C. diff. Research and Development Community; November/December 2014

laboratorybeakers3

Here’s the latest from the

C. diff. Research Community:

 

 
Animal models of Clostridium difficile infection (CDI) are essential for the better understanding of this disease. The historical animal model for studying CDI was the Golden Syrian hamster, and the murine model for CDI has been described by Dr. Ciaran Kelly’s group in 2008. In this current study, Koenigsknecht et al. have used the antibiotic-treated murine model to describe in great detail the early dynamics of CDI in mice from ingestion and colonization, germination and colitis.
http://iai.asm.org/content/early/2014/12/16/IAI.02768-14.long

 

The role of host microbiota in the development of C. diff. infection (CDI) has been studied in great detail. In the current issue of Cell Host Microbe, two studies have looked at two different pathogens and their interactions with host microbiota.

In the first study, by Ferreyra et al, the authors show that following antibiotic treatment                 C. difficile uses host microbiota produced succinate to colonize the gut and cause diarrhea.

In the second study, Curtis et al. show that Bacteroides thetaiotaomicron enhances the expression of virulence genes of enterohemorrhagic Escherichia coli (EHEC) leading to EHEC colonization. B.thetaiotaomicron leads to increased levels of succinate which in turn is sensed by transcription factor Cra, which then leads to the enhanced expression of virulence genes in EHEC.

Although commensal microbiota often prevents pathogens from gaining a foothold in the gut by providing colonization resistance, gut pathogen have evolved in ways so that they can exploit metabolites produced by commnesals to use for their own advantage.

http://ac.els-cdn.com/S1931312814004193/1-s2.0-S1931312814004193-main.pdf?_tid=6ff3eb40-8f91-11e4-b02e-00000aab0f6b&acdnat=1419881733_d475a24b936814a7c30ed35c6ffeffb7
http://ac.els-cdn.com/S1931312814004211/1-s2.0-S1931312814004211-main.pdf?_tid=b1cc6540-8f93-11e4-a2e9-00000aab0f6b&acdnat=1419882703_c8e4440013034567236b8bf782708315

 

Several journal articles in December have been published looking at the efficacy of LFF571 in treateing CDI. LFF571 is a novel semi-synthetic thiopeptide antibacterial that inhibits bacterial protein synthesis.

The first article includes results from a Phase 2 exploratory study where the authors compared the safety and efficacy (based on a non-inferiority analysis) of LFF571 to vancomycin in adults with primary episodes or first recurrences of moderate C. difficile. Results show that based on protocol-specified definition, rates of clinical cure for LFF571 were non-inferior to those of vancomycin, recurrences were lower for LFF571 and LFF571 was generally safe and well-tolerated.
The second article compares the pharmacokinetics (PK) of LFF571 and vancomycin in patients with  a C. difficile infection (CDI) as part of an early efficacy study. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The highest LFF571 serum concentration was 41.7 ng/mL. This is in comparison to peak vancomycin serum level at 2.73 μg/mL. CDI patients had high fecal concentrations and low serum levels of LFF571 which is similar to healthy volunteers.
http://aac.asm.org/content/early/2014/12/16/AAC.04251-14.long
http://aac.asm.org/content/early/2014/12/16/AAC.04252-14.long

 

 

Chandrabali Ghose-Paul,MS,PhD, Chairperson of C. diff. Research and Development