The rise of the Enterococcus: beyond vancomycin resistance

Abstract

The genus Enterococcus includes some of the most important nosocomial multidrug-resistant organisms, and these pathogens usually affect patients who are debilitated by other, concurrent illnesses and undergoing prolonged hospitalization. This Review discusses the factors involved in the changing epidemiology of enterococcal infections, with an emphasis on Enterococcus faecium as an emergent and challenging nosocomial problem. The effects of antibiotics on the gut microbiota and on colonization with vancomycin-resistant enterococci are highlighted, including how enterococci benefit from the antibiotic-mediated eradication of gram-negative members of the gut microbiota. Analyses of enterococcal genomes indicate that there are certain genetic lineages, including an E. faecium clade of ancient origin, with the ability to succeed in the hospital environment, and the possible virulence determinants that are found in these genetic lineages are discussed. Finally, we review the most important mechanisms of resistance to the antibiotics that are used to treat vancomycin-resistant enterococci.

Figure 1. The crucial role of the gastrointestinal tract in enterococcal infection and spread

Enterococci from the gastrointestinal tract can access the bloodstream by moving across the intestinal lining and passing through the liver. When in the bloodstream, these organisms can reach the heart and then potentially cause infective endocarditis. Faecal contamination of the environment (which can then be a source for colonization of other patients) and of the patient’s skin (the main source of infections of the urinary tract and of intravenous catheters) frequently occurs.

Figure 2. The effects of antibiotic administration on the gastrointestinal microbiota and the emergence of vancomycin-resistant enterococci

a. In the absence of antibiotics, mouse intestinal epithelial cells and Paneth cells produce the C-type lectin REGIIIγ, which has antimicrobial activity against Gram-positive bacteria (purple). The production of REGIIIγ is triggered by the presence of Gram-negative bacteria (pink); their MAMPs (microorganism-associated molecular patterns), such as the outer-membrane lipopolysaccharide (in the intestinal lumen) and flagellin (in subepithelial tissues), are recognized by pattern recognition receptors such as Toll-like receptor 4 (TLR4) and TLR5, respectively. b. Antibiotic administration leads to a reduction in the Gram-negative bacteria, which decreases REGIIIγ production by intestinal epithelial cells and Paneth cells. c. Enterococci take advantage of this reduction in REGIIIγ secretion to become the dominant members of the gut microbiota. IL-22, interleukin-22. Figure is modified, with permission, from REF. © (2010) American Society for Clinical Investigation.

Figure 3. Major routes of nosocomial transmission of vancomycin-resistant enterococci

The main risk for colonization and subsequent nosocomial infection with vancomycin-resistant enterococci (VRE) include close physical proximity to patients who are infected or colonized with VRE (or to the rooms of these patients); a long period of hospitalization; hospitalization in long-term facilities, surgical units or intensive-care units; the presence of a urinary catheter; and the administration of multiple courses of antibiotics. Many antibiotics increase the density of VRE organisms in the gastrointestinal tract, which, in turn, facilitates the spread of these organisms through faecal contamination of the hospital environment, including inanimate objects and the hands of health care workers and vistors. Enterococci can survive for long periods on environmental surfaces, including medical equipment, toilets, bed rails and doorknobs, and are tolerant to heat, chlorine and some alcohol preparations. IV, intravenous.

Figure 4. Main mechanisms of enterococcal antibiotic resistance

Enterococci are intrinsically resistant to several antibiotics and can acquire mutations and exogenous genes that confer resistance to additional drugs. The main mechanisms of antibiotic resistance are shown. In Enterococcus faecium, resistance to ampicillin occurs through the production of penicillin-binding protein 5 (PBP5), which has low affinity for β-lactams. Enterococci exhibit intrinsic low-level resistance to aminoglycosides such as streptomycin or gentamicin owing to low uptake of these highly polar molecules. High-level resistance results from the acquisition of aminoglycoside-modifying enzymes or, for streptomycin, can result from ribosomal mutations that result in altered target binding. Resistance to the glycopeptide vancomycin occurs through a well-characterized mechanism of reduced vancomycin-binding affinity, involving alterations in the peptidoglycan synthesis pathway. Resistance of Enterococcus spp. to the streptogramin quinupristin–dalfopristin (Q–D) involves several pathways, including drug modification (by virginiamycin acetyltransferase (Vat)), drug inactivation (through virginiamycin B lysase (Vgb)) and drug efflux (via the ATP-binding cassette protein macrolide streptogramin resistance protein (MsrC)). Resistance to the oxazolidinone linezolid is rare, but the most common pathway involves mutation in the 23S ribosomal RNA ribosome-binding site. Resistance of E. faecalis to the lipopetide daptomycin has been shown to involve altered interactions with the cell membrane and requires the membrane protein LiaF and enzymes involved in phospholipid metabolism, such as a member of the glycerophosphoryl diester phosphodiesterase family (GdpD) and cardiolipin synthase (Cls).