Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile-targeting antibacterial, compared to vancomycin.
Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile-targeting antibacterial, compared to vancomycin.
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DOI：
10.1371/journal.pone.0199810
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Snydman DR
中科院分区：
文献类型：
--
作者：
Thorpe CM;Kane AV;Chang J;Tai A;Vickers RJ;Snydman DR
瑞地尼拉唑是一种正在开发的新型靶向抗菌药物，用于治疗艰难梭菌感染 (CDI) 和预防复发，最近的一项 2 期研究表明，在主要疗效指标、持续临床反应 (SCR) 方面优于万古霉素，其优越性主要是由于 30 天内 CDI 复发率显着降低。瑞地尼唑的耐受性与万古霉素相当。目前的巢式队列研究比较了二期研究参与者治疗期间和治疗后，瑞地尼拉唑和万古霉素对粪便微生物群的影响。使用 qPCR 和高通量测序对多个时间点（基线 [第 1 天]、第 5 天、治疗结束 [EOT；第 10 天]、第 25 天、研究结束 [EOS；第 40 天] 和 CDI 复发时）收集的参与者粪便评估微生物群的变化。 qPCR 分析显示，在万古霉素治疗的 EOT 中，拟杆菌、球状梭菌、薄梭菌和普雷沃氏菌组显着减少，而接受雷迪唑唑治疗的参与者在 EOT 时的薄梭菌组水平略有下降，到第 25 天时水平恢复。万古霉素治疗的参与者中肠杆菌科细菌显着增加，并且这种增加在 EOT 后持续存在。在 EOT 时，两种抗生素的 α 多样性均下降，但瑞地尼唑的程度明显较小 (p <0.0001)。 Beta 多样性分析显示，万古霉素从基线到 EOT 的加权 Unifrac 距离显着增大。从分类学角度来看，瑞地尼唑的影响明显较小，厚壁菌门类群的相对丰度略有减少。与万古霉素相比，瑞地尼唑组的微生物群组成更快恢复到基线。万古霉素治疗导致微生物组范围内的变化，厚壁菌门、拟杆菌门、放线菌门的相对丰度显着降低，变形菌门的丰度显着增加。这些发现表明，与万古霉素相比，瑞地尼拉唑对微生物群的破坏性明显较小，这可能有助于减少 2 期研究中观察到的 CDI 复发。
Ridinilazole, a novel targeted antibacterial being developed for the treatment of C. difficile infection (CDI) and prevention of recurrence, was shown in a recent Phase 2 study to be superior to vancomycin with regard to the primary efficacy measure, sustained clinical response (SCR), with the superiority being driven primarily by marked reductions in the rates of CDI recurrence within 30 days. Tolerability of ridinilazole was comparable to that of vancomycin. The current nested cohort study compared the effects of ridinilazole and vancomycin on fecal microbiota during and after treatment among participants in the Phase 2 study. Changes in the microbiota were assessed using qPCR and high-throughput sequencing on participants’ stools collected at multiple time-points (baseline [Day 1], Day 5, end-of-treatment [EOT; Day 10], Day 25, end-of-study [EOS; Day 40], and at CDI recurrence). qPCR analyses showed profound losses of Bacteroides, C. coccoides, C. leptum, and Prevotella groups at EOT with vancomycin treatment, while ridinilazole-treated participants had a modest decrease in C. leptum group levels at EOT, with levels recovering by Day 25. Vancomycin-treated participants had a significant increase in the Enterobacteriaceae group, with this increase persisting beyond EOT. At EOT, alpha diversity decreased with both antibiotics, though to a significantly lesser extent with ridinilazole (p <0.0001). Beta diversity analysis showed a significantly larger weighted Unifrac distance from baseline-to-EOT with vancomycin. Taxonomically, ridinilazole had a markedly narrower impact, with modest reductions in relative abundance in Firmicutes taxa. Microbiota composition returned to baseline sooner with ridinilazole than with vancomycin. Vancomycin treatment resulted in microbiome-wide changes, with significant reductions in relative abundances of Firmicutes, Bacteroidetes, Actinobacteria, and a profound increase in abundance of Proteobacteria. These findings demonstrate that ridinilazole is significantly less disruptive to microbiota than vancomycin, which may contribute to the reduced CDI recurrence observed in the Phase 2 study.
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DOI：
10.1038/nri3535
发表时间：
2013-11
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/ismej.2012.8
发表时间：
2012-08
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.9
作者：
Louie, Thomas J.;Emery, Judy;Mah, Manuel
通讯作者：
Mah, Manuel
影响因子：
5.8
作者：
Gu, Silan;Chen, Yunbo;Li, Lanjuan
通讯作者：
Li, Lanjuan