Enterococcus spp. are among the common pathogens causing infective endocarditis (IE). Despite major medical advances and new potent antimicrobial agents, the mortality has not significantly improved for several decades. The usual lack of bactericidal activity of penicillin or ampicillin, the toxicity from the combination of penicillin plus aminoglycosides, and the increased reports of high-level resistance to aminoglycosides have led to the exploration of other regimens for treatment of Enterococcus faecalis IE. As an example, ampicillin plus ceftriaxone is now a well-recognized regimen for this organism. However, the emerging of new drug resistances in Enterococcus faecium dramatically reduces the therapeutic alternatives for this organism in IE which continues to be an immense challenge for clinicians even with the availability of newer antimicrobial agents. This article summarizes the current treatment options for enterococcal endocarditis and reviews of recent publications on the topic.
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Levy DM. Centenary of William Osler’s 1885 Gulstonian lectures and their place in the history of bacterial endocarditis. J R Soc Med. 1985;78:1039–46.
Tleyjeh IM, Steckelberg JM, Murad HS, Anavekar NS, Ghomrawi HMK, Mirzoyev Z, et al. Temporal trends in infective endocarditis: a population-based study in Olmsted County, Minnesota. JAMA J Am Med Assoc. 2005;293:3022–8.
Murdoch DR, Corey GR, Hoen B, Miró JM, Fowler Jr VG, Bayer AS, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med. 2009;169:463–73.
Fernández-Guerrero ML, Verdejo C, Azofra J, de Górgolas M. Hospital-acquired infectious endocarditis not associated with cardiac surgery: an emerging problem. Clin Infect Dis Off Publ Infect Dis Soc Am. 1995;20:16–23.
Giannitsioti E, Skiadas I, Antoniadou A, Tsiodras S, Kanavos K, Triantafyllidi H, et al. Nosocomial vs. community-acquired infective endocarditis in Greece: changing epidemiological profile and mortality risk. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2007;13:763–9.
Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev. 1990;3:46–65.
Robbins WC, Tompsett R. Treatment of enterococcal endocarditis and bacteremia; results of combined therapy with penicillin and streptomycin. Am J Med. 1951;10:278–99.
Havard CW, Garrod LP, Waterworth PM. Deaf or dead? A case of subacute bacterial endocarditis treated with penicillin and neomycin. Br Med J. 1959;1:688–9.
Baddour LM, Wilson WR, Bayer AS, Fowler Jr VG, Bolger AF, Levison ME, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394–434.
Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995;39:650–5.
Olaison L, Schadewitz K, Swedish Society of Infectious Diseases Quality Assurance Study Group for Endocarditis. Enterococcal endocarditis in Sweden, 1995–1999: can shorter therapy with aminoglycosides be used? Clin Infect Dis Off Publ Infect Dis Soc Am. 2002;34:159–66.
Dahl A, Rasmussen RV, Bundgaard H, Hassager C, Bruun LE, Lauridsen TK, et al. Enterococcus faecalis infective endocarditis: a pilot study of the relationship between duration of gentamicin treatment and outcome. Circulation. 2013;127:1810–7.
Wilson WR, Wilkowske CJ, Wright AJ, Sande MA, Geraci JE. Treatment of streptomycin-susceptible and streptomycin-resistant enterococcal endocarditis. Ann Intern Med. 1984;100:816–23.
Munita JM, Arias CA, Murray BE. Editorial Commentary: Enterococcus faecalis infective endocarditis: is it time to abandon aminoglycosides? Clin Infect Dis Off Publ Infect Dis Soc Am. 2013;56:1269–72. Comprehensive review of the combination of high dose of ampicillin and ceftriaxone for ampicillin susceptible E. faecalis infective endocarditis.
Mainardi JL, Gutmann L, Acar JF, Goldstein FW. Synergistic effect of amoxicillin and cefotaxime against Enterococcus faecalis. Antimicrob Agents Chemother. 1995;39:1984–7.
Gavaldà J, Torres C, Tenorio C, López P, Zaragoza M, Capdevila JA, et al. Efficacy of ampicillin plus ceftriaxone in treatment of experimental endocarditis due to Enterococcus faecalis strains highly resistant to aminoglycosides. Antimicrob Agents Chemother. 1999;43:639–46.
Gavaldá J, Onrubia PL, Gómez MTM, Gomis X, Ramírez JL, Len O, et al. Efficacy of ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to Enterococcus faecalis with no high-level resistance to aminoglycosides. J Antimicrob Chemother. 2003;52:514–7.
Miro JM, Cervera C, Garcia-de-la-Maria C, Del Rio A, Armero Y, Mestres CA, et al. Success of ampicillin plus ceftriaxone rescue therapy for a relapse of Enterococcus faecalis native-valve endocarditis and in vitro data on double beta-lactam activity. Scand J Infect Dis. 2008;40:968–72.
Gavaldà J, Len O, Miró JM, Muñoz P, Montejo M, Alarcón A, et al. Brief communication: treatment of Enterococcus faecalis endocarditis with ampicillin plus ceftriaxone. Ann Intern Med. 2007;146:574–9.
Fernández-Hidalgo N, Almirante B, Gavaldà J, Gurgui M, Peña C, de Alarcón A, et al. Ampicillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treating enterococcus faecalis infective endocarditis. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013;56:1261–8.
Sakoulas G, Nonejuie P, Nizet V, Pogliano J, Crum-Cianflone N, Haddad F. Treatment of high-level gentamicin-resistant Enterococcus faecalis endocarditis with daptomycin plus ceftaroline. Antimicrob Agents Chemother. 2013;57:4042–5.
Carugati M, Bayer AS, Miró JM, Park LP, Guimarães AC, Skoutelis A, et al. High-dose daptomycin therapy for left-sided infective endocarditis: a prospective study from the international collaboration on endocarditis. Antimicrob Agents Chemother. 2013;57:6213–22.
Sierra-Hoffman M, Iznaola O, Goodwin M, Mohr J. Combination therapy with ampicillin and daptomycin for treatment of Enterococcus faecalis endocarditis. Antimicrob Agents Chemother. 2012;56:6064.
Murray BE. Beta-lactamase-producing enterococci. Antimicrob Agents Chemother. 1992;36:2355–9.
Munita JM, Arias CA, Murray BE. Enterococcal endocarditis: can we win the war? Curr Infect Dis Rep. 2012;14:339–49.
Galloway-Peña J, Roh JH, Latorre M, Qin X, Murray BE. Genomic and SNP analyses demonstrate a distant separation of the hospital and community-associated clades of Enterococcus faecium. PLoS One. 2012;7:e30187. This paper showed community-associated and hospital-associated strains belong to two ancestral clades based on comparison of 100 core genes from E. faecium genomes.
Lebreton F, van Schaik W, McGuire AM, Godfrey P, Griggs A, Mazumdar V, et al. Emergence of epidemic multidrug-resistant Enterococcus faecium from animal and commensal strains. mBio. 2013;4.
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;55:3272–7.
Linden PK, Moellering Jr RC, Wood CA, Rehm SJ, Flaherty J, Bompart F, et al. Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin. Clin Infect Dis Off Publ Infect Dis Soc Am. 2001;33:1816–23.
López F, Culebras E, Betriú C, Rodríguez-Avial I, Gómez M, Picazo JJ. Antimicrobial susceptibility and macrolide resistance genes in Enterococcus faecium with reduced susceptibility to quinupristin-dalfopristin: level of quinupristin-dalfopristin resistance is not dependent on erm(B) attenuator region sequence. Diagn Microbiol Infect Dis. 2010;66:73–7.
Pérez Salmerón J, Martínez García F, Roldán Conesa D, Lorente Salinas I, López Fornás F, Ruiz Gómez J, et al. Comparative study of treatment with quinupristin-dalfopristin alone or in combination with gentamicin, teicoplanin, imipenem or levofloxacin in experimental endocarditis due to a multidrug-resistant Enterococcus faecium. Rev Esp Quimioter Publ Off Soc Esp Quimioter. 2006;19:258–66.
Bethea JA, Walko CM, Targos PA. Treatment of vancomycin-resistant enterococcus with quinupristin/dalfopristin and high-dose ampicillin. Ann Pharmacother. 2004;38:989–91.
Arias CA, Murray BE. Emergence and management of drug-resistant enterococcal infections. Expert Rev Anti-Infect Ther. 2008;6:637–55.
Mendes RE, Flamm RK, Hogan PA, Ross JE, Jones RN. Summary of Linezolid Activity and Resistance Mechanisms Detected during the 2012 Surveillance Program for the United States (LEADER). Antimicrob. Agents Chemother. 2013.
Arias CA, Vallejo M, Reyes J, Panesso D, Moreno J, Castañeda E, et al. Clinical and microbiological aspects of linezolid resistance mediated by the cfr gene encoding a 23S rRNA methyltransferase. J Clin Microbiol. 2008;46:892–6.
Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J. 2009;30:2369–413.
Birmingham MC, Rayner CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis Off Publ Infect Dis Soc Am. 2003;36:159–68.
Falagas ME, Manta KG, Ntziora F, Vardakas KZ. Linezolid for the treatment of patients with endocarditis: a systematic review of the published evidence. J Antimicrob Chemother. 2006;58:273–80.
Lauridsen TK, Bruun LE, Rasmussen RV, Arpi M, Risum N, Moser C, et al. Linezolid as rescue treatment for left-sided infective endocarditis: an observational, retrospective, multicenter study. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2012;31:2567–74.
Arena F, Giani T, Galano A, Pasculli M, Peccianti V, Cassetta MI, et al. Breakthrough bacteremia by linezolid-susceptible Enterococcus faecalis under linezolid treatment in a severe polytrauma patient. Antimicrob Agents Chemother. 2013;57:6411–2.
Tsigrelis C, Singh KV, Coutinho TD, Murray BE, Baddour LM. Vancomycin-resistant Enterococcus faecalis endocarditis: linezolid failure and strain characterization of virulence factors. J Clin Microbiol. 2007;45:631–5.
Berdal J-E, Eskesen A. Short-term success, but long-term treatment failure with linezolid for enterococcal endocarditis. Scand J Infect Dis. 2008;40:765–6.
Schwartz BS, Ngo PD, Guglielmo BJ. Daptomycin treatment failure for vancomycin-resistant Enterococcus faecium infective endocarditis: impact of protein binding? Ann Pharmacother. 2008;42:289–90.
Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis Off Publ Infect Dis Soc Am. 2004;38:994–1000.
Cha R, Rybak MJ. Daptomycin against multiple drug-resistant staphylococcus and enterococcus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. Diagn Microbiol Infect Dis. 2003;47:539–46.
Akins RL, Rybak MJ. Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother. 2001;45:454–9.
Hall AD, Steed ME, Arias CA, Murray BE, Rybak MJ. Evaluation of standard- and high-dose daptomycin versus linezolid against vancomycin-resistant Enterococcus isolates in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother. 2012;56:3174–80.
Vouillamoz J, Moreillon P, Giddey M, Entenza JM. Efficacy of daptomycin in the treatment of experimental endocarditis due to susceptible and multidrug-resistant enterococci. J Antimicrob Chemother. 2006;58:1208–14.
Ramos MC, Grayson ML, Eliopoulos GM, Bayer AS. Comparison of daptomycin, vancomycin, and ampicillin-gentamicin for treatment of experimental endocarditis caused by penicillin-resistant enterococci. Antimicrob Agents Chemother. 1992;36:1864–9.
Cervera C, Castañeda X, Pericas JM, Del Río A, de la Maria CG, Mestres C, et al. Clinical utility of daptomycin in infective endocarditis caused by Gram-positive cocci. Int J Antimicrob Agents. 2011;38:365–70.
Mave V, Garcia-Diaz J, Islam T, Hasbun R. Vancomycin-resistant enterococcal bacteraemia: is daptomycin as effective as linezolid? J Antimicrob Chemother. 2009;64:175–80.
Twilla JD, Finch CK, Usery JB, Gelfand MS, Hudson JQ, Broyles JE. Vancomycin-resistant Enterococcus bacteremia: an evaluation of treatment with linezolid or daptomycin. J Hosp Med Off Publ Soc Hosp Med. 2012;7:243–8. Most recent meta-analysis comparing daptomycin vs. linezolid.
Balli EP, Venetis CA, Miyakis S. Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia. Antimicrob Agents Chemother. 2014;58:734–9.
Whang DW, Miller LG, Partain NM, McKinnell JA. Systematic review and meta-analysis of linezolid and daptomycin for treatment of vancomycin-resistant enterococcal bloodstream infections. Antimicrob Agents Chemother. 2013;57:5013–8.
Kelesidis T, Humphries R, Uslan DZ, Pegues DA. Daptomycin nonsusceptible enterococci: an emerging challenge for clinicians. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011;52:228–34.
Lewis 2nd JS, Owens A, Cadena J, Sabol K, Patterson JE, Jorgensen JH. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother. 2005;49:1664–5.
Munita JM, Tran TT, Diaz L, Panesso D, Reyes J, Murray BE, et al. A liaF codon deletion abolishes daptomycin bactericidal activity against vancomycin-resistant Enterococcus faecalis. Antimicrob Agents Chemother. 2013;57:2831–3. Single gene deletion abolished the bactericidal activity of daptomycin. Data suggest that lower breakpoint (2 μg/mL) for daptomycin may be more predictive of susceptibility.
Sader HS, Jones RN. Antimicrobial susceptibility of Gram-positive bacteria isolated from US medical centers: results of the Daptomycin Surveillance Program (2007–2008). Diagn Microbiol Infect Dis. 2009;65:158–62.
Lee BL, Sachdeva M, Chambers HF. Effect of protein binding of daptomycin on MIC and antibacterial activity. Antimicrob Agents Chemother. 1991;35:2505–8.
Casapao AM, Kullar R, Davis SL, Levine DP, Zhao JJ, Potoski BA, et al. Multicenter study of high-dose daptomycin for treatment of enterococcal infections. Antimicrob Agents Chemother. 2013;57:4190–6.
Kullar R, Casapao AM, Davis SL, Levine DP, Zhao JJ, Crank CW, et al. A multicentre evaluation of the effectiveness and safety of high-dose daptomycin for the treatment of infective endocarditis. J Antimicrob Chemother. 2013;68:2921–6.
Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother. 2006;50:3245–9.
Sakoulas G, Bayer AS, Pogliano J, Tsuji BT, Yang S-J, Mishra NN, et al. Ampicillin enhances daptomycin- and cationic host defense peptide-mediated killing of ampicillin- and vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother. 2012;56:838–44.
Arias CA, Torres HA, Singh KV, Panesso D, Moore J, Wanger A, 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 Off Publ Infect Dis Soc Am. 2007;45:1343–6.
Stevens MP, Edmond MB. Endocarditis Due to vancomycin-resistant enterococci: case report and review of the literature. Clin Infect Dis. 2005;41:1134–42.
Sakoulas G, Rose W, Nonejuie P, Olson J, Pogliano J, Humphries R, et al. Ceftaroline restores daptomycin activity against daptomycin nonsusceptible vancomycin resistant Enterococcus faecium. Antimicrob. Agents Chemother. 2013.
Entenza JM, Giddey M, Vouillamoz J, Moreillon P. In vitro prevention of the emergence of daptomycin resistance in Staphylococcus aureus and enterococci following combination with amoxicillin/clavulanic acid or ampicillin. Int J Antimicrob Agents. 2010;35:451–6.
Jenkins I. Linezolid- and vancomycin-resistant Enterococcus faecium endocarditis: successful treatment with tigecycline and daptomycin. J Hosp Med Off Publ Soc Hosp Med. 2007;2:343–4.
Schutt AC, Bohm NM. Multidrug-resistant Enterococcus faecium endocarditis treated with combination tigecycline and high-dose daptomycin. Ann Pharmacother. 2009;43:2108–12.
Polidori M, Nuccorini A, Tascini C, Gemignani G, Iapoce R, Leonildi A, et al. Vancomycin-resistant Enterococcus faecium (VRE) bacteremia in infective endocarditis successfully treated with combination daptomycin and tigecycline. J Chemother. 2011;23:240–1. Florence Italy.
Dowzicky MJ. Susceptibility to tigecycline and linezolid among gram-positive isolates collected in the United States as part of the tigecycline evaluation and surveillance trial (TEST) between 2004 and 2009. Clin Ther. 2011;33:1964–73.
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Conflict of Interest
Dr. Murray reports grants from Johnson & Johnson, grants from Cubist, grants and personal fees from Theravance, grants from Forest, personal fees and non-financial support from Rib-X, personal fees and non-financial support from Durata Therapeutics, personal fees and non-financial support from Achaogen, personal fees and non-financial support from The Medicines Co., personal fees and non-financial support from GlaxoSmithKline. Dr. Arias reports grants and consulting fees from Pfizer, grants from Forest Pharmaceuticals, grants and consulting fees from Theravance Inc., consulting fees from Novartis, consulting fees from Cubist and consulting fees from Astra Zeneca and he has served as a speaker for Pfizer, Forest Pharmaceutics, Novartis, Cubist and Astra Zeneca. Drs. Nigo and Munita have not conflicts of interest to declare.
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This article is part of the Topical Collection on Cardiovascular Infections
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Nigo, M., Munita, J.M., Arias, C.A. et al. What’s New in the Treatment of Enterococcal Endocarditis?. Curr Infect Dis Rep 16, 431 (2014). https://doi.org/10.1007/s11908-014-0431-z