Tag Archives: C. diff research and development

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

 

Clostridium difficile Research and Development Community; October 2014

Here’s the latest from the Clostridium difficile research community:
The role of hosts gut microbiome plays a critical role in the development of Clostridium difficile infection. Different antibiotic usage leads to the loss of specific bacterial taxa that can lead to different levels of susceptibility to C. difficile. In this study, Buffie et al. report that          Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium, is associated with resistance to CDI which is dependent on secondary bile salts. The major take-home message is that microbiome research can help in identifying potential risks following specific antibiotic treatment and also treatment options such as probiotics.
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13828.html

In the following study, the authors evaluate the safety and rate of resolution of diarrhea following oral FMT with frozen capsules given to patient volunteers with recurrent CDI. Twenty patients received 15 capsules on 2 consecutive days and these patients were followed for 6 months. No SAEs were reported. Diarrhea was resolved in 14 patients following 1 FMT. 4 out of 6 nonresponders resolved after a second FMT, with an overall 90% resolution rate. Larger studies are needed to confirm the current findings.
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2014.13875

 

The use of synthetic polymers as mimics of host-defense antibacterial peptides have been studied by the McBride lab. In vitro analysis of Nylon 3 copolymers against C.difficile shows that peptide LL37 is capable of blocking vegetative cell-growth and inhibiting spore outgrowth and is effective against ribotype 027 and 012 strains, in contrast to vancomycin and nisin. These easy to produce synthetic polymers could be used as a treatment for a CDI.
http://pubs.acs.org/doi/abs/10.1021/ja506798e

 

The following study looks at the role of IL22 and CD160 in the mucosal inflammatory immune response to a CDI. The authors report that in C. difficile-infected mice treated with anti-IL22, anti-CD160 or a combination of the two, STAT3 phosphorylation was significantly reduced compared to infected mice not receieving these antibodies. These treated mice also had reduced influx in neutrophils. These data show that IL22 and CD160 are responsible for a proinflammatory host mucosal response against during CDI in mice.
http://onlinelibrary.wiley.com/doi/10.1111/imm.12414/pdf

 
And lastly, Norway rats (Rattus norvegicus) also known as New York City rats have been found to be widely infected with many common human pathogens such as atypical enteropathogenic Escherichia coli, Clostridium difficile, and Salmonella enterica, as well as infectious agents that have been associated with undifferentiated febrile illnesses, including Bartonella spp., Streptobacillus moniliformis, Leptospira interrogans, and Seoul hantavirus and viruses such as sapoviruses, cardioviruses, kobuviruses, parechoviruses, rotaviruses, and hepaciviruses. Pest control is doubly important in urban settings where these rodents are carriers of such zoonotic diseases and live in close proximity to humans.
http://www.ncbi.nlm.nih.gov/pubmed/25316698

 

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

Rebiotix, Inc. announces results of Phase 2 Punch(TM) CD Study for Treatment of Recurrent C. difficile infections

In The News*

Rebiotix Inc. announced today that results of the Phase 2 PUNCH™ CD Study found that the overall efficacy of RBX2660 in the treatment of recurrent Clostridium difficile infection was 87.1%. The study also found that administration of RBX2660 was well-tolerated and demonstrated satisfactory safety in the 60-day interim analysis.

The results of a 60-day interim analysis of the PUNCH CD study, the first prospective multi-center study of a next generation, standardized, commercially prepared microbiota restoration therapy for recurrent CDI were presented at IDWeek 2014.

Clostridium difficile infection, characterized by severe diarrhea, is a leading healthcare acquired infection and is linked to 14,000 deaths in the U.S. annually. The U.S. Centers for Disease Control recently termed CDI an urgent public health threat. Recurrent CDI is especially challenging to treat, and there are no indicated drugs for the condition.

The primary objective of the PUNCH CD study was product-related adverse events (AEs). A secondary objective was CDI resolution.  A total of 40 patients at 11 centers in the U.S. were enrolled in the study. All of the patients had multi-recurrent CDI and had failed standard therapy.  The PUNCH CD patient population was primarily elderly and female with multiple co-morbidities, thus reflecting the real-world population of patients with recurrent CDI who present with unmet medical needs.

A total of 34 patients received at least one dose of RBX 2660 administered via enema.  A second dose was permitted if CDI recurred

“Years of experience indicate microbiota therapy is highly efficacious for treatment of recurrent CDI. However, adequate data have been lacking on safety,” said Erik R. Dubberke, MD, MSPH, a PUNCH CD investigator and Director, Section of Transplant Infectious Diseases at Washington University School of Medicine, St. Louis, MO. “The phase 2 study indicates RBX2660 efficacy is consistent with past studies, and it is safe and easy to administer.”

The study represents a significant step forward in Rebiotix’s efforts to develop a durable cure for recurrent CDI that is debilitating to patients. RBX2660 will undergo further study in a Phase 2B randomized controlled trial scheduled to begin later this fall.

About Rebiotix Inc.
Rebiotix Inc. is a results-oriented biotechnology company revolutionizing the treatment of challenging gastrointestinal diseases by harnessing the power of the human microbiome. The Roseville, Minn. based company is pioneering Microbiota Restoration Therapy to restore healthy gut flora through the transplantation of live microorganisms. For more information, visit  http://www.rebiotix.com

Rebiotix is the only company that has a microbiota therapy with FDA orphan-drug designation for treatment of recurrent C. diff. infection. Orphan drugs are those intended for the safe and effective treatment, diagnosis or prevention of rare diseases and/or disorders that affect fewer than 200,000 people in the US. The FDA has also designated RBX2660 as a Fast Track product for the treatment of recurrent C. diff. infection. This designation underscores the urgent need for a new therapy to treat patients who have this debilitating and potentially life-threatening disease and means that FDA will act to expedite the development and review of the application for the product, as appropriate.

 

To read the article in its entirety click on the following link:

https://ca.finance.yahoo.com/news/study-shows-rebiotix-microbiota-based-135200811.html

Clostridium difficile Research and Development Community – September 2014

labblueimiage

Here is the latest from the                              Clostridium difficile research community:

The role of host factors especially those involved in the intestinal inflammatory response and pathogenesis of against Clostridium difficile is not well understood. Trindade et all looked at the role of leukotrienes in modulating host susceptibility to CDI in C57BL/6 mice. Leukotrienes are proinflammatory lipid mediators which are not involved in the pathogenesis of CDI.
http://www.sciencedirect.com/science/article/pii/S1075996414001279

 

Scientists from Dr. Rupnik’s group in Slovenia describe the sequence diversity of 16S-23S rRNA intergenic spacer region of 43 C difficile strains representing different PCR ribotypes. Her groups suggests that homologous recombination as a possible mechanism responsible for the evolution of 16S-23S rRNA intergenic spacer region. Diversity in sequence length, the presence or absence of different sequence modules; tRNAAla genes and different combinations of spacers of different lengths (33 bp, 53 bp or 20 bp) and 9 bp direct repeats separating the spacers could be used to describe 22 different structural groups.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0106545

 

The use of the bacterial second messenger cyclic di-GMP (c-di-GMP) as an adjuvant to stimulate inflammation by initiating innate immune cell recruitment and triggering the release of pro-inflammatory cytokines and chemokines was studied in the context of a C.difficile toxin expressed from an adenovirus vaccine. Although co-expression of the cyclic di-GMP via an Ad5 vector expressing diguanylate cyclase lead to modest imcrease in T cell responses, antibody titers were not boosted.

http://cvi.asm.org/cgi/pmidlookup?view=long&pmid=25230938

 

Lipotechoic acids (LTA) are novel targets for vaccination against C.difficile. LTA is expressed on spores as well as vegetative cells. In this study, the authors report on the isolation fo 5 LTAs from C. difficile as a microheterogenous mixture, differing in size and composition, structure–activity relationship studies impossible. The authors describe the synthesis of these LTAs and their functions.
http://onlinelibrary.wiley.com/doi/10.1002/chem.201404336/abstract;jsessionid=9C01075014FEF3357A300E57738049EA.f02t04

 

The microbiome of the infant gut is established very early following birth. In this study the authors report on the resistome of the infant gut consists of aminoglycoside and β-lactam resistance reservoir even in the absence of pathogens that could provide the needed evolutionary pressure. The resistome of the infant gut is also established very early in the life of the infant, probably at birth.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0108016

 

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

 

C Diff Foundation Welcomes Dr. Simon Cutting, MS, PhD

welcome1We are pleased to welcome                              Dr. Simon Cutting, , from the School of Biological Sciences at the Royal Holloway University of London  to the  C Diff Foundation’s

Research and Development Committee and  Research Community.

Professor Simon M. Cutting is a bacterial geneticist with over 25 years of experience with Bacillus since graduating from Oxford University with a D. Phil in 1986. His D.Phil was on understanding the genetic control of spore formation in Bacillus subtilis. After spending 7 years in the renowned laboratory of Professor Richard Losick at Harvard University Biological Laboratories (USA) he spent 3 years as an Assistant Professor at the University of Pennsylvania Medical School in Philadelphia.
He returned to the UK in 1996 and since then has worked on developing bacterial spores as novel oral vaccines at the Royal Holloway, University of London. The Cutting lab has developed a number of prototype oral vaccines and is now entering a ‘first in man’ phase 1/IIa clinical trial of a prototype oral vaccine to Clostridium difficile (see www.cdvax.org).
His work on Bacillus probiotics provides another area of his research interests and he was the first to address the fundamental mechanisms that might enable these bacteria to promote potential health benefit (SporeGen.com)