Vancomycin Resistant Enterococcus (VRE)

Reviewed and revised 7 January 2016

OVERVIEW

Vancomycin Resistant Enterococcus (VRE) are important nosocomial pathogens for which there are limited treatment options. Vancomycin resistance in enterococci was first reported by Uttley and colleagues in 1988

ENTEROCOCCI

Most important are E. faecalis and E. faecium

• gram positive gamma-haemolytic cocci
• formerly known as Lancefield Group D streptococci
• part of the normal flora of the human intestine, the female genital tract and urinary tract
• intrinsically of low pathogenicity with high resistance to antibiotics
• colonisation may last for years
• E. faecalis infection is usually less severe (~11% overall mortality)
• E.faecium infection is usually more severe (~50% overall mortality)
• E.faecium infection is associated with critical illness, nosocomial acquisition, cancer, neutropaenia, renal failre, steroids and/or exposure to antibiotics

ANTIBIOTIC RESISTANCE 

Patterns of resistance

• Enterococci in general are relatively penicillin resistant
• E. faecium is more penicilin-resistant and carbapenem-resistant than E. faecalis, and is more likely to be vancomycin resistant, but is sensitive to Quinupristin-dalfopristin
• E. faecalis is usually sensitive to ampicilin and gentamicin, with innate resistance to carbapenems and quinupristin-dalfopristin
• Most VRE have high-level resistance to β-lactams and aminoglycosides

Mechanisms of resistance

1. penicillin-binding protein mutations (Enterococci naturally have low affinity penicillin-biding proteins)
2. beta-lactamase production
3. aminoglycoside-modifying enzymes (2-phosphotransferase-6-acetyltransferase)
4. antibiotic drug efflux pumps
5. alterations in cell wall components coded by transposons (Van A to G phenotypes)

Vancomycin resistance

• Vancomycin prevents the synthesis of peptidoglycan precursors of the bacterial cell wall by blocking the transglycosylation step and subsequently affecting the transpeptidation step – both are essential for bacterial cell wall cross-linking
• multiple vancomycin-resistance phenotypes (e.g. VanA, VanB, VanC, VanD, VanE, and VanG)
• VanA and VanB are clinically most important
• Van A resistance is common in Australia, so many VRE are teicoplanin resistant
• Van B resistant strains are sensitive to teichoplanin

Vancomycin susceptibility based on minimum inhibitory concentrations (MICs)

• susceptible ≤4μg/ml
• intermediate 8–16μg/ml
• resistant ≥32μg/ml

PREDISPOSING FACTORS FOR VRE

Patient factors

• Previous treatment with anti-microbials (especially vancomycin, cephalosporins and broad- spectrum antibiotics)
• Renal impairment
• Long-term IV access
• Enteral tube feeding
• immunosuppression

Care/ facility factors

• Increased length of stay
• Prevalence of VRE colonized patients in the ICU
• Resident of long-term care facility
• Decreased staff : patient ratios

CONSEQUENCES OF VRE

• Potential transmission of resistance to Staphylococcus aureus
• Determined by site of infection if present (e.g. UTI, bloodstream including endocarditis and rarely respiratory infection)
• Patients with VRE bacteremia are more likely to die that patients with vancomycin-sensitive enterococcal bacteremia
• Colonisation, requiring patient isolation and associated resource consumption

MANAGEMENT OF VRE

Antimicrobial therapy

• Specific antibiotics if infected rather than colonized depending on sensitivities (Van A resistant to vancomycin and teicoplanin; Van B sensitive to teicoplanin)
  – options include teicoplanin, linezolid, daptomycin, quinupristin-dalfopristin, tigecycline, ceftaroline (see below for antibiotic choice)
• Probiotics may have a role

Infection control

• isolation
• contact precautions and PPE
• general infection control measures including surface and environmental cleaning, antibiotic stewardship, screening of contacts and patient surveillance until swabs are negative
• Precautions should continue on discharge from ICU

RATIONALE FOR ANTIBIOTIC CHOICE FOR VRE TREATMENT

Teicoplanin is commonly used in hospitals with VRE strains that are sensitive, however linezolid may be preferred over teicoplanin:

• greater efficacy
• better tissue penetration (it is poorly protein bound, so volume of distribution approximates to total body water)
• No dosage reduction is necessary in renal or hepatic failure
• Van A resistance is common in Australia, so many VRE are teicoplanin resistant
• Tigecycline and daptomycin generally regarded as third line drugs
• Ceftaroline new to practice and limited experience to date
• need to weigh up the importance of antibiotic toxicities for the individual

Antibiotic toxicities

• Teicoplanin: relatively little toxicity, less than vancomycin; thrombocytopenia, anaemia, renal or hepatic dysfunction
• Linezolid: mitochondrial toxin, hence thrombocytopenia, anaemia, peripheral or ocular neuropathy, lactic acidosis, serotonin syndrome
• Tigecycline: nausea & vomiting; teratogenic; catabolic, FDA reports increased risk of death in HAP or VAP compared to alternative treatments
• Daptomycin: myopathy
• Ceftaroline: no significant toxicity

References and Links

Journal articles

• Cetinkaya Y, Falk P, Mayhall CG. Vancomycin-resistant enterococci. Clinical microbiology reviews. 2000; 13(4):686-707 [pubmed]
• Murray BE. The life and times of the Enterococcus. Clinical microbiology reviews. 3(1):46-65. 1990. [pubmed]
• Sujatha S, Praharaj I. Glycopeptide resistance in gram-positive cocci: a review. Interdiscip Perspect Infect Dis. 2012;2012:781679. PMC3388329.