Bacteriophage combinations significantly reduce clostridium difficile growth in vitro and proliferation in vivo.

Janet Y. Nale, Janice Spencer, Katherine R. Hargreaves, Anthony M. Buckley, Przemyslaw Trzepinski, Gillian R. Douce*, Martha R. J. Clokie

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)968-981
Number of pages14
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number2
Early online date7 Dec 2015
DOIs
Publication statusPublished - Feb 2016

Keywords

  • microbiome dysbiosis
  • antibiotics
  • CDI treatment
  • phage treatment

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