New Developments with Vancomycin‐Resistant Enterococci:<i>E. faecium</i>—Friend or Foe?

The occurrence of vancomycin-resistant enterococci (VRE) continues to be an escalating problem throughout the world [1, 2]. The risk of VRE infection is greatest for elderly persons and severely ill patients who have been treated with extensive courses of antibiotics [2] and who are maintained in facilities (intensive care units [ICU] or transplant wards) where the incidence of VRE is high. In this regard, a recent study by Streit et al [1] determined that ∼28% of all enterococci isolated from ICU patients in Canada and the United States were vancomycin resistant The first reports of VRE appeared in the mid-1980s and included patients from both Europe and the United States [3]. More recent analyses of the specific enterococci involved in this resistance reveal that the predominant form of VRE identified in ICUs was E. faecium (almost 70%), whereas E. faecalis was less common (∼10%) [4]. Furthermore, it appears that the incidence of vancomycin-resistant E. faecium is on the rise [5]. As the percentage of positive isolates of vancomycin-resistant E. faecium becomes more prevalent, it is clear that, although our overall understanding of the pathogenesis of E. faecium is very limited [6], knowledge on this topic is becoming a high priority The spread of E. faecium occurs primarily though hospital nosocomial infections. E. faecium is commonly associated with ICU patients who are receiving antibiotic treatment [7], and most strains are resistant to multiple classes of antibiotics [8]. In addition, as the incidence of VRE increases, so does the rate of coinfection with methicillin-resistant Staphylococcus aureus (MRSA) [9, 10]. This coinfection profile appears to have led to the transfer of vancomycin resistance to MRSA. Although the occurrence is relatively small, several multidrug-resistant S. aureus strains have been isolated [11–13 ]. Recently, patients with heteroresistant vancomycin-intermediate S. aureus (hVISA) infection were evaluated and compared with MRSA-infected patients [13], and it was found that the hVISA-infected patients exhibited an extended duration of bacteremia with higher rates of complications [14]. Although few of the patients diagnosed with hVISA infection survived after receiving various treatments, most of these patients had additional health issues that likely contributed to their deaths In this issue of the Journal, Leenderste et al [15] describe provocative data suggesting that a concurrent E. faecium VRE load arising from the intestine can confine polymicrobial peritonitis and attenuate the inflammatory response in a murine model system. The authors evaluated the effect of this clinically relevant organism associated with nosocomial infections by using a hospital isolate that belongs to a genetic subpopulation that is widely found in hospitals—namely, VRE strain E155 Although the mice used in the present study experienced VRE colonization from gastric inoculation, the mice presented with no infections at other sites until cecal ligation and puncture (CLP). Interestingly, the control mice and VRE mice had similar levels of polymicrobial outgrowth in the lungs, peritoneal fluid, blood, and liver at 24 h; however, the VRE mice had reduced aerobic bacterial growth at 48 h. In addition, the reduction at 48 h in the levels of the CXC chemokines, cytokine-induced neutrophil chemoattractant, macrophage inflammatory protein 2, and lipopolysaccharide-induced CXC chemokine were all significantly reduced compared to the controls. Furthermore, levels of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein 1 and the plasma acute phase proteins (C3 and SAA) were also reduced in the presence of VRE. Consistent with the idea that the VRE reduced the bacterial load and inflammatory response from the CLP was the observation that 2 of the 9 control mice died within 48 h after CLP, compared with no fatalities in the treated VRE group. The mitigation of the extent of the infection was further demonstrated by the fact that the mice with VRE had deceased colonization at multiple organ sites It is important to note that, in the model used by Leenderste et al [15], the mice were administered VRE through a gastric tube to colonize the intestinal tract directly. The route of the infection arose from CLP, which allowed for a continuous source of E. faecium and which is proposed to be analogous to a common route of infection in human hospitalized patients. Thus, the authors attempted to mimic the clinical presentation wherein patients are colonized with hospital strains of E. faecium and experience subsequent intestinal damage or leakage. Nonetheless, because the animals used in this study were healthy prior to CLP, they may not fully represent the scenario for patients experiencing VRE infection, who are generally older and present with significant comorbidity. Accordingly, it would be valuable for future studies to assess whether the influence of E. faecium on CLP-induced infection is similar to the present observations when older mice with various comorbidities are examined The present report demonstrates that, when peritonitis is induced via CLP, the presence of the VRE E. faecium attenuates the observed polymicrobial peritonitis and inflammatory response, compared with that measured in the control mice. These observations are noteworthy given that previous reports have suggested that VRE infection is detrimental to the host—that is, experiments performed with rats have revealed that VRE introduced by intraperitoneal injection leads to a rapid decrease in VRE with no apparent attenuation of the inflammatory response [16]. However, these earlier reports differ with regard to the route of infection (intraperitoneal injection vs CLP), the animal model tested (rats vs mice), and in the species of Enterococcus that was used (E. faecalis vs E. faecium). With respect to the latter point, it is noted that there are many differences in virulence factors expressed by various E. faecium and E. faecalis strains, and as such, the generality of the ability of diverse species of Enterococcus to facilitate bacterial clearance and attenuate host inflammatory responses following intestinal perforation is unclear In terms of the cell types that may underlie bacterial clearance in this model, it is probable that neutrophils and macrophages play a key role [17, 18]. In this regard, the authors indicated that there were no detectable differences in the amount of neutrophils present in the peritoneum following VRE colonization and CLP. Earlier studies have demonstrated that the presence of neutrophils is necessary for the clearance of E. faecium in mice subjected to an intraperitoneal injection of E. faecium and that when mice are neutropenic, the extent of the infection is unchecked [17] On the basis of previous data from Leendertse et al [18] and from other laboratories, it is likely that the capacity of VRE to attenuate polymicrobial peritonitis and host inflammatory responses is related to the route of infection. The approach of precolonizing the intestine with E. faecium prior to CLP provides a continuous source of E. faecium throughout the course of the study, as opposed to direct peritoneal injections that will be cleared relatively rapidly, and as such, it may more closely reflect various clinical conditions. Interestingly, the protective effects of VRE were only seen when the intestine was VRE colonized prior to CLP and were not observed when CLP was followed by intraperitoneal injection of VRE [18], perhaps because of the differences in VRE clearance and the bacterial load provided by these 2 different approaches. In a similar vein, these same authors have reported previously [18] that healthy mice rapidly clear intraperitoneally injected VRE, and that the acute phase reactants for VRE-colonized mice after CLP is similar to that seen in mice injected with VRE alone. The response to CLP in the absence of E. faecium however, is greater and more sustained. It is possible that the reduced inflammatory response in VRE-infected mice occurs because of the reduced polymicrobial loads in multiple body sites that occurs in this case and that limits the stimuli provided to immune cells, such as macrophages and neutrophils Considering that E. faecium is a well-identified pathogen and is associated with diseases such as endocarditis, it is important to reflect on its possible immunoregulatory or immunosuppressive role. In this regard, certain strains of E. faecium are known to have probiotic actions that can counter gastrointestinal inflammation and reduce epithelial cell generated cytokines, which in part may be mediated through the release of bacteriocins [19–22 ]. It is intriguing to consider that a “pathogenic” strain of enterococci, which shows extensive resistance to the most widely available antibiotics and that is present in a large percentage of the hospitalized population, may be able to mitigate infections due to other common pathogenic bacteria. Although these results were obtained in a murine model system, it will be of great interest to identify the mechanisms that are responsible for the capacity of E. faecium to modulate polymicrobial peritonitis and host inflammatory responses with an eye towards extrapolating these findings to a clinical setting

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