Enterococci have been recognized as potential human pathogens for more than a century, but only in recent years have these organisms acquired prominence as causes of nosocomial infections. The ability of enterococci to survive and/or disseminate in the hospital environment and to acquire antibiotic resistance determinants makes the treatment of some enterococcal infections in critically ill patients a difficult challenge. Enterococci were first mentioned in the French literature in 1899; the “entérocoque” was found in the human gastrointestinal tract and was noted to have the potential to produce significant disease. Indeed, the first pathologic description of an enterococcal infection dates to the same year. A clinical isolate recovered from a patient who died as a consequence of endocarditis was initially designated Micrococcus zymogenes, was later named Streptococcusfaecalis subspecies zymogenes, and would now be classified as Enterococcus faecalis. The ability of this isolate to cause severe disease in both rabbits and mice illustrated its potential lethality in the appropriate settings.
Enterococci are gram-positive organisms. In clinical specimens, they are usually observed as single cells, diplococci, or short chains (Fig. 137-1), although long chains are noted with some strains. Enterococci were originally classified as streptococci because organisms of the two genera share many morphologic and phenotypic characteristics, including a generally negative catalase reaction. Only DNA hybridization studies and then 16S rRNA sequencing clearly demonstrated that enterococci should be grouped as a genus distinct from the streptococci. Nonetheless, unlike the majority of streptococci, enterococci hydrolyze esculin in the presence of 40% bile salts and grow at high salt concentrations (6.5%) and at high temperatures (46°C). Enterococci are usually reported by the clinical laboratory to be nonhemolytic on the basis of their inability to lyse the ovine or bovine red blood cells (RBCs) commonly used in agar plates; however, some strains of E. faecalis do lyse RBCs from humans, horses, and rabbits. The majority of clinically relevant enterococcal species hydrolyze pyrrolidonyl-β-naphthylamide (PYR); this characteristic is helpful in differentiating enterococci from organisms of the Streptococcus bovis group (S. gallolyticus subsp. gallolyticus, S. gallolyticus subsp. pasteurianus, and S. infantarius subsp. coli) and from Leuconostoc species. Although at least 18 species of enterococci have been isolated from human infections, the overwhelming majority of cases are caused by two species: E. faecalis and E. faecium. Less frequently isolated species include E. gallinarum, E. durans, E. hirae, and E. avium.
Gram's stain of cultured blood from a patient with enterococcal bacteremia. Oval gram-positive bacterial cells are arranged as diplococci and short chains. (Courtesy of Audrey Wanger, PhD.)
Enterococci are normal inhabitants of the large bowel of human adults, although they usually make up <1% of the culturable intestinal microflora. In the healthy human gastrointestinal tract, enterococci are typically symbionts that coexist with other bacteria; in fact, the utility of certain enterococcal strains as probiotics in the treatment of diarrhea suggests their possible role in maintaining the homeostatic equilibrium of the human bowel. Enterococci are intrinsically resistant to a variety of commonly used antibiotics; thus one of the most important factors that disrupts this equilibrium and promotes increased gastrointestinal colonization by enterococci is the administration of antimicrobial agents. In particular, antibiotics that are excreted in the bile and have broad-spectrum activity (i.e., certain cephalosporins that target anaerobes and gram-negative bacteria) are associated with the recovery of higher numbers of enterococci from feces. This increased colonization appears to be due not only to simple enterococcal replacement in a given “biological niche” after the eradication of competing components of the flora but also (at least in mice) to the suppression—upon reduction of the gram-negative microflora by antibiotics—of important immunologic signals (e.g., the lectin RegIIIγ) that help keep enterococcal counts low in the normal human bowel. Several studies have shown that higher levels of gastrointestinal colonization are a critical factor in the pathogenesis of enterococcal infections. However, the mechanisms by which enterococci successfully colonize the bowel and gain access to the lymphatics and/or bloodstream remain incompletely understood.
Several vertebrate, worm, and insect models have been developed to study the role of possible pathogenic determinants of both E. faecalis and E. faecium. Three main groups of factors may increase the ability of enterococci to colonize the gastrointestinal tract and/or cause disease. The first group, enterococcal secreted factors, are molecules released outside the bacterial cell that contribute to the process of infection; the best-studied of these molecules include enterococcal hemolysin/cytolysin and two enterococcal proteases (gelatinase and serine protease). Enterococcal cytolysin is a heterodimeric toxin produced by some strains of E. faecalis that is capable of lysing human RBCs as well as polymorphonuclear leukocytes and macrophages. The E. faecalis proteases GelE and SprE are thought to mediate virulence by several mechanisms, including the degradation of host tissues and the modification of critical components of the immune system. Mutants lacking the genes corresponding to these proteins are highly attenuated in experimental peritonitis, endocarditis, and endophthalmitis.
The second group of virulence factors, enterococcal surface components (e.g., adhesins), are thought to contribute to bacterial attachment to extracellular matrix molecules in the human host. Several molecules on the surface of enterococci have been characterized and shown to play a role in the pathogenesis of enterococcal infections. Among the characterized adhesins is aggregation substance of E. faecalis, which mediates the attachment of cells to each other, thereby facilitating conjugative plasmid exchange. Several lines of evidence indicate that aggregation substance and enterococcal cytolysin act synergistically to increase the virulence potential of E. faecalis strains in experimental endocarditis. The E. faecalis surface protein (adhesin of collagen of E. faecalis, or Ace) and its E. faecium homologue (Acm) are microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) involved in bacterial attachment to host proteins such as collagen, fibronectin, and fibrinogen; both Ace and Acm are important in the pathogenesis of experimental endocarditis. Pili of gram-positive bacteria have been shown to be important mediators of attachment to and invasion of host tissues and are considered potential targets for immunotherapy. Both E. faecalis and E. faecium have surface pili. Mutants of E. faecalis lacking pili are attenuated in both experimental endocarditis and urinary tract infections (UTIs). Other surface proteins that share structural homology with MSCRAMMs and appear to play a role in enterococcal attachment to the host and in virulence include the E. faecalis enterococcal surface protein (Esp) and its E. faecium homologue (Espfm), the second collagen adhesin of E. faecium (Scm), the surface proteins of E. faecium (Fms), SgrA (which binds to components of the basal lamina), and EcbA (which binds to collagen type V). Additional surface components apparently associated with pathogenicity include polysaccharides, which are thought to interfere with phagocytosis of the organism by host immune cells. Some E. faecalis strains appear to harbor at least three distinct classes of capsular polysaccharide; some of these polysaccharides play a role in virulence and are potential targets for immunotherapy.
The third group of virulence factors have not been well characterized: the E. faecalis stress protein Gls24, which has been associated with enterococcal resistance to bile salts and appears to be ...