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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Daptomycin-oxacillin combinations in treatment of experimental endocarditis caused by daptomycin-nonsusceptible strains of methicillin-resistant Staphylococcus aureus with evolving oxacillin susceptibility (the 'seesaw effect').
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Daptomycin-oxacillin combinations in treatment of experimental endocarditis caused by daptomycin-nonsusceptible strains of methicillin-resistant Staphylococcus aureus with evolving oxacillin susceptibility (the 'seesaw effect').

机译：达托霉素-奥沙西林组合治疗由耐达西霉素的耐甲氧西林金黄色葡萄球菌菌株引起的实验性心内膜炎，并伴有不断增长的奥沙西林敏感性（“跷跷板效应”）。

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In vivo development of daptomycin resistance (DAPr) among Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA) strains, in conjunction with clinical treatment failures, has emerged as a major problem. This has raised the question of DAP-based combination regimens to enhance efficacy against such strains. We studied five recent DAP-susceptible (DAPs)/DAPr clinical MRSA strain pairs obtained from patients who failed DAP monotherapy regimens, as well as one DAPs/DAPr MRSA strain pair in which the resistant strain was generated by in vitro passage in DAP. Of note, we identified a DAP-oxacillin (OX) "seesaw" phenomenon in vitro in which development of DAPr was accompanied by a concomitant fall in OX resistance, as demonstrated by 3- to 4-fold decreases in the OX MIC, a susceptibility shift by population analyses, and enhanced early killing by OX in time-kill assays. In addition, the combination of DAP and OX exerted modest improvement in in vitro bactericidal effects. Using an experimental model of infective endocarditis and two DAPs/DAPr strain pairs, we demonstrated that (i) OX monotherapy was ineffective at clearing DAPr strains from any target tissue in this model (heart valve, kidneys, or spleen) and (ii) DAP-OX combination therapy was highly effective in DAPr strain clearances from these organs. The mechanism(s) of the seesaw effect remains to be defined but does not appear to involve excision of the staphylococcal cassette chromosome mec (SCCmec) that carries mecA.
机译：金黄色葡萄球菌菌株，特别是耐甲氧西林的金黄色葡萄球菌（MRSA）菌株中达托霉素抗性（DAPr）的体内发展，连同临床治疗失败，已成为一个主要问题。这就提出了基于DAP的联合方案以增强针对此类菌株的功效的问题。我们研究了从失败的DAP单药治疗方案的患者中获得的五种最近的DAP易感性（DAPs / DAPr）临床MRSA菌株对，以及一种通过在DAP中通过体外传代产生耐药菌株的DAPs​​ / DAPr MRSA菌株对。值得注意的是，我们在体外鉴定出DAP-奥沙西林（OX）的“跷跷板”现象，其中DAPr的发展伴随着OX抗性的下降，这通过OX MIC降低3至4倍来证实。通过群体分析改变，并在时间杀灭试验中增强了OX的早期杀灭作用。此外，DAP和OX的组合在体外杀菌作用方面有适度的改善。使用感染性心内膜炎和两个DAP / DAPr菌株对的实验模型，我们证明（i）OX单一疗法无法从该模型中的任何靶组织（心脏瓣膜，肾脏或脾脏）清除DAPr菌株，以及（ii）DAP -OX联合疗法在清除这些器官中的DAPr菌株方面非常有效。跷跷板效应的机制尚待确定，但似乎不涉及切除携带mecA的葡萄球菌盒式染色体mec（SCCmec）。

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