1 Population analysis profiles for a Isolates with MIC values of 2 mg/L (Microscan) and 1 mg/L (Broth Microdilution, BMD). b Isolates with MIC values of 2 mg/L (Microscan/BMD). c Isolates with MIC values of 4 mg/L (Microscan) and 2 mg/L (BMD). d Isolates with MIC values of 4 mg/L (Microscan/BMD) Molecular characterization of the

twelve strains is displayed in Table 1. The activity of Selleck AZD2281 daptomycin against 2 selected pairs (4 isolates total) in the in vitro PK/PD model of SEVs with the same MIC values but differing daptomycin PAPs is shown in Fig. 2a–d. A daptomycin dose response relationship was observed for all four strains. The daptomycin 6 mg/kg regimen initially had sustained bactericidal CHIR-99021 order activity in the first 24 h against isolates with a left-shift population profile (R6003 and R6219) (Fig. 2a). In contrast, isolates with the

same MIC value and a right-shift profile (R6253 and R6255) displayed bactericidal activity at 8 h but regrowth at 24 h. The two left-shift isolates (R6003 and R6219) began to gradually regrow after 24 h eventually losing their bactericidal activity. In contrast, the two right-shift isolates displayed substantial killing and a more rapid regrowth with the 24 h dose before leveling off. The regimen of daptomycin 6 mg/kg maintained bactericidal activity AZD8931 against R6255 at 96 h. No mutants were recovered. Observed pharmacokinetic parameters were 94.23–109 mg/L and 6.78–7.42 h. Fig. 2 a Activity of daptomycin 6 mg/kg against daptomycin left-shift strains R6003 & R6219. b Activity of daptomycin 10 mg/kg against daptomycin left-shift strains R6003 and R6219.

c Activity of daptomycin 6 mg/kg against daptomycin right-shift strains R6253 & R6255. d Activity of daptomycin 10 mg/kg against daptomycin see more right-shift strains R6253 and R6255. DAP 6 Daptomycin 6 mg/kg/day, DAP 10 daptomycin 10 mg/kg/day, GC growth control The isolates recovered at 96 h from the simulations of daptomycin 6 mg/kg did not have any change in MIC value from the initial isolates. However, examination of the population profiles revealed a rightward shift and increase in AUC. The AUC increased from 0 to 96 h for both R6003 (22.4 vs. 27.3) and R6219 (20.68 vs. 26.15). For isolates with an initial profile with a right shift, the AUC increase from 0 to 96 h for R6253 (23.66 vs. 27.31) and for R6253 (26.85 vs. 27.43) was less pronounced. All initial isolates evaluated in the in vitro PK/PD SEV model (R6003, R6219, R6253, and R6255), and derivatives recovered after 96 h of exposure to a simulated regimen of daptomycin 6 mg/kg/day, underwent sequence analyses of mprF.