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...

IntroductionDespite studies examining daptomycin non-susceptible (DNS) Staphylococcus aureus, examination of the stability and population profiles is limited. The objective was to evaluate the stability, population profiles, and daptomycin activity against DNS isolates.MethodsThe stability of 12 consecutive clinical DNS strains was evaluated by minimum inhibitory concentration (MICs) and population analysis profiles before and after 5 days of serial passage. Two pairs of DNS S. aureus having the same daptomycin MIC but different daptomycin population profiles were evaluated via an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations for 96 h against daptomycin 6 and 10 mg/kg/day. The sequence of mprF was determined for these isolates before and after 96 h of daptomycin exposure in the in vitro PK/PD model.ResultsDaptomycin MIC values were 2–4 mg/L (via Microscan) for the 12 clinical isolates; 9 were confirmed DNS and 3 were within 1 tube dilution of Microscan (daptomycin MIC 1 mg/L). All were stable to serial passage. There was variation in the isolates susceptibility to daptomycin on population analysis (daptomycin population AUC 14.01–26.85). The killing patterns of daptomycin 6 and 10 mg/kg/day differed between isolates with a left-shift and right-shift population profile to daptomycin. Two strains developed additional mprF mutations during daptomycin exposure in the in vitro PK/PD model resulting in P314L, L826F, S337L and a novel Q326Stop mutation.ConclusionsThe collection of DNS isolates was stable and displayed variation in susceptibility to daptomycin on population profile. Further research examining this clinical relevance is warranted.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-013-0021-7) contains supplementary material, which is available to authorized users.