Friday, August 01, 2014

A quickie on C difficile


   I have previously posted on C difficile infections  (Link) as an important point of research especially in the context of noscomial infections. There is currently a lot of research devoted in trying to find a good defence. Faecal transplantation has been an attractive candidate. However, development of drugs and the best probiotic combination is also in research.

Fig 1: Action of CRS3123. Source
    Several antibiotics such as fidaxomicin, REP3123, oritavancin, NVB302 and nitazoxanide have been suggested as good candidates. CRS3123 formerly known as REP3123 is a product of Crestone Inc. methionyl tRNA synthetase or MetRS is an important part of biosynthesis pathway in C difficile. Previously successful chemicals were shown to attack the MetRS and shown to be of potential benefit. CRS3123 is expected to be a narrow range antibiotic that actively attacks C difficile, sparing normal intestinal flora. NIAID has announced the progression to next phase of clinical trials.

     A more recent aspect of combating bacterial infections is "Phage therapy", which I have already discussed in detail in this blog (Link). In 2013, Dr Dr. Martha Clokie, from the University of Leicester's Department of Infection, Immunity and Infection, isolated and characterised 26 different phages. Considering that C difficile strains are much less variant a phage cocktail is expected to work really well. The media named these phages as "Clokie's Phages". The phages were licensed by AmpliPhi Biosciences.

      Now a study has published successful use of DNA vaccine strategy for this nasty pathogen. The researchers developed a vaccine using the RBD (receptor binding domain), of TcdA and Tcd representing the key players in pathogenesis. The mice and non-human primate models were administered the vaccine intramuscularly, through electroporation. Significant antibody production was observed in blood and stool along with RBD-specific antibody-secreting cells. The challenged mice also showed strong protection against clinically isolated strains too. Senior author Kutzler comments "While our research was conducted in animal models, the results are very translatable to the clinic. In some cases, patients who acquire C. difficile can develop serious complications including severe diarrhea, toxic megacolon, bowel perforation, multi-organ failure, and death. Once fully developed, our DNA vaccine could prevent the deadly effects of C. difficile infection when administered to hospital patients at risk of acquiring C difficile". Source
Johnson AP (2010). New antibiotics for selective treatment of gastrointestinal infection caused by Clostridium difficile. Expert opinion on therapeutic patents, 20 (10), 1389-99 PMID: 20698814

Hargreaves KR, & Clokie MR (2014). Clostridium difficile phages: still difficult? Frontiers in microbiology, 5 PMID: 24808893

Baliban SM, Michael A, Shammassian B, Mudakha S, Khan AS, Cocklin S, Zetner I, Latimer BP, Bouillaut L, Hunter M, Marx P, Sardesai NY, Welles SL, Jacobson JM, Weiner DB, & Kutzler MA (2014). An Optimized, Synthetic DNA Vaccine Encoding the Toxin A and Toxin B Receptor Binding Domains of Clostridium difficile Induces Protective Antibody Responses In Vivo. Infection and immunity PMID: 25024365

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