Evaluation of Daptomycin Non-Susceptible Staphylococcus aureus for Stability, Population Profiles, mprF Mutations, and Daptomycin Activity

摘要

Introduction Despite 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. Methods The 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. Results Daptomycin 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. Conclusions The collection of DNS isolates was stable and displayed variation in susceptibility to daptomycin on population profile. Further research examining this clinical relevance is warranted.