Characterizing vancomycin-resistant Enterococcus strains with various mechanisms of daptomycin resistance developed in an in vitro pharmacokinetic/pharmacodynamic model.
Characterizing vancomycin-resistant Enterococcus strains with various mechanisms of daptomycin resistance developed in an in vitro pharmacokinetic/pharmacodynamic model.
复制标题
表征在体外药代动力学/药效模型中开发的具有各种达托霉素耐药机制的万古霉素耐药肠球菌菌株。
DOI：
10.1128/aac.00084-11
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发表时间：
2011
影响因子：
4.9
通讯作者：
Rybak,MichaelJ
中科院分区：
文献类型：
--
作者：
Steed,MollyE;Vidaillac,Celine;Rose,WarrenE;Winterfield,Patricia;Kaatz,GlennW;Rybak,MichaelJ
在药代动力学/药效学(PK/PD)模型中对达托霉素(DAP)的两种方案进行了评估，并检测了恢复的突变株的表型特征变化。3株粪肠球菌(万古霉素耐药肠球菌ATCC 51559、VRE 12311和VRE SF 12047)用于7d、1隔室的体外PK/PD模型。模拟给药方案为DAP6 mg/kg/d(freCmax[fCmax]=7.9μg/ml，半衰期[t1/2]=8h)和DAP10 mg/kg/d(fCmax=13.17μg/ml，t1/2=8h)。每天在含有16μg/ml和50 mg/LCa~(2+)的米勒-辛顿琼脂上培养，以评估细胞对二氨基苯酚的抗性。对于每个菌株，然后评估具有最高DAP MIC的突变体的相对表面电荷、细胞壁厚度和DAP诱导的细胞膜去极化的变化。3株DAPMIC值均为4μg/ml。DAP 6 mg/kg/d和DAP 10 mg/kg/d对3种菌株均有剂量依赖性反应和再生长作用。从DAP6 mg和DAP10 mg方案中分别获得VRE ATCC 51559(MIC=12 8和μg/ml)和VRE 12311(MIC=2 5 6和32μg/ml)突变株。对于VRE SF 12047，从DAP6 mg模型中恢复了一个突变体(MIC=μg/ml)。与各自的亲本菌株相比，所有突变体的相对表面电荷都有所增加。与敏感品系相比，抗性突变体的细胞壁厚度增加了43%~58%(P<；0.0001)，膜去极化降低了53%~65%。具有DAP抗性的VRE表现出表面电荷增加，细胞壁厚度增加，DAP引起的去极化降低，这与先前在DAP敏感性降低的金黄色葡萄球菌中观察到的一致。有必要对抗DAP的VRE进行进一步的表征。
Two daptomycin (DAP) regimens were evaluated in a pharmacokinetic/pharmacodynamic (PK/PD) model, and the mutants recovered were examined for changes in phenotypic characteristics. Three Enterococcus faecium strains (vancomycin-resistant Enterococcus [VRE] ATCC 51559, VRE 12311, and VRE SF 12047) were utilized in a 7-day, 1-compartmentin vitroPK/PD model. The simulated dosing regimens were DAP at 6 mg/kg/day (freeCmax[fCmax] = 7.9 μg/ml, half-life [t1/2] = 8 h) and DAP at 10 mg/kg/day (fCmax= 13.17 μg/ml,t1/2= 8 h). Samples were plated daily on Mueller-Hinton agar containing DAP at 16 μg/ml and 50 mg/liter Ca2+to assess the emergence of DAP resistance. For each strain, the mutant with the highest DAP MIC was then evaluated for changes in relative surface charge, cell wall thickness, and cytoplasmic membrane depolarization induced by DAP. The initial DAP MICs were 4 μg/ml for all 3 strains. A dose-dependent response and regrowth were observed for DAP 6 mg/kg/day and DAP 10 mg/kg/day against all 3 strains. Mutants of VRE ATCC 51559 (MIC = 128 and 64 μg/ml) and VRE 12311 (MIC = 256 and 32 μg/ml) were recovered from the DAP 6 mg and DAP 10 mg regimen, respectively. For VRE SF 12047, a mutant (MIC = 64 μg/ml) was recovered from the DAP 6 mg model. All mutants displayed an increase in relative surface charge compared to those of their respective parent strains. The DAP-resistant mutants displayed a 43 to 58% increase in cell wall thickness (P< 0.0001), while DAP membrane depolarization decreased by 53 to 65% compared to that of the susceptible strains. VRE with DAP resistance displayed increased surface charge, increased cell wall thickness, and decreased depolarization induced by DAP, consistent with previous observations in Staphylococcus aureus with reduced DAP susceptibility. Further characterization of DAP-resistant VRE is warranted.