Correlation between Mutations in liaFSR of Enterococcus faecium and MIC of Daptomycin: Revisiting Daptomycin Breakpoints
Correlation between Mutations in liaFSR of Enterococcus faecium and MIC of Daptomycin: Revisiting Daptomycin Breakpoints
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DOI：
10.1128/aac.00509-12
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Arias, Cesar A.
中科院分区：
文献类型：
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作者：
Munita, Jose M.;Panesso, Diana;Arias, Cesar A.
liaFSR（一种控制细胞包膜应激反应的三元调控系统）的突变最近与肠球菌中达托霉素（DAP）耐药性的出现有关。我们之前的工作表明，liaF突变使万古霉素耐药粪肠球菌菌株的DAP MIC从1μg/ml增加至3μg/ml（DAP断点为4μg/ml），这表明liaFSR系统中的突变可能是DAP耐药发展的关键初始事件。假设 DAP MIC 在 3 至 4 μg/ml 之间的临床肠球菌分离株可能含有 liaFSR 突变，我们研究了 38 个屎肠球菌血流分离株，其中 8 个通过 Mueller-Hinton 琼脂中的 Etest 检测其 DAP MIC 在 3 至 4 μg/ml 之间。有趣的是，这 8 个分离株中的 6 个预测了 LiaFSR 系统中的氨基酸变化。此外，我们之前表明，在 6 株 DAP 抗性屎肠球菌分离株（MIC > 4 μg/ml）中，有 5 株在 liaFSR 中存在突变。相比之下，通过使用脑心浸液琼脂 (BHIA)（一种更好支持肠球菌生长的培养基）的 Etest，没有分离出 16 株屎肠球菌分离株的 DAP MIC = 16 mu g/ml。我们的研究结果提供了上易感范围内的 DAP MIC 与 liaFSR 系统突变之间的密切关联。 BHIA 的伴随药敏试验可能有助于鉴定这些屎肠球菌第一步突变体。我们的结果还表明，当前的屎肠球菌 DAP 断点可能需要重新评估。
Mutations in liaFSR, a three-component regulatory system controlling cell-envelope stress response, were recently linked with the emergence of daptomycin (DAP) resistance in enterococci. Our previous work showed that a liaF mutation increased the DAP MIC of a vancomycin-resistant Enterococcus faecalis strain from 1 to 3 mu g/ml (the DAP breakpoint is 4 mu g/ml), suggesting that mutations in the liaFSR system could be a pivotal initial event in the development of DAP resistance. With the hypothesis that clinical enterococcal isolates with DAP MICs between 3 and 4 mu g/ml might harbor mutations in liaFSR, we studied 38 Enterococcus faecium bloodstream isolates, of which 8 had DAP MICs between 3 and 4 mu g/ml by Etest in Mueller-Hinton agar. Interestingly, 6 of these 8 isolates had predicted amino acid changes in the LiaFSR system. Moreover, we previously showed that among 6 DAP-resistant E. faecium isolates (MICs of >4 mu g/ml), 5 had mutations in liaFSR. In contrast, none of 16 E. faecium isolates with a DAP MIC of = 16 mu g/ml by Etest using brain heart infusion agar (BHIA), a medium that better supports enterococcal growth. Our findings provide a strong association between DAP MICs within the upper susceptibility range and mutations in the liaFSR system. Concomitant susceptibility testing on BHIA may be useful for identifying these E. faecium first-step mutants. Our results also suggest that the current DAP breakpoint for E. faecium may need to be reevaluated.