Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Mechanisms of antibiotic resistance in enterococci

Cesar A Arias, MD, PhD
Barbara E Murray, MD
Section Editor
David C Hooper, MD
Deputy Editor
Elinor L Baron, MD, DTMH


Enterococci, formerly called group D streptococci, come well equipped with a variety of intrinsic (ie, naturally occurring) antibiotic resistances; they are also capable of acquiring new resistance genes and/or mutations. The combination of high-level resistance to ampicillin, vancomycin, and aminoglycosides is now very common among hospital-acquired Enterococcus faecium in the United States and has a major impact on therapeutic options. (See "Epidemiology, prevention, and control of vancomycin-resistant enterococci".)

Problems in the treatment of enterococcal infections were noticed as early as the 1950s with the observation that enterococcal endocarditis was not cured nearly as often as streptococcal endocarditis with penicillin [1]. The reason for the poorer response appears to be that penicillin is not as bactericidal against enterococci as it is (or was in the 1950s) against most viridans streptococci. This phenomenon, which has been commonly described as tolerance, is characteristic of many enterococcal strains and, even in those that do not initially display tolerance, can be rapidly elicited by pulsed (intermittent) penicillin exposure. The latter observation led to some support for the use of continuous-infusion penicillin or ampicillin in an attempt to avoid eliciting tolerance [2].


Until the last few decades, enterococci could be treated with penicillin, ampicillin, or vancomycin with or without an aminoglycoside. Some enterococci have now acquired resistance to these and many other agents as a result of mutations (eg, causing high-level resistance to streptomycin or to fluoroquinolones) or the acquisition of new gene(s).

With respect to the acquisition of new genes, enterococci have several different ways of transferring DNA by conjugation (bacterial mating):

One mechanism, involving pheromone-responsive plasmids, causes plasmid transfer between Enterococcus faecalis isolates at a very high frequency [3].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jun 20, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. GERACI JE, MARTIN WJ. Antibiotic therapy of bacterial endocarditis. VI. Subacute enterococcal endocarditis; clinical, pathologic and therapeutic consideration of 33 cases. Circulation 1954; 10:173.
  2. Hodges TL, Zighelboim-Daum S, Eliopoulos GM, et al. Antimicrobial susceptibility changes in Enterococcus faecalis following various penicillin exposure regimens. Antimicrob Agents Chemother 1992; 36:121.
  3. Dunny GM, Leonard BA, Hedberg PJ. Pheromone-inducible conjugation in Enterococcus faecalis: interbacterial and host-parasite chemical communication. J Bacteriol 1995; 177:871.
  4. Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev 1990; 3:46.
  5. Clewell DB, Gawron-Burke C. Conjugative transposons and the dissemination of antibiotic resistance in streptococci. Annu Rev Microbiol 1986; 40:635.
  6. Roberts MC. Characterization of the Tet M determinants in urogenital and respiratory bacteria. Antimicrob Agents Chemother 1990; 34:476.
  7. Manson JM, Hancock LE, Gilmore MS. Mechanism of chromosomal transfer of Enterococcus faecalis pathogenicity island, capsule, antimicrobial resistance, and other traits. Proc Natl Acad Sci U S A 2010; 107:12269.
  8. Murray BE. Beta-lactamase-producing enterococci. Antimicrob Agents Chemother 1992; 36:2355.
  9. Sarti M, Campanile F, Sabia C, et al. Polyclonal diffusion of beta-lactamase-producing Enterococcus faecium. J Clin Microbiol 2012; 50:169.
  10. Clinical Laboratory Standards Institute. Performance standards for antimicrobial testing: Twentieth informational supplement. Document M100-S20, Clinical Laboratory Standards Institute; Wayne, PA 2010.
  11. Grayson ML, Eliopoulos GM, Wennersten CB, et al. Increasing resistance to beta-lactam antibiotics among clinical isolates of Enterococcus faecium: a 22-year review at one institution. Antimicrob Agents Chemother 1991; 35:2180.
  12. Fontana R, Ligozzi M, Pittaluga F, Satta G. Intrinsic penicillin resistance in enterococci. Microb Drug Resist 1996; 2:209.
  13. Galloway-Peña JR, Rice LB, Murray BE. Analysis of PBP5 of early U.S. isolates of Enterococcus faecium: sequence variation alone does not explain increasing ampicillin resistance over time. Antimicrob Agents Chemother 2011; 55:3272.
  14. Rice LB, Bellais S, Carias LL, et al. Impact of specific pbp5 mutations on expression of beta-lactam resistance in Enterococcus faecium. Antimicrob Agents Chemother 2004; 48:3028.
  15. Mainardi JL, Legrand R, Arthur M, et al. Novel mechanism of beta-lactam resistance due to bypass of DD-transpeptidation in Enterococcus faecium. J Biol Chem 2000; 275:16490.
  16. Mainardi JL, Morel V, Fourgeaud M, et al. Balance between two transpeptidation mechanisms determines the expression of beta-lactam resistance in Enterococcus faecium. J Biol Chem 2002; 277:35801.
  17. Kristich CJ, Wells CL, Dunny GM. A eukaryotic-type Ser/Thr kinase in Enterococcus faecalis mediates antimicrobial resistance and intestinal persistence. Proc Natl Acad Sci U S A 2007; 104:3508.
  18. Desbonnet C, Tait-Kamradt A, Garcia-Solache M, et al. Involvement of the Eukaryote-Like Kinase-Phosphatase System and a Protein That Interacts with Penicillin-Binding Protein 5 in Emergence of Cephalosporin Resistance in Cephalosporin-Sensitive Class A Penicillin-Binding Protein Mutants in Enterococcus faecium. MBio 2016; 7:e02188.
  19. Costa Y, Galimand M, Leclercq R, et al. Characterization of the chromosomal aac(6')-Ii gene specific for Enterococcus faecium. Antimicrob Agents Chemother 1993; 37:1896.
  20. HAVARD CW, GARROD LP, WATERWORTH PM. Deaf or dead? A case of subacute bacterial endocarditis treated with penicillin and neomycin. Br Med J 1959; 1:688.
  21. Eliopoulos GM, Farber BF, Murray BE, et al. Ribosomal resistance of clinical enterococcal to streptomycin isolates. Antimicrob Agents Chemother 1984; 25:398.
  22. Courvalin P, Carlier C, Collatz E. Plasmid-mediated resistance to aminocyclitol antibiotics in group D streptococci. J Bacteriol 1980; 143:541.
  23. Mederski-Samoraj BD, Murray BE. High-level resistance to gentamicin in clinical isolates of enterococci. J Infect Dis 1983; 147:751.
  24. Chow JW. Aminoglycoside resistance in enterococci. Clin Infect Dis 2000; 31:586.
  25. Chow JW, Zervos MJ, Lerner SA, et al. A novel gentamicin resistance gene in Enterococcus. Antimicrob Agents Chemother 1997; 41:511.
  26. Galimand M, Schmitt E, Panvert M, et al. Intrinsic resistance to aminoglycosides in Enterococcus faecium is conferred by the 16S rRNA m5C1404-specific methyltransferase EfmM. RNA 2011; 17:251.
  27. Gavaldà J, Len O, Miró JM, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Intern Med 2007; 146:574.
  28. Tascini C, Doria R, Leonildi A, et al. Efficacy of the combination ampicillin plus ceftriaxone in the treatment of a case of enterococcal endocarditis due to Enterococcus faecalis highly resistant to gentamicin: efficacy of the "ex vivo" synergism method. J Chemother 2004; 16:400.
  29. Singh KV, Weinstock GM, Murray BE. An Enterococcus faecalis ABC homologue (Lsa) is required for the resistance of this species to clindamycin and quinupristin-dalfopristin. Antimicrob Agents Chemother 2002; 46:1845.
  30. Sharkey LK, Edwards TA, O'Neill AJ. ABC-F Proteins Mediate Antibiotic Resistance through Ribosomal Protection. MBio 2016; 7:e01975.
  31. Chenoweth CE, Robinson KA, Schaberg DR. Efficacy of ampicillin versus trimethoprim-sulfamethoxazole in a mouse model of lethal enterococcal peritonitis. Antimicrob Agents Chemother 1990; 34:1800.
  32. Grayson ML, Thauvin-Eliopoulos C, Eliopoulos GM, et al. Failure of trimethoprim-sulfamethoxazole therapy in experimental enterococcal endocarditis. Antimicrob Agents Chemother 1990; 34:1792.
  33. Reynolds PE, Arias CA, Courvalin P. Gene vanXYC encodes D,D -dipeptidase (VanX) and D,D-carboxypeptidase (VanY) activities in vancomycin-resistant Enterococcus gallinarum BM4174. Mol Microbiol 1999; 34:341.
  34. Arias CA, Martín-Martinez M, Blundell TL, et al. Characterization and modelling of VanT: a novel, membrane-bound, serine racemase from vancomycin-resistant Enterococcus gallinarum BM4174. Mol Microbiol 1999; 31:1653.
  35. Arias CA, Courvalin P, Reynolds PE. vanC cluster of vancomycin-resistant Enterococcus gallinarum BM4174. Antimicrob Agents Chemother 2000; 44:1660.
  36. Leclercq R, Dutka-Malen S, Duval J, Courvalin P. Vancomycin resistance gene vanC is specific to Enterococcus gallinarum. Antimicrob Agents Chemother 1992; 36:2005.
  37. Navarro F, Courvalin P. Analysis of genes encoding D-alanine-D-alanine ligase-related enzymes in Enterococcus casseliflavus and Enterococcus flavescens. Antimicrob Agents Chemother 1994; 38:1788.
  38. Reynolds PE. Structure, biochemistry and mechanism of action of glycopeptide antibiotics. Eur J Clin Microbiol Infect Dis 1989; 8:943.
  39. Fines M, Perichon B, Reynolds P, et al. VanE, a new type of acquired glycopeptide resistance in Enterococcus faecalis BM4405. Antimicrob Agents Chemother 1999; 43:2161.
  40. McKessar SJ, Berry AM, Bell JM, et al. Genetic characterization of vanG, a novel vancomycin resistance locus of Enterococcus faecalis. Antimicrob Agents Chemother 2000; 44:3224.
  41. Boyd DA, Willey BM, Fawcett D, et al. Molecular characterization of Enterococcus faecalis N06-0364 with low-level vancomycin resistance harboring a novel D-Ala-D-Ser gene cluster, vanL. Antimicrob Agents Chemother 2008; 52:2667.
  42. Lebreton F, Depardieu F, Bourdon N, et al. D-Ala-d-Ser VanN-type transferable vancomycin resistance in Enterococcus faecium. Antimicrob Agents Chemother 2011; 55:4606.
  43. Guardabassi L, Agersø Y. Genes homologous to glycopeptide resistance vanA are widespread in soil microbial communities. FEMS Microbiol Lett 2006; 259:221.
  44. Arthur M, Courvalin P. Genetics and mechanisms of glycopeptide resistance in enterococci. Antimicrob Agents Chemother 1993; 37:1563.
  45. Dutka-Malen S, Evers S, Courvalin P. Detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci by PCR. J Clin Microbiol 1995; 33:1434.
  46. Patel R, Piper K, Cockerill FR 3rd, et al. The biopesticide Paenibacillus popilliae has a vancomycin resistance gene cluster homologous to the enterococcal VanA vancomycin resistance gene cluster. Antimicrob Agents Chemother 2000; 44:705.
  47. Guardabassi L, Christensen H, Hasman H, Dalsgaard A. Members of the genera Paenibacillus and Rhodococcus harbor genes homologous to enterococcal glycopeptide resistance genes vanA and vanB. Antimicrob Agents Chemother 2004; 48:4915.
  48. Leclercq R, Courvalin P. Resistance to glycopeptides in enterococci. Clin Infect Dis 1997; 24:545.
  49. Reynolds PE, Depardieu F, Dutka-Malen S, et al. Glycopeptide resistance mediated by enterococcal transposon Tn1546 requires production of VanX for hydrolysis of D-alanyl-D-alanine. Mol Microbiol 1994; 13:1065.
  50. Arthur M, Depardieu F, Molinas C, et al. The vanZ gene of Tn1546 from Enterococcus faecium BM4147 confers resistance to teicoplanin. Gene 1995; 154:87.
  51. Mevius D, Devriese L, Butaye P, et al. Isolation of glycopeptide resistant Streptococcus gallolyticus strains with vanA, vanB, and both vanA and vanB genotypes from faecal samples of veal calves in The Netherlands. J Antimicrob Chemother 1998; 42:275.
  52. Stinear TP, Olden DC, Johnson PD, et al. Enterococcal vanB resistance locus in anaerobic bacteria in human faeces. Lancet 2001; 357:855.
  53. Gu L, Cao B, Liu Y, et al. A new Tn1546 type of VanB phenotype-vanA genotype vancomycin-resistant Enterococcus faecium isolates in mainland China. Diagn Microbiol Infect Dis 2009; 63:70.
  54. Yowler CJ, Blinkhorn RJ, Fratianne RB. Vancomycin-dependent enterococcal strains: case report and review. J Trauma 2000; 48:783.
  55. Van Bambeke F, Chauvel M, Reynolds PE, et al. Vancomycin-dependent Enterococcus faecalis clinical isolates and revertant mutants. Antimicrob Agents Chemother 1999; 43:41.
  56. San Millan A, Depardieu F, Godreuil S, Courvalin P. VanB-type Enterococcus faecium clinical isolate successively inducibly resistant to, dependent on, and constitutively resistant to vancomycin. Antimicrob Agents Chemother 2009; 53:1974.
  57. Shinabarger DL, Marotti KR, Murray RW, et al. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother 1997; 41:2132.
  58. Leach KL, Swaney SM, Colca JR, et al. The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria. Mol Cell 2007; 26:393.
  59. Meka VG, Gold HS. Antimicrobial resistance to linezolid. Clin Infect Dis 2004; 39:1010.
  60. Gonzales RD, Schreckenberger PC, Graham MB, et al. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001; 357:1179.
  61. Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001; 358:207.
  62. Raad II, Hanna HA, Hachem RY, et al. Clinical-use-associated decrease in susceptibility of vancomycin-resistant Enterococcus faecium to linezolid: a comparison with quinupristin-dalfopristin. Antimicrob Agents Chemother 2004; 48:3583.
  63. Prystowsky J, Siddiqui F, Chosay J, et al. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci. Antimicrob Agents Chemother 2001; 45:2154.
  64. Bourgeois-Nicolaos N, Massias L, Couson B, et al. Dose dependence of emergence of resistance to linezolid in Enterococcus faecalis in vivo. J Infect Dis 2007; 195:1480.
  65. Marshall SH, Donskey CJ, Hutton-Thomas R, et al. Gene dosage and linezolid resistance in Enterococcus faecium and Enterococcus faecalis. Antimicrob Agents Chemother 2002; 46:3334.
  66. Mendes RE, Deshpande LM, Castanheira M, et al. First report of cfr-mediated resistance to linezolid in human staphylococcal clinical isolates recovered in the United States. Antimicrob Agents Chemother 2008; 52:2244.
  67. Toh SM, Xiong L, Arias CA, et al. Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid. Mol Microbiol 2007; 64:1506.
  68. Kehrenberg C, Schwarz S, Jacobsen L, et al. A new mechanism for chloramphenicol, florfenicol and clindamycin resistance: methylation of 23S ribosomal RNA at A2503. Mol Microbiol 2005; 57:1064.
  69. Arias CA, Vallejo M, Reyes J, et al. Clinical and microbiological aspects of linezolid resistance mediated by the cfr gene encoding a 23S rRNA methyltransferase. J Clin Microbiol 2008; 46:892.
  70. Liu Y, Wang Y, Wu C, et al. First report of the multidrug resistance gene cfr in Enterococcus faecalis of animal origin. Antimicrob Agents Chemother 2012; 56:1650.
  71. Diaz L, Kiratisin P, Mendes RE, et al. Transferable plasmid-mediated resistance to linezolid due to cfr in a human clinical isolate of Enterococcus faecalis. Antimicrob Agents Chemother 2012; 56:3917.
  72. Wang Y, Lv Y, Cai J, et al. A novel gene, optrA, that confers transferable resistance to oxazolidinones and phenicols and its presence in Enterococcus faecalis and Enterococcus faecium of human and animal origin. J Antimicrob Chemother 2015; 70:2182.
  73. Cavaco LM, Bernal JF, Zankari E, et al. Detection of linezolid resistance due to the optrA gene in Enterococcus faecalis from poultry meat from the American continent (Colombia). J Antimicrob Chemother 2017; 72:678.
  74. Pogue JM, Paterson DL, Pasculle AW, Potoski BA. Determination of risk factors associated with isolation of linezolid-resistant strains of vancomycin-resistant Enterococcus. Infect Control Hosp Epidemiol 2007; 28:1382.
  75. Herrero IA, Issa NC, Patel R. Nosocomial spread of linezolid-resistant, vancomycin-resistant Enterococcus faecium. N Engl J Med 2002; 346:867.
  76. Dobbs TE, Patel M, Waites KB, et al. Nosocomial spread of Enterococcus faecium resistant to vancomycin and linezolid in a tertiary care medical center. J Clin Microbiol 2006; 44:3368.
  77. Rahim S, Pillai SK, Gold HS, et al. Linezolid-resistant, vancomycin-resistant Enterococcus faecium infection in patients without prior exposure to linezolid. Clin Infect Dis 2003; 36:E146.
  78. Kaatz GW, Lundstrom TS, Seo SM. Mechanisms of daptomycin resistance in Staphylococcus aureus. Int J Antimicrob Agents 2006; 28:280.
  79. Pogliano J, Pogliano N, Silverman JA. Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins. J Bacteriol 2012; 194:4494.
  80. Müller A, Wenzel M, Strahl H, et al. Daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains. Proc Natl Acad Sci U S A 2016.
  81. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004; 38:1673.
  82. Poutsiaka DD, Skiffington S, Miller KB, et al. Daptomycin in the treatment of vancomycin-resistant Enterococcus faecium bacteremia in neutropenic patients. J Infect 2007; 54:567.
  83. Sakoulas G, Bayer AS, Pogliano J, et al. Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother 2012; 56:838.
  84. Chavada R, Ghosh N, Sandaradura I, et al. Establishment of an AUC0-24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother 2017; 61.
  85. Britt NS, Potter EM, Patel N, Steed ME. Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients. Clin Infect Dis 2015; 61:871.
  86. Munoz-Price LS, Lolans K, Quinn JP. Emergence of resistance to daptomycin during treatment of vancomycin-resistant Enterococcus faecalis infection. Clin Infect Dis 2005; 41:565.
  87. Lewis JS 2nd, Owens A, Cadena J, et al. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother 2005; 49:1664.
  88. Kamboj M, Cohen N, Gilhuley K, et al. Emergence of daptomycin-resistant VRE: experience of a single institution. Infect Control Hosp Epidemiol 2011; 32:391.
  89. Kelesidis T, Humphries R, Uslan DZ, Pegues D. De novo daptomycin-nonsusceptible enterococcal infections. Emerg Infect Dis 2012; 18:674.
  90. Arias CA, Panesso D, McGrath DM, et al. Genetic basis for in vivo daptomycin resistance in enterococci. N Engl J Med 2011; 365:892.
  91. Tran TT, Panesso D, Gao H, et al. Whole-genome analysis of a daptomycin-susceptible enterococcus faecium strain and its daptomycin-resistant variant arising during therapy. Antimicrob Agents Chemother 2013; 57:261.
  92. Tran TT, Munita JM, Arias CA. Mechanisms of drug resistance: daptomycin resistance. Ann N Y Acad Sci 2015; 1354:32.
  93. Tran TT, Panesso D, Mishra NN, et al. Daptomycin-resistant Enterococcus faecalis diverts the antibiotic molecule from the division septum and remodels cell membrane phospholipids. MBio 2013; 4.
  94. Arias CA, Torres HA, Singh KV, et al. Failure of daptomycin monotherapy for endocarditis caused by an Enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster. Clin Infect Dis 2007; 45:1343.
  95. Sakoulas G, Nonejuie P, Nizet V, et al. Treatment of high-level gentamicin-resistant Enterococcus faecalis endocarditis with daptomycin plus ceftaroline. Antimicrob Agents Chemother 2013; 57:4042.
  96. Clinical Laboratory Standards Institute. Performance standard for antimicrobial susceptibility testing. 15th informational supplement M100-S15. Clinical Laboratory Standards Institute; Wayne, PA 2005.
  97. Coque TM, Murray BE. Identification of Enterococcus faecalis strains by DNA hybridization and pulsed-field gel electrophoresis. J Clin Microbiol 1995; 33:3368.
  98. Contreras GA, DiazGranados CA, Cortes L, et al. Nosocomial outbreak of Enteroccocus gallinarum: untaming of rare species of enterococci. J Hosp Infect 2008; 70:346.
  99. Dutka-Malen S, Blaimont B, Wauters G, Courvalin P. Emergence of high-level resistance to glycopeptides in Enterococcus gallinarum and Enterococcus casseliflavus. Antimicrob Agents Chemother 1994; 38:1675.
  100. Johnson AP, Mushtaq S, Warner M, Livermore DM. Calcium-supplemented daptomycin Etest strips for susceptibility testing on Iso-Sensitest agar. J Antimicrob Chemother 2004; 53:860.