Vancomycin-Resistant Enterococcus (VRE)

This chapter addresses the expectations of  Section 2.1.1 ("Structure and Process") from the CICM Second Part General Exam Syllabus (First Edition).  Yes, VRE is "structure and process", even though all of the author's brainstem nuclei revolt against this classification, but when pushed against the wall, most people will eventually agree that there is nothing clever about reactively prescribing linezolid, and that the intelligence involved in managing VRE is mostly related to the control of its spread and the measures one designs to prevent colonisation. 

VRE comes up often in this exam:

• Question 2 from the second paper of 2012
• Question 30 from the first paper of 2012
• Question 26 from the first paper of 2007
• Question 9 from the second paper of 2004
• Question 1b from the first paper of 2004

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?

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:

Consequences of VRE colonisation

• Need for isolation
• Potential for clinically significant VRE infection
• Potential for transmission of vancomycin resistance to S.aureus

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. The Van genes mediate the production of modified peptidoglycan precursors, where the usual D-alanine-D-alanine is replaced by D-alanine-D-lactate.  Vancomycin loves the D-alanine-D-alanine linkage, but not so much the other one (binding to it with a three magnitude lower affinity). This means that it would be impossible to ever give enough vancomycin to bypass this resistance. The activity of carbapenems againt either E.faecalis or E.faecium is apparently poor, and other active agents (aminoglycosides, nitrofurantoin, chloramphenicol) are usually too toxic to be acceptable for long term treatment. With vancomycin off the table, the following options remain:

• Another glycopeptide? Oritavancin, telavancin or dalbavancin  are "lipoglycopeptides" with long lipophilic tails trailing off of what appears to be a classical-looking vanc-like core. That means they still attack the D-Ala-D-Ala linkage and therefore Van A enterococci are immune to the latter two, but oritavancin remains active against them all because it  also has a second mechanism of offense against the pentaglycyl (Asp/Asn) bridging segment of peptidoglycan ( Zhanel et al, 2012, details the molecular biochemistry for the interested reader). The main superpower of oritavancin is an extremely long half-life (300-400 hours!), as well as a tendency to accumulate in macrophages. It is entirely unphased by organ system failures and undergoes no metabolism, nor does it damage the kidneys, making it a very attractive candidate, considering the alternatives:
• Linezolid - an antiribosomal oxazolidinone antibiotic that cares little for peptidoglycan shenanigans - is effective for VRE, but it is not exactly a vigorous killer. It gently bores the VRE to death by interfering with protein synthesis, and is generally described as "bacteriostatic". Its superpower is the excellent oral bioavailability and good tissue (includioiong bone) penetration, but clinical use is hampered by its tendency to produce thrombocytopenia and to act as a monoamine oxidase inhibitor.
• Daptomycin routinely appears as the leader in studies where it is compared against linezolid, especially when it is used in a high dose (~10mg/kg). It is a cyclic lipopeptide that introduces itself into the cell membrane of gram-posititives, eventually accumulating there in such concentrations that it disrupts the membrane and causes it to leak. By virtue of this mechanism it is truly bactericidal. It has the unfortunate tendency to be deactivated by alveolar surfactant, and can cause rhabdomyolysis (Papadopoulos et al, 2006)
• Tigecycline,  a version of a tetracycline (glycylcycline to be precise), is less susceptible to bacterial efflux pumps than normal tetracyclines, bypassing a common reason for resistance. It is bacteriostatic, because the mechanism of action again involves disabling protein synthesis, but the activity is still described as "excellent", and it is a popular choice because of its low toxicity and tendency to accumulate in abdominal organs and soft tissue. The disadvantage is purely pharmacokinetic: it distributes out of the bloodstream rapidly, and is therefore poorly suited to clearing bloodstream infections. 
• Quinupristin-dalfopristin are a pair of streptogramins, vaguely relayed to macrolides by their antiribosomal mechanism of action, and are therefore also bacteriostatic.  The reason for giving both is a synergistic effect that forms a very stable drug-ribosome complex where dalfopristin binding causes a conformational change in the ribosome that increases the binding of quinupristin. Their special power is to be excreted along with their active metabolites via the biliary tract, which helps if this is where your VRE is coming from. The downside of this is an isolated  hyperbilirubinemia which can get up to five times the upper range of normal in up to a quarter of patients. Another charming adverse effect is arthralgia.

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.