The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted.

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus (VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti-VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including b-lactams and fosfomycin, and the promising results from in vitro, animal studies, and clinical experience in the treatment of VRE faecium will be discussed.

Dalbavancin is a lipoglycopeptide antibiotic recently approved by the United States Food and Drug Administration (FDA) for acute bacterial skin and skin structure infections (ABSSSIs). It is active against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), and minimum inhibitory concentrations (MICs) are consistently <0.125 µg/ml, much lower than most other anti-MRSA agents. Dalbavancin possesses an extended half-life of over 1 week, allowing an initial dose of 1000 mg followed by 500 mg 1 week later to complete a course of therapy for ABSSSI. It is approximately 95% protein bound and is widely distributed throughout the body, achieving concentrations similar to plasma levels in numerous tissues. Against MRSA, dalbavancin is 4–8 times more potent than vancomycin in vitro, and limited data suggest it possesses activity against MRSA with reduced susceptibility to vancomycin such as hVISA and VISA. Dalbavancin also possesses in vitro activity against streptococci and enterococci, although activity against vancomycin-resistant enterococci is lacking. In phase 3 ABSSSI studies, dalbavancin demonstrated similar activity to vancomycin and provides a more convenient dosing regimen. Limited phase 2 data suggest dalbavancin also possesses activity in catheter-related bloodstream infections. Potential further therapeutic uses include conditions that require long-term treatment such as osteomyelitis and infective endocarditis, although data are currently lacking. The extended half-life of dalbavancin, along with its in vitro activity against gram-positive organisms with reduced susceptibility to other anti-MRSA antibiotics, suggest it could have an exciting clinical role going forward.

Tedizolid MICs demonstrate activity against isolates with decreased susceptibility to alternative agents, including linezolid. Tedizolid may be a viable treatment option in clinical situations with MDR Gram-positive pathogens.

Enterococcus faecalis and Enterococcus faecium are frequently resistant to vancomycin and ␤-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate ␤-lactam synergy with daptomycin (DAP) against resistant enterococci. One E. faecalis strain (R6981) and two E. faecium strains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h, in vitro models were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 g/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P < 0.001 and log 10 CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P < 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P < 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted. Enterococcus faecalis and Enterococcus faecium together account for 12% of hospital-acquired infections in the United States (1). Often, enterococcal infections are caused by multidrug-resistant strains. For example, 0.4 to 5.2% and 70 to 92.6% of E. faecalis and E. faecium strains are resistant to ampicillin, respectively, and vancomycin resistance is present in up to 12.5% of E. faecalis and 79.7% of E. faecium (2-4). Vancomycin-resistant enterococci (VRE) are associated with increased mortality and complicated infections, such as infective endocarditis (5). Treatment of VRE infections can prove problematic, as available treatment options are potentially limited by static activity and/or platelet suppression with long-term use (6-8). Daptomycin (DAP) is a bactericidal lipopeptide often used against resistant enterococci (9). Mechanistically, it binds with calcium to form a cationic moiety that disrupts membrane potential to confer its antimicrobial effects, similar to endogenous, cationic antimicrobial peptides (10, 11). DAP is frequently dosed at 6 mg/kg body weight daily, although recent clinical and in vitro data suggest improved efficacy at higher doses (7,(12)(13)(14). DAP retains excellent in vitro activity against E. faecalis and E. faecium, with MIC 50/90 values of 1/2 and 2/4 g/ml, respectively (15). Reports of DAP-nonsuscept...