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...

Annually, medical device infections are associated with >250,000 catheter-associated bloodstream infections (CLABSI), with up to 25% mortality. Staphylococcus aureus, a primary pathogen in these infections, is capable of biofilm production, allowing organism persistence in harsh environments, offering antimicrobial protection. With increases in S. aureus isolates with reduced susceptibility to current agents, ceftaroline (CPT) offers a therapeutic alternative. Therefore, we evaluated whether CPT would have a role against biofilm-producing methicillin-resistant S. aureus (MRSA), including those with decreased susceptibilities to alternative agents. In this study, we investigated CPT activity alone or combined with daptomycin ( The Infectious Diseases Society of America has recognized several pathogens for which novel therapies are needed, including Staphylococcus aureus (1). Not only are rates of S. aureus infections increasing, but the frequency of methicillin resistance is as well, ultimately promoting vancomycin as a first-line therapy to combat these infections (2). This increased usage is a driving force of resistance, as S. aureus isolates are now demonstrating decreased susceptibility to vancomycin (3-5).In addition to increasing resistance rates and prevalence, S. aureus also has the propensity to produce bacterial biofilm, a serious concern in patients with prosthetic material, including intravenous catheters (6). Essentially, biofilm encapsulates the microorganism, creating an outer layer of glycocalyx, a layer of actively dividing cells, and a layer of stationary cells. Antimicrobials are often rendered ineffective, not only due to lack of penetration into the cellular component, but also because several agents, most notably ␤-lactams, are dependent upon active cellular division for activity. As such, stationary cells are inherently resistant to cell wall-active agents (7,8). Therefore, combination therapy is often employed (9).Combination therapy against MRSA-infected prostheses typically employs rifampin as the synergistic agent. However, potent in vitro synergy has been identified with the combination of ␤-lactam antibiotics plus either daptomycin or vancomycin (10, 11). Data evaluating either cefazolin or ceftaroline plus daptomycin, vancomycin, or rifampin against biofilm-producing MRSA have been described in time-kill methodologies, and these combinations may be effective, although pharmacokinetic/pharmacodynamic (PK/PD) modeling has not yet been performed (12). Therefore, our objective was to evaluate ceftaroline alone and in combination against biofilm-producing MRSA strains in an in vitro PK/PD model of bacterial biofilms. MATERIALS AND METHODSBacterial strains and culture media. Three methicillin-resistant and daptomycin-nonsusceptible S. aureus strains were evaluated in this study. These strains included a vancomycin-susceptible strain and an iso-

IntroductionOritavancin is a novel lipoglycopeptide approved for acute bacterial skin and skin structure infections. The pharmacokinetic profile and convenient one-time dosing make oritavancin an enticing option for other serious Gram-positive infections requiring prolonged treatment courses. Unfortunately, data for using oritavancin in these populations are limited.MethodsWe report ten cases of oritavancin use for invasive Gram-positive infections in our health system, and provide a review of the currently available literature regarding oritavancin therapy for invasive infections.ResultsAmong the ten patients who received oritavancin, the most common infection was methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia (n = 5, 50%). Other indications for oritavancin use included methicillin-resistant S. aureus (MRSA) bursitis (n = 1, 10%), group B streptococcal bacteremia with native tricuspid valve infective endocarditis (n = 1, 10%), coagulase-negative staphylococcal bacteremia (n = 1, 10%), MSSA deep tissue infection (n = 1, 10%), and enterococcal bacteremia (n = 1, 10%). Oritavancin was well tolerated, and 7/10 (70%) patients were successfully treated.ConclusionOritavancin is a potential option for patients with invasive Gram-positive infections. Further study is warranted.

Imipenem‐cilastatin‐relebactam (IMI‐REL) is a novel β‐lactam–β‐lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β‐lactamase inhibitor with the ability to inhibit a broad spectrum of β‐lactamases such as class A and class C β‐lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem‐resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI‐REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem‐resistant bacteria. In a phase III trial comparing IMI‐REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30‐minute infusion of imipenem 500 mg–cilastatin 500 mg–relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI‐REL represents another important step in the ongoing fight against multidrug‐resistant gram‐negative pathogens.