017) Colonization with vancomycin-resistant Enterococci and risk for bloodstream infection among patients with malignancy: a systematic review and meta-analysis. Open Forum Infect Dis 4(1):ofw246. Google Scholar
  16. 16.
    Bhavnani SM, Drake JA, Forrest A, Deinhart JA, Jones RN, Biedenbach DJ, Ballow CH (2000) A nationwide, multicenter, case-control study comparing risk factors, treatment, and outcome for vancomycin-resistant and -susceptible enterococcal bacteremia. Diagn Microbiol Infect Dis 36(3):145–158CrossRefGoogle Scholar
  17. 17.
    Hefazi M, Damlaj M, Alkhateeb HB, Partain DK, Patel R, Razonable RR, Gastineau DA, Al-Kali A, Hashmi SK, Hogan WJ, Litzow MR, Patnaik MM (2016) Vancomycin-resistant enterococcus colonization and bloodstream infection: prevalence, risk factors, and the impact on early outcomes after allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. Transpl Infect Dis 18(6):913–920. CrossRefGoogle Scholar
  18. 18.
    Webb BJ, Healy R, Majers J, Burr Z, Gazdik M, Lopansri B, Hoda D, Petersen FB, Ford C (2017) Prediction of bloodstream infection due to vancomycin-resistant enterococcus in patients undergoing leukemia induction or hematopoietic stem-cell transplantation. Clin Infect Dis 64(12):1753–1759. CrossRefGoogle Scholar
  19. 19.
    DiazGranados CA, Zimmer SM, Klein M, Jernigan JA (2005) Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis 41(3):327–333. CrossRefGoogle Scholar
  20. 20.
    Prematunge C, MacDougall C, Johnstone J, Adomako K, Lam F, Robertson J, Garber G (2016) VRE and VSE bacteremia outcomes in the era of effective VRE therapy: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 37(1):26–35. CrossRefGoogle Scholar
  21. 21.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383CrossRefGoogle Scholar
  22. 22.
    Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, Januel JM, Sundararajan V (2011) Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 173(6):676–682. CrossRefGoogle Scholar
  23. 23.
    U.S. Department of Health and Human Services NIoH, National Cancer Institute Common terminology criteria for adverse events (CTCAE)Google Scholar
  24. 24.
    Meyer E, Beyersmann J, Bertz H, Wenzler-Rottele S, Babikir R, Schumacher M, Daschner FD, Ruden H, Dettenkofer M, Group O-KS (2007) Risk factor analysis of blood stream infection and pneumonia in neutropenic patients after peripheral blood stem-cell transplantation. Bone Marrow Transplant 39(3):173–178. CrossRefGoogle Scholar
  25. 25.
    Mikulska M, Del Bono V, Prinapori R, Boni L, Raiola AM, Gualandi F, Van Lint MT, Dominietto A, Lamparelli T, Cappellano P, Bacigalupo A, Viscoli C (2010) Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis 12(6):505–512. CrossRefGoogle Scholar
  26. 26.
    Pallares R, Pujol M, Pena C, Ariza J, Martin R, Gudiol F (1993) Cephalosporins as risk factor for nosocomial Enterococcus faecalis bacteremia. A matched case-control study. Arch Intern Med 153(13):1581–1586CrossRefGoogle Scholar
  27. 27.
    Remschmidt C, Schroder C, Behnke M, Gastmeier P, Geffers C, Kramer TS (2018) Continuous increase of vancomycin resistance in enterococci causing nosocomial infections in Germany - 10 years of surveillance. Antimicrob Resist Infect Control 7:54. CrossRefGoogle Scholar
  28. 28.
    Cho SY, Lee DG, Choi SM, Kwon JC, Kim SH, Choi JK, Park SH, Park YJ, Choi JH, Yoo JH (2013) Impact of vancomycin resistance on mortality in neutropenic patients with enterococcal bloodstream infection: a retrospective study. BMC Infect Dis 13:504. CrossRefGoogle Scholar
  29. 29.
    Vergis EN, Hayden MK, Chow JW, Snydman DR, Zervos MJ, Linden PK, Wagener MM, Schmitt B, Muder RR (2001) Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. A prospective multicenter study. Ann Intern Med 135(7):484–492CrossRefGoogle Scholar
  30. 30.
    Shay DK, Maloney SA, Montecalvo M, Banerjee S, Wormser GP, Arduino MJ, Bland LA, Jarvis WR (1995) Epidemiology and mortality risk of vancomycin-resistant enterococcal bloodstream infections. J Infect Dis 172(4):993–1000CrossRefGoogle Scholar
  31. 31.
    Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, Young JA (2012) Enterococcal bacteremia is associated with increased risk of mortality in recipients of allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 55(6):764–770. CrossRefGoogle Scholar
  32. 32.
    Edmond MB, Ober JF, Dawson JD, Weinbaum DL, Wenzel RP (1996) Vancomycin-resistant enterococcal bacteremia: natural history and attributable mortality. Clin Infect Dis 23(6):1234–1239CrossRefGoogle Scholar
  33. 33.
    Chou CH, Lee NY, Lee HC, Chang CM, Lee CC, Ko WC (2012) Emergence of vancomycin-resistant Enterococcus bloodstream infections in southern Taiwan. J Microbiol Immunol Infect 45(3):221–227. CrossRefGoogle Scholar
  34. 34.
    Salgado CD, Farr BM (2003) Outcomes associated with vancomycin-resistant enterococci: a meta-analysis. Infect Control Hosp Epidemiol 24(9):690–698. CrossRefGoogle Scholar
  35. 35.
    Yoo JH, Lee DG, Choi SM, Choi JH, Shin WS, Kim M, Yong D, Lee K, Min WS, Kim CC (2005) Vancomycin-resistant enterococcal bacteremia in a hematology unit: molecular epidemiology and analysis of clinical course. J Korean Med Sci 20(2):169–176. CrossRefGoogle Scholar
  36. 36.
    Chen CY, Tien FM, Sheng WH, Huang SY, Yao M, Tang JL, Tsay W, Tien HF, Hsueh PR (2017) Clinical and microbiological characteristics of bloodstream infections among patients with haematological malignancies with and without neutropenia at a medical centre in northern Taiwan, 2008-2013. Int J Antimicrob Agents 49(3):272–281. CrossRefGoogle Scholar
  37. 37.
    de Bruin MA, Riley LW (2007) Does vancomycin prescribing intervention affect vancomycin-resistant enterococcus infection and colonization in hospitals? A systematic review. BMC Infect Dis 7:24. CrossRefGoogle Scholar
  38. 38.
    Lisboa LF, Miranda BG, Vieira MB, Dulley FL, Fonseca GG, Guimaraes T, Levin AS, Shikanai-Yasuda MA, Costa SF (2015) Empiric use of linezolid in febrile hematology and hematopoietic stem cell transplantation patients colonized with vancomycin-resistant Enterococcus spp. Int J Infect Dis 33:171–176. CrossRefGoogle Scholar
  39. 39.
    Kamboj M, Cohen N, Huang YT, Kerpelev M, Jakubowski A, Sepkowitz KA, Papanicolaou GA, Seo SK (2018) Impact of empiric treatment for vancomycin-resistant Enterococcus (VRE) in colonized patients early after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant.
  40. 40.
    Todeschini G, Tecchio C, Borghero C, D'Emilio A, Pegoraro E, de Lalla F, Benedetti P, Spolaore P, Pellizzer G (2006) Association between enterococcus bacteraemia and death in neutropenic patients with haematological malignancies. J Inf Secur 53(4):266–273. Google Scholar
  41. 41.
    Marin M, Gudiol C, Ardanuy C, Garcia-Vidal C, Calvo M, Arnan M, Carratala J (2014) Bloodstream infections in neutropenic patients with cancer: differences between patients with haematological malignancies and solid tumours. J Inf Secur 69(5):417–423. Google Scholar
  42. 42.
    Islas-Munoz B, Volkow-Fernandez P, Ibanes-Gutierrez C, Villamar-Ramirez A, Vilar-Compte D, Cornejo-Juarez P (2018) Bloodstream infections in cancer patients. Risk factors associated with mortality. Int J Infect Dis 71:59–64. CrossRefGoogle Scholar
  43. 43.
    Gudiol C, Garcia-Vidal C, Arnan M, Sanchez-Ortega I, Patino B, Duarte R, Carratala J (2014) Etiology, clinical features and outcomes of pre-engraftment and post-engraftment bloodstream infection in hematopoietic SCT recipients. Bone Marrow Transplant 49(6):824–830. CrossRefGoogle Scholar
  44. 44.
    Ford CD, Lopansri BK, Haydoura S, Snow G, Dascomb KK, Asch J, Bo Petersen F, Burke JP (2015) Frequency, risk factors, and outcomes of vancomycin-resistant Enterococcus colonization and infection in patients with newly diagnosed acute leukemia: different patterns in patients with acute myelogenous and acute lymphoblastic leukemia. Infect Control Hosp Epidemiol 36(1):47–53. CrossRefGoogle Scholar
  45. 45.
    Rinaudo M, Cobos-Trigueros N, Sole M, Castro P, Hernandez C, Nicolas JM, Vila J, Morata L, Pumarol J, Soriano A, Mensa J, Martinez JA (2013) Comparison of acquisition of resistant microorganisms and infections in critically-ill patients with and without malignancies. Minerva Anestesiol 79(11):1217–1228Google Scholar
  46. 46.
    Mioljevic V, Markovic-Denic L, Vidovic A, Jovanovic M, Tosic T, Tomin D (2013) Risk factors for vancomycin-resistant Enterococcus colonization in hematologic patients. Vojnosanit Pregl 70(12):1109–1116CrossRefGoogle Scholar
  47. 47.
    Kim MH, Ahn JY, Song JE, Choi H, Ann HW, Kim JK, Kim JH, Jeon YD, Kim SB, Jeong SJ, Ku NS, Han SH, Song YG, Choi JY, Kim YS, Kim JM (2015) The C-reactive protein/albumin ratio as an independent predictor of mortality in patients with severe sepsis or septic shock treated with early goal-directed therapy. PLoS One 10(7):e0132109. CrossRefGoogle Scholar
  48. 48.
    Ranzani OT, Zampieri FG, Forte DN, Azevedo LC, Park M (2013) C-reactive protein/albumin ratio predicts 90-day mortality of septic patients. PLoS One 8(3):e59321. CrossRefGoogle Scholar
  49. 49.
    Harada K, Sekiya N, Konishi T, Nagata A, Yamada Y, Takezaki T, Kaito S, Kurosawa S, Sakaguchi M, Yasuda S, Sasaki S, Yoshioka K, Watakabe-Inamoto K, Igarashi A, Najima Y, Hagino T, Muto H, Kobayashi T, Doki N, Kakihana K, Sakamaki H, Ohashi K (2017) Predictive implications of albumin and C-reactive protein for progression to pneumonia and poor prognosis in Stenotrophomonas maltophilia bacteremia following allogeneic hematopoietic stem cell transplantation. BMC Infect Dis 17(1):638. CrossRefGoogle Scholar
  50. 50.
    Yin M, Si L, Qin W, Li C, Zhang J, Yang H, Han H, Zhang F, Ding S, Zhou M, Wu D, Chen X, Wang H (2016) Predictive value of serum albumin level for the prognosis of severe sepsis without exogenous human albumin administration. J Intensive Care Med 33:687–694. CrossRefGoogle Scholar
  51. 51.
    Artero A, Zaragoza R, Camarena JJ, Sancho S, Gonzalez R, Nogueira JM (2010) Prognostic factors of mortality in patients with community-acquired bloodstream infection with severe sepsis and septic shock. J Crit Care 25(2):276–281. CrossRefGoogle Scholar
  52. 52.
    Lee JH, Kim J, Kim K, Jo YH, Rhee J, Kim TY, Na SH, Hwang SS (2011) Albumin and C-reactive protein have prognostic significance in patients with community-acquired pneumonia. J Crit Care 26(3):287–294. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sarah Weber
    • 1
    • 2
    Email author
  • Michael Hogardt
    • 2
    • 3
    • 4
  • Claudia Reinheimer
    • 2
    • 3
    • 4
  • Thomas A. Wichelhaus
    • 2
    • 3
    • 4
  • Volkhard A. J. Kempf
    • 2
    • 3
    • 4
  • Johanna Kessel
    • 2
    • 5
  • Sebastian Wolf
    • 1
    • 2
  • Hubert Serve
    • 1
    • 2
  • Björn Steffen
    • 1
    • 2
  • Sebastian Scheich
    • 1
    • 2
  1. 1.Department of Hematology and OncologyUniversity Hospital FrankfurtFrankfurt am MainGermany
  2. 2.University Center for Infectious Diseases (UCI), University Hospital FrankfurtFrankfurt am MainGermany
  3. 3.Institute of Medical Microbiology and Infection ControlUniversity Hospital FrankfurtFrankfurt am MainGermany
  4. 4.University Center of Competence for Infection Control, University Hospital FrankfurtFrankfurt am MainGermany
  5. 5.Department of Medicine, Infectious Diseases UnitUniversity Hospital FrankfurtFrankfurt am MainGermany

Personalised recommendations