Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management

Figures & data

Table 1 Characteristics of glycopeptide resistance phenotypes in Enterococcus

Resistance	Acquired								Intrinsic
	High		Variable	Moderate	Low				Low
Phenotype	VanA	VanM	VanB	VanD	VanE	VanG	VanL	VanN	VanC
Vancomycin MIC (mg/L)	64–1,000	>256	4–1,000	64–128	8–32	≤16	8	16	2–32
Teicoplanin MIC (mg/L)	16–512	96	0.5–1	4–64	0.5	Sensitive	≤0.5	≤0.5	0.5–1
Modification	d-Ala-d-Lac	d-Ala-d-Lac	d-Ala-d-Lac	d-Ala-d-Lac	d-Ala-d-Ser	d-Ala-d-Ser	d-Ala-d-Ser	d-Ala-d-Ser	d-Ala-d-Ser
Location	Plasmid or chromosome	Plasmid or chromosome	Plasmid or chromosome	Plasmid or chromosome	Chromosome	Chromosome	Chromosome	Plasmid	Chromosome
Transferrable	Yes	Yes	Yes	No	No	Yes	No	Yes	No
Expression	Inducible	Inducible	Inducible	Constitutive or inducible	Inducible	Inducible	Inducible	Constitutive	Constitutive or inducible
Main Species	E. faecalis, E. faecium	E. faecium	E. faecalis, E. faecium	E. faecalis, E. faecium	E. faecalis	E. faecalis	E. faecalis	E. faecium	E. gallinarum, E. casseliflavus

Notes: Data from Boyd et al,²⁸ Lebreton et al,²⁹ McKessar et al,³⁰ and Xu et al.³¹ Adapted from Courvalin P. Vancomycin resistance in Gram-positive cocci. Clin Infect Dis. 2006;42(Suppl l):S25–S34, by permission of Oxford University Press.²⁷

Abbreviations: MIC, minimum inhibitory concentration; d-Ala-d-Lac, d-alanine-d-lactate; d-Ala-d-Ser, d-alanine-d-serine.

Table 2 Surveillance of vancomycin-resistant enterococci around the world

Species	Percent of Enterococcus isolates resistant to vancomycin by region (no of isolates)
	Europe^Citation8 2013	US^Citation11 2009–2010	Worldwide^Citation115 2007–2012	Canada^Citation50 2007–2011	Asia-Pacific^Citation118 2007–2008	Latin America^Citation118 2007–2008
E. faecium	8.8 (729)	79.4 (2,572)	–	22.4 (60)	14.1 (270)	48.1 (54)
E. faecalis	1.0 (126)	8.5 (444)	10.3 (27)	0.1 (1)	0.01 (440)	3.1 (195)
All enterococci	4.0 (855)	35.5 (3,016)	–	6.0 (61)	11.9 (710)	12.9 (249)

Note: Adapted by permission of Oxford University Press from Cattoir V, Leclercq R. Twenty-five years of shared life with vancomycin-resistant enterococci: is it time to divorce? J Antimicrob Chemother. 2013;68(4):731–742.¹⁴

Abbreviations: VRE, vancomycin-resistant Enterococcus; US, United States

Table 3 Agents used for the treatment of serious ampicillin and vancomycin-resistant enterococcal infections with high-level resistance to aminoglycosides

Therapeutic class and agent	Mechanism of action	Dosing by FDA-approved indication(s)	Dosage adjustment	VRE indication(s)	Notable adverse events	Comments
Oxazolidinone
Linezolid^Citation116	Inhibits protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit	vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia; nosocomial pneumonia; CAP; complicated and uncomplicated SSSI: 600 mg IV or PO every 12 hours	For HD, normal dose, but dose post-HD on HD days	FDA approved for vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia	Headache (5.7%–8.8%), nausea (5.1%–6.6%), vomiting (2%–4.3%), diarrhea (8.2%–8.3%), serotonin syndrome, lactic acidosis Duration related: optic neuritis, peripheral neuropathy, myelosuppression	• Bacteriostatic; • Nonselective monoamine oxidase inhibitor; Avoid use with serotonergic agents; • Myelosuppression with duration >2 weeks
Tedizolid^Citation119	Inhibits protein synthesis by binding to the 50S ribosomal subunit	Acute bacterial SSSI: 200 mg IV or PO every 24 hours	None	Bacteremia; pneumonia	Diarrhea (4.0%), nausea (8.0%), vomiting (3.0%), headache (6.0%), thrombocytopenia (2.3%), neutropenia (0.5%)	• Bacteriostatic; • weaker monoamine oxidase inhibitor than linezolid; • extent of myelosuppression not fully elucidated due to short study durations
Streptogramin
Quinupristin/dalfopristin^Citation71	Each agent acts differently with the 50S ribosome to inhibit early and late phase protein synthesis	Complicated SSSI: 7.5 mg/kg IV every 12 hours	None	Serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium bacteremia 7.5 mg/kg IV every 8 hours Complicated SSSI, UTI, IAI	Injection site reactions: edema (17.3%), infammation (42.0%), pain (40.0%), rash (2.5%) Asymptomatic hyperbilirubinemia (0.9% to 25%), dose and/or frequency related arthralgias and myalgias (3.3% to 47%)	• Bacteriostatic; • No activity against E. faecalis; • Inhibitor of liver enzymes
Cyclic lipopeptide
Daptomycin^Citation117	Binding to cell membrane (concentration- and calcium-dependent); causes rapid depolarization of the membrane, inhibiting protein, DNA, and RNA synthesis, leading to cell death	Complicated SSSI: 4 mg/kg IV every 24 hours; Staphylococcus aureus bacteremia, including those with right-sided endocarditis: 6 mg/kg IV every 24 hours (consider higher dosing for severe VRE infections =8–12 mg/kg IV every 24 hours)	Complicated SSSI: CrCl,30 mL/min =4 mg/kg IV every 48 hours HD =4 mg/kg IV every 48 hours following HD on HD days Bacteremia: CrCl,30 mL/min =6 mg/kg IV every 48 hours HD =6 mg/kg IV every 48 hours following HD on HD days	Complicated SSSI, bacteremia, IE, CNS, IAI, UTI	Myopathy (especially with higher dose and/or concurrent HMG-CoA reductase inhibitor therapy), neuropathy, acute eosinophilic pneumonia	• Concentration-dependent bactericidal activity; • Inactivated by pulmonary surfactant (avoid use for primary pulmonary infections)
Glycylcycline
Tigecycline^Citation118	Inhibits protein translation by binding to the 30S ribosomal subunit	Complicated SSSI; IAI; CAP: 100 mg IV loading dose, then 50 mg IV every 12 hours	Severe hepatic impairment (Child-Pugh C): 100 mg IV day 1, then 25 mg IV every 12 hours	Complicated SSSI, IAI, CNS, UTI	Nausea (24% to 35%), vomiting (16% to 20%), acute pancreatitis	• Bacteriostatic; • Avoid in pregnancy (Class D) and for pediatric patients; • Low blood concentrations, avoid use in bacteremia; • Increased mortality with VAP treatment
Lipoglycopeptide
Telavancin^Citation109	Dual mechanism: Disrupts cell wall synthesis by binding to d-Ala-d-Lac of peptidoglycan, preventing cross-linking Disrupts membrane integrity and increases cell membrane permeability, causing cell lysis	Complicated SSSI; HAP/vAP: 10 mg/kg IV every 24 hours	CrCl 30–50 mL/min =7.5 mg/kg every 24 hours CrCl 10–30 mL/min =10 mg/kg every 48 hours CrCl,10 mL/min = IE HD = IE	Complicated SSSI, pneumonia	Taste disturbance (33%), foamy urine (13%), renal impairment (5%), GI disturbance (5%–27%), QT prolongation (8%)	• Concentration-dependent bactericidal activity (static against VRE expressing vanB); • Only active against VRE expressing vanB; • Higher nephrotoxicity compared to vancomycin; • Black box warning: increased mortality in moderate or severe renal impairment; • Avoid in pregnancy (class C, animal studies demonstrate fetal harm)
Dalbavancin^Citation108	Disrupts cell-wall synthesis by binding to d-Ala-d-Lac of peptidoglycan, preventing cross-linking	Acute bacterial SSSI: 1,000 mg IV on day 1, then 500 mg IV on day 8	CrCl,30 mL/min and no HD =750 mg on day 1, 375 on mg day 8	Acute bacterial SSSI; bacteremia	Constipation (18.2%), diarrhea (4.4%), nausea (5.5%), headache (4.7%), anaphylactoid reactions (<2%), “Red-Man syndrome” with rapid infusion (<30 minutes)	• Concentration-dependent bactericidal activity; • Only active against VRE expressing vanB; • Increased risk of hypersensitivity with a history of glycopeptide sensitivity has been noted
Oritavancin^Citation120	Triple mechanism: Inhibition of cell wall transglycosylation by binding to d-Ala-d-Lac Inhibition of cell wall transpeptidation by binding to the bridging segment Disruption of membrane integrity, increasing permeability, causing cell lysis	Acute bacterial SSSI: 1,200 mg IV once	None (not studied in CrCl,30 mL/min)	Acute bacterial SSSI; bacteremia	Nausea (9.9%), vomiting (4.6%), headache (7.1%), arm abscesses (3.8%), asymptomatic ALT elevations (2.8%), hypersensitivity (<1.5%) infusion site reactions (slow or stop infusion to abate)	• Concentration-dependent bactericidal activity; • Falsely elevated aPTT and INR post-infusion; • weak inducer and inhibitor of liver enzymes

Abbreviations: CAP, community-acquired pneumonia; d-Ala-d-Lac, d-alanine-d-lactate; aPTT, activated partial thromboplastin time; SSSI, skin and skin structure infection; IV, intravenous; PO, oral; HD, hemodialysis; UTI, urinary tract infection; IAI, intra-abdominal infection; CNS, central nervous system HAP, hospital-acquired pneumonia; VAP, ventilator-associated pneumonia; IE, insuffcient evidence; GI, gastrointestinal; INR, international normalized ratio; VRE, vancomycin-resistant Enterococcus; ALT, alanine aminotransferase; FDA, Food and Drug Administration.

Table 4 Suggested regimens for the treatment of serious ampicillin and vancomycin-resistant enterococcal infections with high-level resistance to aminoglycosides

Infection type	Therapeutic regimen	Comments
Bacteremia
Preferred	Linezolid
	Daptomycin	• Consider 8–12 mg/kg/day
Alternatives	Q/D	• Only active against E. faecium
	Daptomycin combination	• Combine with either HD ampicillin, ceftaroline, ceftobiprole, or tigecycline
Infective endocarditis
Preferred	Daptomycin	• Consider 8–12 mg/kg/day
Alternatives	Q/D	• Only active against E. faecium
	Daptomycin combination	• Combine with either HD ampicillin, ceftaroline, ceftobiprole, or tigecycline
	Linezolid
Central nervous system
Preferred	Linezolid
	Daptomycin	• ± concurrent intrathecal/intraventricular administration
Alternatives	Q/D	• Q/D + daptomycin is an option • ± concurrent intrathecal/intraventricular administration • Only active against E. faecium
	Tigecycline
Intra-abdominal
Preferred	Linezolid
	Daptomycin	• Intraperitoneal administration is an option
	Tigecycline
Alternatives	Q/D	• Only active against E. faecium
Skin and skin structure
Preferred	Linezolid	• Oral option
	Daptomycin
Alternatives	Tedizolid	• Oral option
	Oritavancin
	Dalbavancin	• Only active against VanB
	Telavancin	• Only active against VanB
	Q/D	• Only active against E. faecium
Urinary tract
Preferred	Nitrofurantoin	• Only for uncomplicated UTI
	Fosfomycin	• Only for uncomplicated UTI
	Linezolid	• ± concurrent bladder irrigation with linezolid • Oral option
Alternatives	Daptomycin HD ampicillin or amoxicillin Q/D	• Only active against E. faecium

Abbreviations: VRE, vancomycin-resistant Enterococcus; US, United States.

Table 5 Overview of recent evidence supporting combination therapy with daptomycin and a β-lactam for the treatment of vancomycin-resistant enterococcal infections

Regimen	Indication	Methodology	Outcomes	Comments	Reference
In vitro
Daptomycin + ampicillin	–	Broth macrodilution	Prevention of daptomycin resistance in VRE faecalis and faecium	VRE faecium isolate also ampicillin-resistant due to PBP5	^Citation99
Daptomycin (6 and 12 mg/kg/day) + ceftriaxone (2 g every 24 hours)	Infective endocarditis	Simulated endocardial vegetations	Increased activity against VRE faecalis and faecium Prevented resistance in VRE faecalis and faecium (only daptomycin 12 mg/kg + ceftriaxone combination)	Combination decreased surface charge of VRE faecium increasing daptomycin binding	^Citation100
Daptomycin + ampicillin and Daptomycin + ceftaroline	–	Time-kill assays	Synergy against VRE faecium (ampicillin and ceftaroline combinations) Synergy against daptomycin-nonsusceptible VRE faecium (ceftaroline combination)	Ceftaroline combination increased daptomycin surface binding with increases in membrane fluidity and net negative surface charge	^Citation98
Daptomycin + ampicillin	–	Genome sequencing, mutational analysis, and time-kill assays	Synergy against VRE faecium with changes in LiaFSR system No synergy against VRE faecium with changes in the yycFG system	–	^Citation102
Daptomycin + ceftobiprole and Daptomycin + ampicillin	–	Broth microdilution and time-kill assays	Synergy against 4/6 isolates of ampicillin-resistant VRE faecalis and faecium (both combinations)	Ceftobiprole combination increased daptomycin binding 2.8-fold	^Citation97
Case reports
Daptomycin 12 mg/kg/day + ampicillin 1 g every 6 hours	Infective endocarditis with bacteremia	–	Microbiological eradication of an ampicillin-resistant VRE faecium strain within 24 hours of initiation	Initially refractory to 7 days of therapy with daptomycin 6 mg/kg/day + linezolid 600 mg IV every 12 hours Adding ampicillin reduced the net positive bacterial surface charge	^Citation101

Abbreviations: VRE, vancomycin-resistant Enterococcus; PBP, penicillin-binding protein; IV, intravenous.

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