The clinical importance of the genus Enterococcus is directly related to its antibiotic resistance, which contributes to the risk of colonization and infection. The species of the greatest clinical importance are Enterococcus faecalis and Enterococcus faecium. Although the resistance characteristics of these two species differ in important ways, they can generally be categorized as intrinsic resistance, acquired resistance, and tolerance.
Relative to the streptococci, enterococci are intrinsically resistant to many commonly used antimicrobial agents. All enterococci exhibit decreased susceptibility to penicillin and ampicillin, as well as high-level resistance to most cephalosporins and all semi-synthetic penicillins, as the result of expression of low-affinity penicillin-binding proteins. For many strains, their level of resistance to ampicillin does not preclude the clinical use of this agent. In fact, ampicillin remains the treatment of choice for enterococcal infections that lack other mechanisms for high-level resistance. Enterococci are also intrinsically resistant to clindamycin, which is mediated by the product of the lsa gene, although the mechanism remains poorly defined. Trimethoprim-sulfamethoxazole appears to be active against enterococci when tested in vitro on folate-deficient media, but fails in animal models, presumably because enterococci can absorb folate from the environment (Zervos & Schaberg, 1985). Enterococci also have a native resistance to clinically achievable concentrations of aminoglycosides, which precludes their use as single agents. Although E. faecalis is naturally resistant to quinupristin-dalfopristin, this combination is highly active against E. faecium strains that lack specific resistance determinants.
Enterococci are tolerant to the (normally) bactericidal activity of cell-wall active agents, such as β–lactam antibiotics and vancomycin. Tolerance implies that the bacteria can be inhibited by clinically achievable concentrations of the antibiotic, but will only be killed by concentrations far in excess of the inhibitory concentration. Enterococcal tolerance can be overcome by combining cell-wall active agents with an aminoglycoside. The mechanism by which β–lactam-aminoglycoside combinations yield synergistic bactericidal activity remains a mystery, but in vitro data indicate that a higher concentration of aminoglycoside enters cells that are also treated with agents that inhibit cell wall synthesis, which suggests that the cell wall active agents promote uptake of the aminoglycoside (Mohr, Friedrich, Yankelev, & Lamp, 2009).
Tolerance is normally detected in vitro by plotting survival in kill curves, and can be observed for a number of antibiotic-bacteria combinations. In vitro tolerance has an important impact on therapy for treating enterococcal infections. The treatment of endocarditis requires bactericidal therapy, due to the inaccessibility of the bacteria within the cardiac vegetations to the mammalian immune system. Recognition of synergism between penicillin-streptomycin led to an improvement in cure rates for enterococcal endocarditis, from approximately 40% to greater than 80% (Jensen, Frimodt-Møller, & Aarestrup, 1999; Rice & Carias, 1998). Despite considerable effort, investigators have yet to find other combinations of antibiotics that are synergistically bactericidal against enterococci.
In addition to intrinsic resistance and tolerance, enterococci have been extraordinarily successful at rapidly acquiring resistance to virtually any antimicrobial agent put into clinical use. Introduction of chloramphenicol, erythromycin and tetracyclines was quickly followed by the emergence of resistance, in some cases reaching a prevalence that precluded their empirical use. While the occurrence of ampicillin resistance in E. faecalis has been quite rare, there is now widespread, high-level resistance to ampicillin among clinical E. faecium isolates. High-level aminoglycoside resistance, which negates the synergism between cell-wall active agents and aminoglycosides, has been recognized for several decades. Vancomycin resistance is widely prevalent in E. faecium, although it remains relatively rare in E. faecalis. In response to the growing problem of vancomycin resistance in enterococci, the pharmaceutical industry has developed a number of newer agents that have activity against vancomycin-resistant enterococci (VRE). However, none of these newly licensed agents (quinupristin-dalfopristin, linezolid, daptomycin, tigecycline) has been entirely free of resistance. Thus, the widespread resistance of enterococci has had a substantial impact on our use of both empirical and definitive antibiotics for the treatment of enterococcal infections, a situation that is likely to persist for the foreseeable future.