Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo.
Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo.
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DOI：
10.1128/aac.01774-15
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发表时间：
2016-02
影响因子：
4.9
通讯作者：
Clokie MR
中科院分区：
文献类型：
--
作者：
Nale JY;Spencer J;Hargreaves KR;Buckley AM;Trzepiński P;Douce GR;Clokie MR
抗生素治疗引起的微生物群失调与艰难梭菌感染(CDI)的易感性和复发有关。噬菌体疗法提供了靶向特异性和原位剂量放大，但很少有研究关注其在CDI治疗中的应用。这主要反映了针对这种病原体的严格毒力噬菌体的缺乏。虽然人们普遍认为温带噬菌体由于其转导潜力而不适合用于治疗目的，但对7个艰难梭菌噬菌体的分析证实，通过应用多种噬菌体类型可以减少这种影响。在这里，对代表21个主要流行核型和临床严重核型的80株病毒进行了6种肌型病毒和1种梭状病毒的宿主范围分析。噬菌体具有互补的覆盖率，分别裂解了18个核糖体类型和62个被测菌株。核糖体076、014/020和027菌株的单噬菌体处理显示出最初的细菌负荷减少，随后出现了抗噬菌体菌落。然而，这些菌落仍然容易受到一种无关噬菌体的感染。相反，特定的噬菌体组合导致艰难梭菌在体外完全溶解，并防止出现抗性/溶原性克隆。在仓鼠模型中，口服优化的噬菌体组合导致艰难梭菌在感染后36小时的定植减少。有趣的是，此时从肠道中回收了游离噬菌体。在疾病的挑战模型中，与未治疗的动物相比，噬菌体治疗将症状出现的时间推迟了33小时。这些数据证明了噬菌体组合治疗CDI的治疗潜力。
The microbiome dysbiosis caused by antibiotic treatment has been associated with both susceptibility to and relapse of Clostridium difficile infection (CDI). Bacteriophage (phage) therapy offers target specificity and dose amplification in situ, but few studies have focused on its use in CDI treatment. This mainly reflects the lack of strictly virulent phages that target this pathogen. While it is widely accepted that temperate phages are unsuitable for therapeutic purposes due to their transduction potential, analysis of seven C. difficile phages confirmed that this impact could be curtailed by the application of multiple phage types. Here, host range analysis of six myoviruses and one siphovirus was conducted on 80 strains representing 21 major epidemic and clinically severe ribotypes. The phages had complementary coverage, lysing 18 and 62 of the ribotypes and strains tested, respectively. Single-phage treatments of ribotype 076, 014/020, and 027 strains showed an initial reduction in the bacterial load followed by the emergence of phage-resistant colonies. However, these colonies remained susceptible to infection with an unrelated phage. In contrast, specific phage combinations caused the complete lysis of C. difficile in vitro and prevented the appearance of resistant/lysogenic clones. Using a hamster model, the oral delivery of optimized phage combinations resulted in reduced C. difficile colonization at 36 h postinfection. Interestingly, free phages were recovered from the bowel at this time. In a challenge model of the disease, phage treatment delayed the onset of symptoms by 33 h compared to the time of onset of symptoms in untreated animals. These data demonstrate the therapeutic potential of phage combinations to treat CDI.