Tag Archives: C. difficile research community

U.Va.’s Division of Infectious Diseases and International Health Could Lead To a New Treatment For C. diff. Infection (CDI)

 

Every year, about half a million patients are infected by Clostridium difficile, an otherwise harmless bacterium that can multiply out of control when the use of antibiotics upsets the balance of microorganisms in the gut. In 2011, about 15,000 deaths were directly attributable to the infection, according to a recent study by the federal Centers for Disease Control and Prevention (CDC).

Current probiotic treatments, which promote the growth of helpful bacteria, have been ineffective against the infection, also known as C. diff.

But work being done at U.Va.’s Division of Infectious Diseases and International Health could lead to a new treatment by the end of the calendar year, according to Dr. Bill Petri, chief of the division. That’s an unusually optimistic estimate in medical research, where scientific breakthroughs predate new treatments by several years.

“Some of these advanced probiotics are actually being tested today in the clinic for their role,” Petri said. “We’re actually participating in advanced clinical trials at U.Va.”

Immunologist Erica L. Buonomo was the driving force behind the new discovery, Petri said, which has to do with the role of white blood cells in protecting against C. diff.

Buonomo found that a particular type of white blood cells, called eosinophils, act as a barrier against the infection, which breaks down the lining of the gut. These eosinophils are recruited by a protein called IL-25. A serious C. diff infection kills eosinophils, allowing the bacteria to enter the gut.

The researchers found that gut bacteria stimulate the production of IL-25, so the right probiotic could help with the production of protective eosinophils.

“We identified a pathway in the immune response that reduces the severity of an infection,” Buonomo said. “When we activate this pathway, we find mice are a lot less sick.”

The discovery would be especially helpful for elderly patients, who are most at risk. It also could have larger implications in the world of microbiology.

Eosinophils are best known for their role in allergic reactions and asthma attacks, when a high number of eosinophils cause inflammation.

The function of these cells was not entirely clear before Buonomo’s discovery. She believes this knowledge could help doctors fight other types of gastrointestinal disorders, such as irritable bowel syndrome.

U.Va. is now working on a probiotic with a Boston-based firm called Seres Therapeutics 

The finished product will be tested in Charlottesville, Petri said.

To read the article in its entirety please click on the link below:

The United States Adopted Names Council (USAN) Of the American Medical Association Has Approved the Use Of “ribaxamase” For Synthetic Biologics’ SYN-004 For the Prevention Of C. difficile Infection (CDI)

The United States Adopted Names Council (USAN) of the American Medical Association has approved the use of “ribaxamase” (Rye-bak’-sa-mase) for Synthetic Biologics’ SYN-004.

Ribaxamase is the Company’s Phase 2 development candidate designed to protect the gut microbiome from the unintended effects of certain commonly used intravenous (IV) beta-lactam antibiotics for the prevention of C. difficile infection (CDI), antibiotic-associated diarrhea (AAD) and the emergence of antibiotic-resistant organisms.

Synthetic Biologics recently reported positive results from two Phase 2a clinical trials demonstrating a correlation of the 150 mg dose of ribaxamase with the degradation of residual IV ceftriaxone alone, and in the presence of the proton pump inhibitor (PPI), esomeprazole, to levels that were near or below detectable in the intestinal chyme of healthy participants with functioning ileostomies. A Phase 2b proof-of-concept, randomized, placebo-controlled clinical trial is currently underway to evaluate the ability of ribaxamase to prevent CDI and AAD in patients hospitalized with a lower respiratory tract infection and receiving IV ceftriaxone. An interim analysis of blinded data performed by an independent data monitoring committee is expected in summer of 2016.

“The approval of the generic name ribaxamase for SYN-004 by USAN is a defining milestone for Synthetic Biologics. Ribaxamase represents a newly created and innovative first-in-class drug designed to protect the naturally occurring gut microbiome from the unintended consequences of antibiotic use,” said Jeffrey Riley, President and Chief Executive Officer. “By degrading certain IV beta-lactam antibiotics before they reach the gastrointestinal (GI) tract, ribaxamase may not only prevent the onset of CDI and AAD, but has the potential to be an instrumental tool for preventing the emergence of antibiotic resistance in organisms which comprise the gut microbiome. We are excited for the continued clinical development of ribaxamase and look forward to sharing our progress including announcing results from our ongoing global Phase 2b proof-of-concept clinical trial.”

 

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

http://www.syntheticbiologics.com/news-media/press-releases/detail/215/synthetic-biologics-receives-usan-approval-for-generic-name

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

Clostridium difficile Research and Development Community – September 2014

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

 

Clostridium difficile Research and Development Community August 2014

Here’s the latest from the

Clostridium difficile Research Community:

 

 
Scientists at the University of Leicester have identified a rapid method of identifying C.difficile based on volatile organic compounds (VOCs) emitted by different C.difficile strains using Proton transfer reaction–time of flight–mass spectrometry (PTR–ToF–MS). Current methods of detecting and diagnosing CDI take anywhere between 2-5 days, leading to a delay in treatment that could have potential life threatening implications in some patients. PTR–ToF–MS analysis is capable of detecting VOCs of C.difficile metabolites in cultures within minutes and could potentially be used to detect VOCs in fecal samples from CDI patients.
http://download.springer.com/static/pdf/426/art%253A10.1007%252Fs11306-014-0692-4.pdf?auth66=1409931636_01f1fc8253ca189e0b0aba9b0e213055&ext=.pdf

 
CRISPR/Cas system is a form of bacterial adaptive immunity that helps control phage infections. Multiple CRISPR/Cas arrays have been identified in C.difficile. In this artciel by Hargreaves et al. the distribution and diversity of the CRISPRs have been studied and how these affect phage predation, evolution and pathogenecity.
http://www.ncbi.nlm.nih.gov/pubmed/25161187

 
C. difficile express flagella as a mechanism for motility, although the role of flagella in the pathogenecity of CDI is not clearly understood. Faulds-Pain et al have studied the post-translational modification of flagellin in C. difficile 630 using NMR and have identified 4 gene modification locus. Mutants strains had some impact on motility, colonization, and recurrence in a murine model of CDI showing that alterations in the flagellar structure can play a significant role in disease.
http://onlinelibrary.wiley.com/doi/10.1111/mmi.12755/pdf

 
A history of C.difficile from the beginning to where we are today.
http://cid.oxfordjournals.org/content/59/suppl_2/S66.long

 

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