used for GRE endocarditis in both E. faecalis and E. faecium, both with and without additional agents. To date, it has not been shown that combination therapy is more efficacious than monotherapy in this setting. Because linezolid is not bactericidal, treatment of GRE endocarditis with linezolid remains controver- sial.23 Quinupristin-dalfopristin can be efficacious against E. faecium, but should not be used to treat E. faecalis due to the intrinsic presence of lsa-mediated resistance (described above). When using quinupristin-dalfopristin for treatment of severe or complicated GRE infections, combination therapy may be necessary although the optimal choice and dose of adjunct antibiotic has yet to be determined. Several studies have compared linezolid to quinupristin-dalfopristin. In a small, single-center study, Chong et al.137 found increased resistance and increased number of days of bacteremia in patients treated with quinupristin-dalfopristin. Several other studies also reported more resistance to quinupristin-dalfopristin than linezolid,56,138 suggest- ing that of the two linezolid may be superior for GRE treatment. Use of daptomycin for GRE infections, particularly endocard- itis, is appealing because of its bactericidal activity against enterococci.104 While monotherapy may be adequate in many GRE infections, daptomycin failure has been reported.106,139 Arias et al.139 reported subsequent response to the combination of daptomycin/gentamicin/ampicillin after failing daptomycin monotherapy, which may be explained by a synergistic effect of the triple therapy. Daptomycin synergy has been described in vitro with ampicillin, cephalosporins, imipenem, rifampin and gentamicin.140-143 As with quinupristin-dalfopristin, there may be a role for adjunct antibiotics to achieve a synergistic effect, although appropriate agents and dosing regimens have not been adequately evaluated in humans. Tigecycline has also been used off-label for treatment of GRE. Cai et al.115 performed a meta-analysis of randomized trials to evaluate the use of tigecycline for GRE infections. While efficacy of treatment was no different for tigecycline monotherapy than other empirical regimens, there were significantly more adverse events and a non-significant trend toward higher mortality. As such, tigecycline monotherapy should not be considered as first line for treatment of GRE infections. Tigecycline demonstrates in vitro synergism with a number of other agents, including rifampin and daptomycin, although these combinations have not been evaluated beyond small case series in humans.144 Future Directions Over the years enterococci have demonstrated the potential to harbor and transfer resistance genes and as such have become an important clinical pathogen. A better understanding of resistance mechanisms to daptomycin and tigecycline is needed and will aid in the prediction and prevention of epidemiologic spread. Several new drugs are emerging as potential options for GRE treatment. Ceftaroline has been shown to be more efficacious than linezolid in animals and may play a larger role in the future.145 Additionally, arbekacin, which is not currently available in the United States, has demonstrated synergistic killing in combina- tion with penicillins even in the presence of high-level gentamicin and streptomycin resistance.146 A number of antibiotic combina- tions, including those mentioned in the management section, have shown in vitro synergistic activity and are promising as potential treatment modalities for complicated GRE infections, but must first be evaluated more rigorously in humans. The novel glycopeptide oritavancin is currently under investigation and shows promise in treating GRE infections. In addition, non- antimicrobial pharmacotherapy targeted at specific virulence factors (such as anti-adhesions) may play a preventative or therapeutic role in the management of enterococcal infections. Future directions of research must focus on development of new antimicrobial agents. Finally, efforts must continue to prevent development of antibiotic resistance and spread in the enterococci through infection control and antibiotic stewardship programs. 1. 2. 3. 4. 5. References Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev 1990; 3:46-65; PMID:2404568 Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, et al, National Healthcare Safety Network Team, Participating National Healthcare Safety Network Facilities. NHSN annual update: antimicrobial-resistant pathogens associated with healthcare-associated infec- tions: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. 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How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol 2010; 8:423-35; PMID:20440275; http:// dx.doi.org/10.1038/nrmicro2333 www.landesbioscience.com Virulence 429