Abstract
Clostridium difficile infection (CDI) is a major cause of infectious diarrhea. Conventional antibiotics are not universally effective for all ribotypes, and can trigger dysbiosis, resistance and recurrent infection. Thus, novel therapeutics are needed to replace and/or supplement the current antibiotics. Here, we describe the activity of an optimised 4-phage cocktail to clear cultures of a clinical ribotype 014/020 strain in fermentation vessels spiked with combined fecal slurries from four healthy volunteers. After 5 h, we observed ~6-log reductions in C. difficile abundance in the prophylaxis regimen and complete C. difficile eradication after 24 h following prophylactic or remedial regimens. Viability assays revealed that commensal enterococci, bifidobacteria, lactobacilli, total anaerobes, and enterobacteria were not affected by either regimens, but a ~2-log increase in the enterobacteria, lactobacilli, and total anaerobe abundance was seen in the phage-only-treated vessel compared to other treatments. The impact of the phage treatments on components of the microbiota was further assayed using metagenomic analysis. Together, our data supports the therapeutic application of our optimised phage cocktail to treat CDI. Also, the increase in specific commensals observed in the phage-treated control could prevent further colonisation of C. difficile, and thus provide protection from infection being able to establish.
Highlights
Antimicrobial resistance is a global health threat to clinical practice and public health [1,2,3,4]
Prior to mixing the slurries together, we determined the microbiome composition from the individual donors by fecal slurries together, we determined the microbiome composition from the individual donors resuspending the fecal matter in the minimal medium and enumerating the bacteria present on by resuspending the fecal matter in the minimal medium and enumerating the bacteria present selective agar media targeting five commonly occurring gut commensals [44,51]
After establishing the efficacy of the phage cocktail to clear C. difficile in the batch fermentation model, we investigated their impact on five common major bacterial groups in the human gut
Summary
Antimicrobial resistance is a global health threat to clinical practice and public health [1,2,3,4]. Over the last decade, there has been an increasing interest in the isolation, characterisation and development of phages for therapeutic use in humans, animals, and plants [9,10,11,12,13]. This revived interest is mainly driven by problems associated with ineffective antibiotics. These natural bacterial predators have the potential to provide a safe and suitable supplement, or replacement for antibiotics because of their specificity and amplification at the site of infection [14,15,16,17]. Phage products have been developed for medical use, and some can be found as over-the-counter medicines and are used as decontamination agents in food industries [10,18,19,20]
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