An orally administered drug prevents selection for antibiotic-resistant bacteria in the gut during daptomycin therapy.
An orally administered drug prevents selection for antibiotic-resistant bacteria in the gut during daptomycin therapy.
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DOI：
10.1093/emph/eoac035
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发表时间：
2022
影响因子：
3.7
通讯作者：
Read, Andrew F.
中科院分区：
文献类型：
--
作者：
Morley, Valerie J.;Sim, Derek G.;Penkevich, Aline;Woods, Robert J.;Read, Andrew F.
以前，我们在小鼠模型中证明了口服考来烯胺可防止达托霉素治疗期间胃肠道（GI）中耐达托霉素屎肠球菌的富集。考来烯胺在肠道中与达托霉素结合，这消除了达托霉素的选择压力，从而防止耐药克隆的富集。在这里，我们调查了两个开放的问题，与这种方法：（i）考来烯胺可以防止丰富的不同达托霉素突变出现在肠道从头？和（ii）考来烯胺给药的时机如何影响其抑制耐药性的能力？GI E小鼠。屎肠球菌分别用达托霉素加或不加考来烯胺处理，E.从粪便中培养屎菌以测量达托霉素敏感性的变化。克隆的一个子集进行测序，以研究达托霉素耐药性的基因组基础。考来烯胺阻止了达托霉素治疗小鼠中从头出现的多种耐药突变的富集。全基因组测序显示，耐药性通过多种遗传途径出现，大多数候选耐药突变在clsA基因中观察到。此外，我们观察到考来烯胺在达托霉素首次给药前开始给药时最有效。然而，在第一次达托霉素剂量后开始考来烯胺治疗可降低耐药大肠杆菌的频率。与完全不使用考来烯胺相比，考来烯胺阻止了肠E.屎肠球菌种群，它是一个很有前途的工具，用于管理传播的达托霉素耐药E。屎室
Previously, we showed proof-of-concept in a mouse model that oral administration of cholestyramine prevented enrichment of daptomycin-resistant Enterococcus faecium in the gastrointestinal (GI) tract during daptomycin therapy. Cholestyramine binds daptomycin in the gut, which removes daptomycin selection pressure and so prevents the enrichment of resistant clones. Here, we investigated two open questions related to this approach: (i) can cholestyramine prevent the enrichment of diverse daptomycin mutations emerging de novo in the gut? and (ii) how does the timing of cholestyramine administration impact its ability to suppress resistance? Mice with GI E. faecium were treated with daptomycin with or without cholestyramine, and E. faecium was cultured from feces to measure changes in daptomycin susceptibility. A subset of clones was sequenced to investigate the genomic basis of daptomycin resistance. Cholestyramine prevented the enrichment of diverse resistance mutations that emerged de novo in daptomycin-treated mice. Whole-genome sequencing revealed that resistance emerged through multiple genetic pathways, with most candidate resistance mutations observed in the clsA gene. In addition, we observed that cholestyramine was most effective when administration started prior to the first dose of daptomycin. However, beginning cholestyramine after the first daptomycin dose reduced the frequency of resistant E. faecium compared to not using cholestyramine at all. Cholestyramine prevented the enrichment of diverse daptomycin-resistance mutations in intestinal E. faecium populations during daptomycin treatment, and it is a promising tool for managing the transmission of daptomycin-resistant E. faecium.
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影响因子：
56.3
作者：
Kokai-Kun, John F.;Roberts, Tracey;Sliman, Joseph
通讯作者：
Sliman, Joseph
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
4.1
作者：
Lellek, Heinrich;Franke, Gefion C.;Rohde, Holger
通讯作者：
Rohde, Holger
影响因子：
4.9
作者：
Tarkkanen, Ann-Mari;Heinonen, Tuula;Nord, Carl Erik
通讯作者：
Nord, Carl Erik
影响因子：
4.9
作者：
WOODWORTH, JR;NYHART, EH;BLACK, HR
通讯作者：
BLACK, HR