早期、高剂量利奈唑胺对万古霉素中介耐药肠球菌的药效学研究，该肠球菌具有升高的 MIC 值和预先存在的基因突变。
Pharmacodynamics of early, high-dose linezolid against vancomycin-resistant enterococci with elevated MICs and pre-existing genetic mutations.
机构信息
Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
出版信息
J Antimicrob Chemother. 2012 Sep;67(9):2182-90. doi: 10.1093/jac/dks201. Epub 2012 Jun 8.
OBJECTIVES
Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial killing and suppression of resistance against VRE strains with defined genetic mutations.
METHODS
Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis. A hollow fibre infection model (HFIM) simulated traditional and front-loaded human therapeutic linezolid regimens against VRE strains at 10(6) cfu/mL over 240 h. Translational modelling was performed using S-ADAPT and NONMEM.
RESULTS
Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity with >2 log(10) cfu/mL killing for all strains with an MIC of 4 and minimal activity against VRE with MICs of 16 and 64 mg/L. Against one strain with no resistant alleles (MIC 4 mg/L), 600 mg of linezolid every 12 h achieved maximal reductions of 0.96 log(10) cfu/mL over 240 h in the HFIM, whereas front-loaded 1200 mg of linezolid every 12 h ×10 doses or 2400 mg of linezolid every 12 h ×10 doses followed by 600 mg of linezolid every 12 h provided significantly improved killing with maximal reductions of 3.02 and 3.46 log(10) cfu/mL. Front-loaded regimens suppressed amplification of resistant subpopulations against VRE strains with no resistant alleles (MIC 4 mg/L) and postponed regrowth of resistant subpopulations against a VRE with 3.2 resistant alleles (MIC 4 mg/L). Modelling yielded excellent population fits (r = 0.934) and identified the number of sensitive alleles as a critical covariate.
CONCLUSIONS
Early, high-dose regimens of linezolid provided promising killing against selected susceptible strains and may be clinically beneficial if early bactericidal activity is necessary.
目的
耐万古霉素肠球菌（VRE）已成为全球医疗中心重要的医院获得性病原体。本研究评估了利奈唑胺的负荷剂量对具有明确遗传突变的 VRE 菌株的杀菌作用和耐药抑制的影响。
方法
在 48 小时的时间杀伤实验中，评估了利奈唑胺对 8 株耐万古霉素粪肠球菌的浓度效应关系。中空纤维感染模型（HFIM）模拟了传统和负荷剂量的利奈唑胺治疗方案，针对 10（6）cfu/mL 的 VRE 菌株，治疗时间为 240 小时。使用 S-ADAPT 和 NONMEM 进行转化模型。
结果
在 48 小时的时间杀伤实验中，利奈唑胺对所有 MIC 为 4 的菌株均表现出抑菌活性，可使细菌减少超过 2 个对数级（10 cfu/mL），而对 MIC 为 16 和 64 mg/L 的 VRE 菌株仅有最小的活性。对于没有耐药等位基因的一株菌株（MIC 为 4 mg/L），HFIM 中每 12 小时给予 600 mg 的利奈唑胺，可在 240 小时内使细菌减少 0.96 个对数级，但每 12 小时给予负荷剂量 1200 mg 的利奈唑胺×10 剂或每 12 小时给予负荷剂量 2400 mg 的利奈唑胺×10 剂，随后每 12 小时给予 600 mg 的利奈唑胺，可显著提高杀菌效果，使细菌减少 3.02 和 3.46 个对数级。负荷剂量方案抑制了对 MIC 为 4 mg/L 的无耐药等位基因的 VRE 菌株的耐药亚群的扩增，并推迟了对 MIC 为 4 mg/L 的具有 3.2 个耐药等位基因的 VRE 菌株的耐药亚群的再生长。模型拟合度良好（r=0.934），并确定敏感等位基因的数量是一个关键的协变量。
结论
早期给予高剂量的利奈唑胺方案对选定的敏感菌株具有有希望的杀菌作用，如果需要早期杀菌活性，这可能具有临床益处。
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