Evaluation of Standard- and High-Dose Daptomycin versus Linezolid against Vancomycin-Resistant Enterococcus Isolates in an In Vitro Pharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations

Abstract

Daptomycin MICs for enterococci are typically 1-to 2-fold higher than those for Staphylococcus aureus, and there is an imminent need to establish the optimal dose for appropriate treatment of enterococcal infections. We investigated the bactericidal activity of daptomycin at various dose exposures compared to that of linezolid against vancomycin-resistant enterococcus (VRE) in an in vitro pharmacokinetic/pharmacodynamic model utilizing simulated endocardial vegetations over 96 h. Daptomycin at doses of 6, 8, 10, and 12 mg/kg of body weight/day and linezolid at a dose of 600 mg every 12 h were evaluated against two clinical vancomycin-resistant Enterococcus faecium strains (EFm11499 and 09-184D1051), one of which was linezolid resistant (09-184D1051), and one clinical vancomycin-resistant Enterococcus faecalis strain (EFs11496). Daptomycin MICs were 4, 2, and 0.5 g/ml for EFm11499, 09-184D1051, and EFs11496, respectively. Bactericidal activity, defined as a >3 log 10 CFU/g reduction from the initial colony count, was demonstrated against all three isolates with all doses of daptomycin; however, bactericidal activity was not sustained with the daptomycin 6-and 8-mg/kg/day regimens. Linezolid was bacteriostatic against EFm11499 and displayed no appreciable activity against 09-184D1051 or EFs11496. Concentration-dependent killing was displayed with more sustained reduction in colony count (3.58 to 6.46 and 5.89 to 6.56 log 10 CFU/g) at 96 h for the simulated regimen of daptomycin at doses of 10 and 12 mg/kg/day, respectively (P < 0.012). No E. faecium mutants with reduced susceptibility were recovered at any dosage regimen; however, the E. faecalis strain developed reduced daptomycin susceptibility with daptomycin at 6, 8, and 10 but not at 12 mg/kg/day. Daptomycin displayed a dose-dependent response against three VRE isolates, with high-dose daptomycin producing sustained bactericidal activity. Further research is warranted. D aptomycin (DAP) is a lipopeptide antibiotic with concentration-dependent activity against Gram-positive bacteria that is currently approved for the treatment of staphylococcus bacteremia and right-sided endocarditis at a dose of 6 mg/kg of body weight/day (7). Daptomycin also displays in vitro activity against almost all Enterococcus spp., including those resistant to other antibiotics, such as vancomycin, linezolid (LZD), and quinupristindalfopristin (3, 22, 38). Daptomycin exhibits a lower potency against enterococci than that against staphylococci, demonstrating higher Clinical Laboratory and Standards Institute (CLSI) breakpoints (Յ4 g/ml versus Յ1 g/ml), MIC 50 values (1 to 2 g/ml versus 0.25 g/ml), and MIC 90 values (1 to 2 g/ml versus 0.5 g/ml) (11, 38). Based on in vivo neutropenic mice infection models, maximum concentration (C max )/MIC and area under the concentration-time curve (AUC)/MIC ratios are the best predictors for efficacy of daptomycin against infections caused by both Staphylococcus spp. and Enterococcus spp. (39) Additionally, in vitro pharmacokinetic/pharmacodynamic (P...

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Daptomycin is one of the only agents to offer bactericidal activity against VRE, but dose optimization remains a challenge (38). The general consensus among experts is that high doses of daptomycin (greater than 8 mg/kg/day) are necessary to achieve clinical success in the setting of serious enterococcal infections, and emerging data indicate that doses of Ն10 mg/kg/day are necessary for resistance prevention (20,(38)(39)(40)(41)(42). Resistance to daptomycin in VRE is an emerging threat that requires immediate attention to derive new therapeutic strategies, such as dose optimization and combination therapy, in order to preserve the clinical utility of this drug.…”

Activity of Daptomycin or Linezolid in Combination with Rifampin or Gentamicin against Biofilm-Forming Enterococcus faecalis or E. faecium in an In Vitro Pharmacodynamic Model Using Simulated Endocardial Vegetations and an In Vivo Survival Assay Using Galleria mellonella Larvae

“…As described previously, organism stocks containing approximately 10 10 CFU/ml were prepared by inoculating 5-ml test tubes of normal saline with colonies harvested from fresh overnight growth on TSA (20,22,24,31,32). Simulated endocardial vegetations (SEVs) containing 10 9 CFU/g were prepared by combining 0.05 ml of the organism suspension with 0.4 ml of human cryoprecipitated antihemolytic factor (AHF) from volunteer donors (Rhode Island Blood Bank, Providence, RI), 0.05 ml of an aprotinin suspension, and 0.025 ml of a platelet suspension (platelets mixed with normal saline; 250,000 to 500,000 platelets per clot) in 1.5-ml Eppendorf tubes.…”

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

“…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).…”