Review

Clinical Considerations in the Approach to Vancomycin-Resistant Enterococci: A Narrative Review

John W. Beale¹, Marina Durward-Diioia²

doi: http://dx.doi.org/10.5195/ijms.2022.1010

Volume 10, Number 2: 202-209
Received 16 04 2021: Rev-request 18 05 2021: Rev-request 03 08 2021: Rev-request 03 11 2021: Rev-request 01 02 2022: Rev-recd 19 05 2021: Rev-recd 25 08 2021: Rev-recd 22 11 2021: Rev-recd 28 03 2022: Accepted 04 04 2022

ABSTRACT

Vancomycin-Resistant Enterococci (VRE) increasingly colonize and infect assorted patient populations throughout the world, maintaining a continual reservoir of opportunistic pathogens with varying antibiotic resistance. Here we present the current general epidemiology and classification of these pathogens within the scope of healthcare-associated infections (HAIs). Risk factors for colonization and conditions for subsequent infection are reviewed, along with infection characteristics. Current infection control protocols and their effectiveness, selected evidence-based medical therapies, and ongoing research into alternative therapies are summarized.

Keywords: Vancomycin-resistant enterococci; Enterococcus faecalis; Enterococcus faecium; Vancomycin resistance; Healthcare-associated infection; Nosocomial infection (Source: MeSH-NLM).

Introduction

First identified in the United Kingdom and France during the 1980s, Enterococci possessing vancomycin-resistance (VRE) colonizes patients in the United States (U.S.) at increasing rates.^1,2 Infections stemming from VRE colonization account for approximately 30% of all healthcare-associated Enterococci infections in the U.S.³ During the late 2000s, VRE-related hospitalizations doubled in the U.S. alone.¹ Worldwide reported VRE surveillance data varies widely by continent and country. Reports from Africa are diverse, with the published prevalence of VRE among human isolates varying from 2.5% to 44.3%.⁴ 2016 data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) reported that between 25% and 50% of surveillance isolates of E. faecium from Ireland, Eastern, and Southern Europe were positive for VRE.⁵ While a U.S. Centers for Disease Control (CDC) report in 2019 showed decreasing cases over the last several years from 84,800 confirmed VRE infections in hospitalized patients in 2012 to 54,500 cases in 2017; the prevalence of vancomycin resistance is still alarmingly high at 30% of all healthcare-associated infections.⁶ Variable surveillance data from Asia and Australasia suggest a low prevalence of VRE compared to Europe and the U.S. for instance, a 5-year study in Singapore found a prevalence of vancomycin resistance in isolates at 0.4-0.7%, but these rates appear to be increasing.⁷ The variable yet increasing prevalence of vancomycin resistance should concern physicians, scientists, and patients worldwide.

Colonization rate increases may be attributed to Enterococci's natural habitat and genetic structure. One of many bacterial species composing normal human enteric microbiota, Enterococci gaining vancomycin-resistance are perfectly positioned for enhanced opportunistic pathogenicity. Enterococci already possess intrinsic resistance to many antibacterial agents, including β-lactams and aminoglycosides.^8–10 Existence with other commensal bacteria provides ample opportunities for acquiring vancomycin resistance via transposition of resistance-containing plasmids.^11–13 Nine different phenotypes – VanA, VanB, VanC, VanD, VanE, VanG, VanL, VanM, and VanN – named for the vancomycin-resistance gene (van) expressed currently describe degrees of vancomycin-resistance and pathogenicity within Enterococci.^11,14,15 For example, E. faecium most frequently expresses the vanA gene and thus is most frequently associated with the VanA phenotype, which identifies the highest vancomycin resistance and, consequently, the highest pathogenicity.^10,14 The VanB phenotype identifies expression of the vanB gene and an intermediate level of vancomycin-resistance that, while less pathogenic, still commonly appears in surveillance cultures of patient populations.^10,15–17 VanC phenotype Enterococci express the vanC gene and possess much lower vancomycin-resistance.^10,15 VRE are thus a family of variably-resistant opportunistic pathogens, with E. faecium and E. faecalis being the most commonly identified.^8–10,18 Increasing VRE prevalence intensifies the need to quickly identify patients at risk for colonization and infection to treat colonized and infected patients with the potential to lower overall colonization rates.

This review aims to present the general epidemiology and medical management of healthcare-associated VRE infections. In order to clarify the variable at-risk patient populations, we reviewed essential factors for colonization. We recently reported conditions for subsequent infection, followed by a review of infection control protocols, which are of heightened importance in health care settings. Further, recent updates to the pharmacological interventions and alternative therapies, including rebiosis, are discussed and compared.

Methods

A narrative review of English language literature from 1994 to August 2019 was utilized to assess the historical development of vancomycin resistance within the Enterococcus family. This timeline was revisited prior to publication and updated to include the time frame to March 2022. Scale for Assessment of Narrative Review Articles (SANRA) was used to guide appropriate research methods.¹⁹ The primary research method was an online search conducted in September 2019 on Google Scholar and PubMed. Search terms included: vancomycin resistance OR vre OR “vancomycin-resistant” OR multidrug-resistant OR mdro OR infec* AND enterococc* OR “E. faecalis” OR “E. faecium” OR “enterococcus faecalis” OR “enterococcus faecium” OR microbiome OR microbiota. Meta-analyses and systematic reviews were given a narrower time frame, namely the past 10 years compared to case reports or series and other literature reviews or position papers. This allowed for more recent data on current treatment practices and protocols while allowing a broader scope for assessing the historical development and response to vancomycin-resistant Enterococci. The competencies of evidence-based medicine were utilized when developing inclusion/exclusion criteria.²⁰ These competencies include recognizing a problem, retrieving and critically appraising the literature, and intergrating information found. Papers dealing specifically with human models were preferred; however, some animal model studies were included due to a lack of data with human models.

Inclusion required:

• Title or abstract inclusion of at least two of the search term(s) OR
• Significant (two+ pages) discussion of at least two of the search terms within the body of the paper OR
• Position papers whose content would apply to at least two of the search terms, even if not explicitly stated.

Exclusion required:

• Any paper published more than 25 years ago at the time of search (1994 or earlier)
• Any meta-analysis or systematic review published more than 10 years ago at the time of search (2009 or earlier)
• Any paper that contained only one search term and failed to meet the inclusion criteria outlined above
• Any paper that included one or more search terms whose primary focus was either another form of drug resistance or another species of bacteria (e.g., methicillin-resistant Staphylococcus aureus).

Results and Discussion

Colonization and Infections

Colonization, or the incorporation of a microorganism into a host, occurs through the interaction of the host with a reservoir of that microorganism. Studies by Hamel et al. in 2010 and Kaki et al. in 2014 identified VRE colonized patients and contaminated surfaces within hospitals or care centers as possible VRE reservoirs.^21,22 Enterococci inhabit every human colon, but colonization with VRE rarely occurs among healthy populations.²³ Further, in a recent large study (n=674 including controls) of healthcare personnel and their rates of colonization with multi-drug resistant organisms (MDROs), Decker et al. found that there were not any healthcare workers or control subjects positive for VRE colonization, including those in contact with MDRO+ patients.²⁴ A meta-analysis of 37 studies found that 10% of patients in Intensive Care Units (ICU) are already colonized with VRE at admission, and an additional 10% were colonized during their ICU stay.^23,25 A meta-analysis of dialysis patients, who are typically immunocompromised in the U.S. found that more than 6% are colonized with VRE.²⁶

VRE colonization risk is multifactorial. Recent high-dose antibiotic use, especially vancomycin, is the most frequently identified risk factor in multiple studies.^13,22,26 Surgical, oncological, and dialysis patients demonstrate increased risk, especially when recovery requires ICU services.^{3,10,23,25–28} Patients sharing a room with a VRE colonized patient have a one in three chance of becoming colonized during hospitalization.^21,22,29 Acquired immunodeficiency from Human Immunodeficiency Virus (HIV) infection or medically-induced immunosuppression may also increase VRE colonization risk.^{18,27,28,30–32}

Immunocompromised patients requiring recurrent medical interventions within a hospital or long-term care center thus comprise both the highest risk group for colonization and the potentially largest VRE reservoir.^3,33 Patients in these circumstances are prime for a VRE-mediated infection when a critical lapse in immune function occurs. For example, Brennen et al. found only 1% of colonized patients in a nursing facility develop VRE infections.³⁴ Yet Zaas et al. reported that 13% of colonized oncology patients develop VRE infections.³⁵ In a 2008 study, Zirakzadeh et al. found that hematopoietic stem cell transplant (HSCT) patients colonized with VRE have a significantly higher 100-day mortality rate (45%) compared to non-colonized patient controls (25%) and are more prone to develop VRE bacteremia (27%) than non-colonized patients (0%).³⁰ Colonized dialysis patients demonstrate significantly higher VRE infection risk than to non-colonized patients, especially when recently hospitalized.²⁶ A 2013 meta-analysis by Ziakas et al. found that among ICU patients, VRE infection rates among those colonized can be anywhere from 0%-45%, yet the infection rate for non-colonized patients consistently stayed below 2%.²³ As recently as 2018, Freedberg et al. found that VRE colonization was associated with a 19% increased risk for death (P<.01) and a 22% increased risk of infection (P<.01).²⁵ Infection rate discrepancies indicate a predisposition among VRE-colonized patients to acquire a VRE infection after a major medical procedure.

VRE infections generally correlate with either the location or method of medical intervention (Figure 1). VRE infections may localize around surgical incisions with limited spread to adjacent tissues.²⁷ VRE meningitis, while rare, may complicate cranial surgical procedures in colonized patients.^9,18,36 VRE urinary tract infections (UTIs) commonly afflict colonized patients with indwelling catheters.²⁷ Peritoneal dialysis in patients colonized with VRE may result in VRE peritonitis.^9,26,37 Up to 10% of patients undergoing HSCT or solid organ transplants that develop VRE bacteremia may experience VRE infective endocarditis.^9,18,31 These patients may also be more likely to progress to septic shock.^30,32

Figure 1

Common Locations of Medical Procedures with Resulting VRE-Mediated Infections.

Legend: Note the localized nature of the resulting infections, with two significant exceptions: Solid organ transplant and hematopoietic stem cell transplant (HSCT). Patients undergoing these major medical interventions are more likely to suffer from systemic VRE-mediated infections such as: bacteremia, infective endocarditis (IE), sepsis and possible progression and worsening to septic shock. This may be due to the highly vascular nature of both solid organs and bone marrow which facilitate the systemic spread of VRE in susceptible patients.

All VRE infections cause significant increases in morbidity and mortality when compared to similar infections with vancomycin-sensitive Enterococci (VSE).^10,25,26,30 Mortality rates for surgical patients with VRE bacteremia may be as high as 67%, nearly double the rate for matched control patients.^30,33 VRE infections among leukemia patients may result in mortality rates as high as 73%.¹⁸ Mortality rates among VRE-infected allogeneic HSCT recipients with VRE infections vary between 45% and 80%, depending on the infection.³⁰

Infection Control Protocols

Alarmingly high mortality rates underscore the extensive research and discussion surrounding VRE infection control protocols. The CDC published recommendations for identifying and preventing VRE colonization in the mid-1990s.^27,28 Recommendations included: active patient surveillance using perianal swabs, culture on selective media, using gloves and gowns for universal contact precautions (CP), and isolating VRE-colonized patients during treatment.^27,28 These recommendations became the standard in hospital-based VRE infection control protocols, and for other multidrug-resistant organisms (MDROs). Numerous studies since the CDC's guidelines were published have evaluated the effectiveness and limitations of these infection control measures, as discussed below.

Active surveillance of high-risk patients, typically those hospitalized in the intensive care unit or receiving intravenous antibiotic therapy, has been a mainstay of infection control; however, limitations primarily involve the time required to culture the surveillance swabs. Cultures take 48 to 72 hours to grow, during which time yet undetected VRE may colonize additional patients.^17,38 In 2017, Holzknecht et al. demonstrated that Polymerase Chain Reaction (PCR) assay for the vanA and/or vanB genes might significantly reduce the time required to identify VRE-colonized patients (eight hours for PCR assay compared to 48-72 hours for culture). Very recent PCR assay development has led to a vastly reduced time frame of two hours to identify VRE, though costs and availability issues remain.³⁹ This is built on the work of Paule et al., which showed in 2003 that PCR of the vanA gene demonstrates a high specificity (99.7%) and sensitivity (87.1%) for identifying VRE (compared to about 60% sensitivity for swab and culture).^16,17,38,40 Decreased detection time may lead to the earlier implementation of universal CP and isolation, thus preventing further VRE exposure in unprotected patients and healthcare workers.

Studies evaluating universal CP in VRE infection control protocols contain positive but non-specific findings. Research by Calfee et al. in 2003 confirmed the work done earlier by Montecalvo et al. in 1999, reporting a 50% decrease in the incidence of VRE colonization following CP implementation.^27,38,41 Research by Slaughter et al. in 1996 affirmed the use of universal CP; however, they could find no additional reduction in VRE colonization when using gloves and gowns compared to gloves alone.⁴² More recent studies by Harris et al. in 2013 and Morgan et al. in 2015 argue for the continued use of universal CP for MDROs, including VRE, while acknowledging that the clinical research supporting such practice is still lacking.^43–45 Recent research by Eichel et al. found that CP did not alter the transmission rates of VRE nor the rate of VRE bacteremia while hand and environment hygiene were maintained.⁴⁶

VRE patient isolation protocols focus on maintaining the standard of care. Montecalvo et al. and Calfee et al. both reported isolation as a component of successful VRE colonization reduction; however, the degree of benefit that isolation alone provided remains unquantified.^27,38,41 Unlike gloves or surveillance cultures, which cause little to no harm to patients, isolation protocols may actually cause harm to patients. In 2003, Stelfox et al. reported that isolated patients experience two adverse events during treatment compared to one for non-isolated patients.⁴⁷ The charts of isolated patients contained fewer vital sign records, fewer physician progress notes, and elevated complaint and dissatisfaction levels at discharge.⁴⁷ While evidence supports isolation as a component of VRE infection control protocols; concerted efforts must ensure these patients receive the same standard of care during treatment compared to their non-isolated counterparts.

The CDC continually updates practice guidelines for VRE and other MDROs, advocating for the effective use of infection control measures in a multi-disciplinary approach that emphasizes prevention as well as treatment.⁴⁸ Prevention methods include sterilizing medical equipment, using anti-bacterial washes on patients, and hand hygiene.⁴⁸ In 2019, Messler et al. reported that octenidine-based body washing reduced VRE colonization by 65% in a German surgical ICU population.⁴⁰ This infection control technique, alongside established recommendations, may combat rising VRE colonization rates more effectively.

Medical Management

Despite the best efforts of healthcare teams and continual refinement of infection control protocols, VRE infections continually plague susceptible patients. Proper culture and resistance profiling of patient isolates are essential to ensure patients receive the most appropriate course of treatment. Few effective antibacterial agents remain to treat vancomycin-resistant enterococcal infections. Table 1 summarizes commonly cited medical therapies that are now or have been indicated for VRE infections, including their class and mechanism of action. Currently, the only antibiotic approved by the U.S. Food and Drug Administration (FDA) for medical management of VRE-mediated infections is linezolid, an oxazolidinone. While only bacteriostatic to VRE, linezolid has been successfully used as a monotherapy in several VRE infective endocarditis cases.^13,31 VRE-mediated UTIs and central nervous system infections also respond well to linezolid monotherapy.^13,36 Daptomycin, a cyclic lipopeptide, has a bactericidal action against VRE in certain disease states and may be used for both VRE-mediated UTIs and infective endocarditis.^8,13,32 A recent comparison study revealed that linezolid was associated with a significantly lower rate of clinical failure compared to the standard dose of daptomycin.⁴⁹ The same study found that higher doses of daptomycin may overcome some of the clinical failures.

A recent study by Kelly et al. found that most patients receiving daptomycin for VRE infections had no side effects at a dose of 8-12mg/kg/day.⁵⁰ Further, a cost analysis found that these therapies are similar, with linezolid being slightly more cost-effective in the U.S.⁵¹ Other medications once indicated for VRE infections, such as chloramphenicol and quinupristin/dalfopristin, have fallen into disuse due to low bacteriostatic/bactericidal activity or side effects requiring cessation of medical therapy.^13,30

Current VRE antimicrobial therapy relies heavily on two primary agents: linezolid and daptomycin, both of which have a normal incidence of notable adverse events in patients. Linezolid can lead to the central nervous system and gastrointestinal symptoms in up to 9.8% of patients, including headache, nausea, vomiting, and diarrhea.⁵² Daptomycin is reported to be associated with myopathies at higher doses, neuropathy, and acute eosinophilic pneumonia, though this is considered rare.^53,54 Additionally, both linezolid and daptomycin use can lead to anemia, thrombocytopenia, and renal insufficiency in patients.⁵⁵ The prevalence of these adverse events underscores the importance of antibiotic development against VRE.

The World Health Organization (WHO), CDC, and other national and international organizations continually urge pharmaceutical and academic entities to develop novel regimens.^6,56 VRE resistance to linezolid, though currently a rare occurrence, only accentuates the need for new approaches to VRE infection management.^8,13 A new oxazolidinone, tedizolid, may be efficacious against linezolid-resistant VRE strains, though the FDA does not currently approve it for that indication.^13,32 Recent investigations into the use of oritavancin, a lipoglycopeptide, and omadacycline, a tetracycline, are showing significant efficacy against VRE in small studies, though more coordinated clinical studies are required.^57–59 In vitro studies exploring combinations of daptomycin and ceftaroline, a fifth-generation cephalosporin, showed promise against VRE infections; however, Chuang et al. in 2017 found no significant difference in mortality between patients receiving the combination therapy compared to daptomycin monotherapy.^8,13,56

High mortality rates underscore the need for effective antibiotics against VRE.²⁷ Two studies examining VRE bacteremia in transplant patients reported 80% and 100% mortality rates despite treatment with linezolid, daptomycin, and quinupristin/dalfopristin.^13,30 While VRE infection may not have been the sole cause of death in all instances, reported mortality rates would not have been this high without VRE infection.^27,30,32 Further research must focus on finding alternative antimicrobial therapies or combination therapies that provide more significant efficacy against VRE infections.

Potential Therapies

New research into alternative treatment options is producing promising results. Our current understanding of the human microbiome and its synergistic effects on health has led to new, targeted treatment modalities affecting several physiological processes, including metabolism and the immune response.^60,61 Colonic dysbiosis, or the disruption of normal enteric microbiota favoring opportunistic infections, is a proven component of disease pathogenesis in Clostridioides difficile infections, irritable bowel syndrome, and Crohn's disease.^60,61 Currently, research examining the links between colonic dysbiosis and VRE colonization is underway by multiple groups.^60–64 This research may lead to new treatment paradigms that can reduce VRE colonization rates, morbidity, and mortality associated with VRE infections.

Clinical application of current research offers two different therapeutic approaches: primary rebiosis and secondary rebiosis. Primary rebiosis consists of integrating probiotic species, or components of these species, within the human microbiome to restore normal immune function and prevent seeding by opportunistic pathogens such as VRE.^61–63 Secondary rebiosis consists of integrating a donor microbiome en totum to a dysbiotic individual, most commonly accomplished via Fecal Microbiota Transplant (FMT).^60,64 This procedure isolates and purifies a healthy donor sample for direct implantation into a dysbiotic colon.^60,61

Primary rebiosis shows encouraging results in both animal models and preliminary clinical trials. A 2018 study by Wasilewska et al. of Streptococcus and Lactobacillus in mouse models confirms earlier reports that probiotic regimens have a two-fold benefit in combating enteric-related infections: modulating colonic immune responses to favor healthy gut microbiota and enhancing immune response against opportunistic pathogens within intestinal lymphoid tissues.⁶⁵ Research by Li et al. of Lactobacillus extracellular vesicles in worm models suggests that components of this probiotic species alone may be effective in treating VRE colonization.⁶³ Kim et al. studied Blautia producta in mouse models suggesting that administration in a newly colonized host may restore natural resistance to VRE colonization after antibiotic administration.⁶⁶ A 2019 retrospective analysis by Borgmann et al. of probiotic therapy conducted in Ingolstadt, Germany, suggests that adding the probiotics Saccharomyces boulardii and Escherichia coli Nissle to traditional antibiotic regimens reduces VRE transmission in stroke and trauma patients without any adverse side effects.⁶² Following the implementation of probiotic regimens, VRE colonization rates dropped from 78 patients per year to 51 per year, an overall 35% reduction.⁶² These studies highlight the potential impact of primary rebiosis as an emerging VRE therapy that may improve the efficacy of existing antimicrobial regimens.

Secondary rebiosis via FMT may be effective in reducing VRE colonization where other methods have proven ineffective. First employed in refractory Clostridium difficile infections in 2013, FMT has shown surprising efficacy.^60,61 Research utilizing mouse model FMT treatments for VRE colonization reduced overall VRE load, though the effect was transient.⁶⁴ In 2018, Davido et al. performed the largest human trial to date utilizing FMT as a treatment to decolonize VRE, resulting in seven of eight initial study patients remaining VRE free 3 months post-FMT.⁶⁴ Ongoing trials will assess whether these limited but encouraging results will hold up in larger clinical studies.⁶⁷ FMT has been shown to be relatively safe, with the most common side-effects being mild and self-limiting increases in flatulence, changes in bowel regularity, and abdominal bloating and tenderness.⁶⁸ Identification and screening of healthy donor material play a large role in mitigating the risks associated with the procedure.⁶⁸ Directly replacing a patient's colonized colonic microbiome with a healthy, VRE-free microbiome may provide the means to greatly reduce the functional reservoir of VRE and prevent continued colonization.

Conclusion

Since physicians have identified vancomycin-resistant Enterococci, our understanding of this family of multidrug-resistant, opportunistic pathogens has grown exponentially. While this body of evidence has grown, we are still looking for the most appropriate measures to limit the spread of antibiotic-resistant infections. Clinical cases and meta-analyses have provided clues into the reservoirs of VRE and the patient populations most at risk from VRE colonization. Incredibly high morbidity and mortality rates have prompted the development of VRE infection control protocols that have been implemented, studied, and critiqued for their relative effectiveness. Further, the development of cost-effective rapid diagnostic testing may limit the spread of unidentified VRE infections in healthcare settings. Current medical therapies for VRE infections are unfortunately limited and resistance to linezolid has been reported but is not widespread as of yet, adding credence to the cries of the WHO, CDC, and others for new antimicrobial therapies. Ongoing research into the human microbiome has provided two potentially promising alternative therapy choices, primary and secondary rebiosis. Though both are still in development, the potential benefits of replacing a defective microbiome with a healthy and balanced population of normal non-pathogenic microbes highlight how increased understanding of our own being may provide the key to discovering how to control and contain vancomycin-resistant Enterococci without the risk of additional antimicrobial resistance. The evidence we have reviewed here suggests the necessity of a multifactorial approach to VRE: combining surveillance of at-risk populations, infection control measures, rapid diagnostics, and safe therapies

Conflict of Interest Statement & Funding

The Authors declare that there is no conflict of interest. This work was supported by start-up grants from ICOM and WVSOM to M.D.

Author Contributions

Conceptualization: JWB, MDD; Data Curation: JWB; Formal Analysis: JWB; Funding Acquisition: MDD; Investigation: JWB; Methodology: JWB, MDD; Project Administration: MDD; Resources: JWB, MDD; Software: JWB, MDD; Supervision: MDD; Validation: MDD; Visualization: JWB; Writing – Original Draft Preparation: JWB, MDD; Writing – Review & Editing: JWB, MDD.

Acknowledgments

None.

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John W. Beale, 1 Fourth-year Medical Student, Idaho College of Osteopathic Medicine, Meridian, Idaho, United States.

Marina Durward-Diioia, 2 Ph.D., West Virginia School of Osteopathic Medicine, Lewisburg, West Virginia, United States.

About the Author: John W. Beale is currently a fourth-year medical student at the Idaho College of Osteopathic Medicine in Meridian, ID, USA, a four-year program.

Correspondence: John W. Beale, Address: 1401 E Central Dr, Meridian, ID, 83642, United States. Email: mdiioia@osteo.wvsom.edu

Editor: Francisco J. Bonilla-Escobar Student Editors: Duha Shellah & Leah Komer Copyeditor: Madeleine J. Cox Proofreader: Kiera Liblik Layout Editor: Cesare Mercalli Process: Peer-reviewed

Cite as: Beale, JW, Durward-Diioia, M. Clinical Considerations in the Approach to Vancomycin-Resistant Enterococci: A Narrative Review. Int J Med Stud. 2022 Apr-Jun;10(2):202-9.

Copyright © 2022 John W. Beale, Marina Durward-Diioia

This work is licensed under a Creative Commons Attribution 4.0 International License.

International Journal of Medical Students, VOLUME 10, NUMBER 2, April 2022