VRE comes up often in this exam:

LITFL have a CCC chapter on VRE which covers this topic with characteristic clarity.
If one were a time-poor CICM exam candidate in need of a single all-encompassing literature reference for this topic, this article from Clinical Microbiology Reviews (2000) would satisfy that need. On the other hand, if one were a total microbiology fiend with no life, one could derive a great deal of enjoyment from Barbara Murray's "The Life and Times of the Enterococcus", from 1990.

Microbiology of VRE

Though initially included in the Streptococcus genus (they were the Lancefield Group D strep), in the 1980s enterococci were ultimately removed into their own genus on genetic grounds.

These cocci are intrinsically quite benign. They have low pathogenicity, forming a calm and law-abiding population in the human colon. In fact if you didn't have any enterococci in your stool you would be a rare individual; according to studies of faecal microflora 97% of the population excrete an enterococcus of some sort. The two clinically relevant species are E.faecalis and E.faecium, of which E. faecalis seems to be more common and tends to be found in higher numbers.

What is the clinical significance of the two species, you might ask?

Differences between the Enterococcus species

Features

E.faecalis

E.faecium

Factors associated with infection
  • Illness of lesser severity
  • Critical illness
  • Nosocomial acquisition
  • Cancer and neutropenia
  • Renal failure
  • Steroids
  • Exposure to antibiotics 
Mortality from bacteraemia

11%

50%

Naive antibiotic susceptibility
  • Benzylpenicillin
  • Ampicillin
  • Quinupristin-dalfopristin
Innate antibiotic resistances
  • Carbapenems
  • Quinupristin-dalfopristin
  • β-lactams
  • Carbapenems
  • Vancomycin (usually)

In general:

  • E.faecium attacks debilitated patients, is more antibiotic-resistant in general, and specifically it is usually vancomycin-resistant.
  • Quinupristin-dalfopristin (Synercid) kills E.faecium but not E.faecalis.

Mechanisms of antibiotic resistance among VRE organisms

β-lactam resistance

Enterococci have intrinsic resistance to most β-lactam antibiotics (including carbapenems) due to the low affinity of their penicillin-binding proteins. Interestingly, piperacillin has approximately the same activity as benzylpenicillin against these enterococci; ticarcillin and cephalosporins have about four times less activity, and are thus essentially useless. Of the two species, E.faecium is the more β-lactam-resistant, whereas E.faecalis is frequently susceptible to ampicillin.

Aminoglycoside resistance

Enterococci may develop resistance to aminoglycosides by producing an inactivating enzyme (2-phosphotransferase-6-acetyltransferase). Generally speaking if they are resistant to gentamicin they will also be resistant to amikacin. If this enzyme is present, there will be no β-lactam-aminoglycoside synergy.

Vancomycin resistance: VanA and VanB phenotypes

These are mutants with vancomycin resistance.

A good table describing these phenotypes is available.

In brief:

  • Van A are teicoplanin-resistant, and vancomycin-resistant to an extreme degree.
  • Van B are teicoplanin-sensitive, and modestly vancomycin-resistant.

Both VanA and VanB resistance can be transferred from one strain of enterococcus to another.

Of the two, VanA is the more widely distributed.

Resistance mechanism rests in the synthesis of abnormal D-Ala–D-lactate peptidoglycans, instead of the normal D-Ala–D-Ala (to which the vancomycin binds).

Risk factors for VRE colonisation:

These risk factors are listed by a 2012 Mebourne study, which was a cross-sectional assessment of colonisation prevalence in a tertiary hospital:

  • Proximity to other VRE patients - especially those with diarrhoea
  • Advanced age
  • Severe underlying illness
  • Inter-hospital transfer
  • Nursing home residency
  • Extended hospitalization
  • Specialized nutritional support
  • Central venous catheterization
  • Haematologic malignant tumours
  • Solid organ allograft
  • Chronic haemodialysis
  • Antibiotic exposure to vancomycin, third-generation cephalosporins, metronidazole, and any antibiotics with anti-anaerobic activity.
  • Exposure to multiple antibiotics
  • Prolonged duration of antibiotic therapy

Consequences of VRE colonisation

Management of the VRE-colonised patient

  • Isolation
  • Protective equipment
  • Scrupulous attention to cleaning areas where the patient has been
  • Surveillance swabs until the patient tests negative

Management of the clinically relevant VRE infection

When offering their antibiotic suggestions, the Sanford Guide quoted this 2010 article as their main inspiration.

  • Linezolid
  • Daptomycin
  • Tigecycline

The activity of carbapenems againt either E.faecalis or E.faecium is apparently poor.

The clinical relevance of enterococcal bacteraemia

Question 1b from the first paper of 2004 doesn't go into VRE right away, but rather presents the candidate with some blood cultres which have grown E.faecalis. The 1988 article by Maki and Agger suggests that normally the enterococci are avirulent, meaning that in the healthy host their presence in the bloodstream is fairly benign. However, in the altered host (eg. a critically ill patient) they become opportunistic pathogens. Corresponding to this, the celebrated 1997 review by Weinstein et al remarks that "whereas pneumococci always represented real infection, enterococcal isolates did so only 70% of the time". In that review, enterococcal bacteraemia was not found to be a factor which influenced prognosis.

References

Bonten, Marc JM, et al. "Epidemiology of colonisation of patients and environment with vancomycin-resistant enterococci." The Lancet 348.9042 (1996): 1615-1619.

MacIntyre, C. Raina, et al. "Risk factors for colonization with vancomycin-resistant enterococci in a Melbourne hospital." Infection control and hospital epidemiology 22.10 (2001): 624-629.

Tornieporth, Nadia G., et al. "Risk factors associated with vancomycin-resistant Enterococcus faecium infection or colonization in 145 matched case patients and control patients." Clinical infectious diseases 23.4 (1996): 767-772.

Karki, Surendra, et al. "Prevalence and risk factors for VRE colonisation in a tertiary hospital in Melbourne, Australia: a cross sectional study." Antimicrob Resist Infect Control 1.1 (2012): 31.

DeLisle, Sylvain, and Trish M. Perl. "Vancomycin-resistant enterococci: a road map on how to prevent the emergence and transmission of antimicrobial resistance." Chest journal 123.5_suppl (2003): 504S-518S.

Patel, Robin. "Clinical impact of vancomycin-resistant enterococci." Journal of Antimicrobial Chemotherapy 51.suppl 3 (2003): iii13-iii21.

Noble, W. C., Zarina Virani, and Rosemary GA Cree. "Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus ." FEMS Microbiology letters93.2 (1992): 195-198.

Hollenbeck, Brian L., and Louis B. Rice. "Intrinsic and acquired resistance mechanisms in enterococcus." Virulence 3.5 (2012): 421-433.

Kaye, Donald. "Enterococci: biologic and epidemiologic characteristics and in vitro susceptibility." Archives of Internal Medicine 142.11 (1982): 2006-2009.

Cetinkaya, Yesim, Pamela Falk, and C. Glen Mayhall. "Vancomycin-resistant enterococci." Clinical microbiology reviews 13.4 (2000): 686-707.

Murray, Barbara E. "The life and times of the Enterococcus." Clinical microbiology reviews 3.1 (1990): 46-65.

Benno, Yoshimi, et al. "Comparison of the fecal microflora in rural Japanese and urban Canadians." Microbiology and immunology 30.6 (1986): 521-532.

Noskin, Gary A., Lance R. Peterson, and John R. Warren. "Enterococcus faecium and Enterococcus faecalis bacteremia: acquisition and outcome."Clinical infectious diseases 20.2 (1995): 296-301.

Hayakawa, Kayoko, et al. "Comparison of the clinical characteristics and outcomes associated with vancomycin-resistant Enterococcus faecalis and vancomycin-resistant E. faecium bacteremia." Antimicrobial agents and chemotherapy (2012): AAC-06299.

Hayakawa, Kayoko, et al. "Growing prevalence of vancomycin-resistant Enterococcus faecalis in the region with the highest prevalence of vancomycin-resistant Staphylococcus aureus." Infection Control 32.09 (2011): 922-924.

Arias, Cesar A., German A. Contreras, and Barbara E. Murray. "Management of multidrug‐resistant enterococcal infections." Clinical microbiology and infection 16.6 (2010): 555-562.

Poh, C. H., H. M. L. Oh, and A. L. Tan. "Epidemiology and clinical outcome of enterococcal bacteraemia in an acute care hospital." Journal of Infection 52.5 (2006): 383-386.

Weinstein, Melvin P., et al. "The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults." Clinical Infectious Diseases 24.4 (1997): 584-602.

Bota, Daliana Peres, et al. "Body temperature alterations in the critically ill."Intensive care medicine 30.5 (2004): 811-816.

MAKI, DENNIS G., and WILLIAM A. AGGER. "Enterococcal bacteremia: clinical features, the risk of endocarditis, and management." Medicine 67.4 (1988): 248.