Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA.
Antimicrob Agents Chemother. 2012 Jun;56(6):3174-80. doi: 10.1128/AAC.06439-11. Epub 2012 Apr 2.
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 μg/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.
万古霉素耐药肠球菌（VRE）的 MIC 通常比金黄色葡萄球菌高 1-2 倍，因此迫切需要确定合适的剂量以治疗肠球菌感染。我们利用模拟心内膜赘生物的体外药代动力学/药效动力学模型，在 96 小时内研究了不同剂量达托霉素与利奈唑胺对万古霉素耐药粪肠球菌（EFm11499 和 09-184D1051）和万古霉素耐药屎肠球菌（EFs11496）的杀菌活性。达托霉素剂量为 6、8、10 和 12 mg/kg/体重/天，利奈唑胺剂量为 600 mg/12 h，用于评估两种临床分离的万古霉素耐药粪肠球菌（EFm11499 和 09-184D1051）和一种临床分离的万古霉素耐药屎肠球菌（EFs11496）。EFm11499、09-184D1051 和 EFs11496 的达托霉素 MIC 分别为 4、2 和 0.5μg/ml。所有剂量的达托霉素均对所有三种分离株表现出杀菌活性，定义为初始菌落计数减少≥3 log10 CFU/g；然而，达托霉素 6 和 8 mg/kg/天方案未能维持杀菌活性。利奈唑胺对 EFm11499 呈抑菌作用，对 09-184D1051 和 EFs11496 无明显活性。在模拟达托霉素剂量为 10 和 12 mg/kg/天的方案中，96 小时时，更多剂量的达托霉素表现出浓度依赖性杀菌作用，菌落计数减少更持久（3.58 至 6.46 和 5.89 至 6.56 log10 CFU/g）（P≤0.012）。在任何剂量方案中均未恢复到具有降低敏感性的粪肠球菌突变株；然而，在 6、8 和 10 mg/kg/天的达托霉素剂量下，屎肠球菌对达托霉素的敏感性降低，但在 12 mg/kg/天的剂量下则不然。达托霉素对三种 VRE 分离株呈剂量依赖性反应，高剂量达托霉素产生持续的杀菌活性。需要进一步的研究。
