Tag Archives: C. difficile research

DEINOVE Announced Enrollment of First Patient in Phase II Trial Testing DNV3837 in Clostridioides difficile infections

On January 27, 2020, DEINOVE announced the inclusion of the first patient in the Phase II trial testing DNV3837.

 

  • The Phase II clinical trial aims to evaluate the efficacy, safety, and pharmacokinetics of DNV3837 in patients with Clostridioides difficile gastrointestinal infection (CDI).
  • The trial will be conducted mainly in 15 centers in the United States, in two successive stages:
    • a cohort of 10 patients with moderate to severe CDI treated with DNV3837,
    • a randomized cohort study testing DNV3837 against the standard of care in 30 patients with severe CDI.
  • The final results of this trial are expected by the end of 2020.
  • DEINOVE is the only French player to conduct a clinical trial with an antibiotic.
  • On 17 January, the WHO warned about the extreme lack of new antibiotics and the threat posed by antibiotic resistance.

DEINOVE (Euronext Growth Paris: ALDEI), a French biotech company that uses a disruptive approach to develop innovative antibiotics and bio-based active ingredients for cosmetics, announced the inclusion of the first patient in the Phase II trial testing DNV3837.

DNV3837 targets the treatment of Clostridioides difficile infections (CDI), a disease classified as a priority by the WHO and one of the global leading causes of healthcare-related infections*.

DNV3837 is an intravenous antibiotic that, when converted to its active form DNV3681, crosses the gastrointestinal barrier and accumulates in the intestinal lumen, allowing it to precisely target the infection site. DNV3837 has demonstrated a promising efficacy profile and acceptable tolerance in Phase I trials (on healthy volunteers). It has also demonstrated its ability to eliminate Clostridioides bacteria without affecting the gut microbiota. It has been granted Fast Track status and QIDP designation**.

The Phase II trial aims to evaluate the efficacy of DNV3837 in pathological conditions (through monitoring of symptoms, stool analysis, etc.), as well as to consolidate the safety and pharmacokinetic data of the antibiotic candidate.

This trial is concentrated in the United States. It will take place in two stages:

  • In the first phase, involving 5 centers, a cohort of 10 patients with moderate to severe CDI will be treated with DNV3837. At the end of this phase, the DSMB*** will review the interim results.
  • The second phase will involve 30 patients with severe CDI and will be carried out in 15 investigation centers. This will be an open-label randomized trial testing DNV3837 (in 2/3 of patients) against an approved standard of care**** (1/3 of patients) for comparison purposes.

The results of this clinical trial should be available by the end of 2020.

 “The start of this Phase II clinical trial is a significant step forward for DEINOVE and a great hope for patients. We are very proud to provide a potential solution to this unmet medical need and, to this end, work with the best American specialists in this area. The investigation centers are very committed to conducting this trial which, in the event of positive results, will be an important milestone towards the registration of DNV3837,” said Dr. Georges Gaudriault, Scientific Director of DEINOVE.

This announcement echoes warnings issued by the WHO about the lack of antibiotics renewal.

Dr. Tedros Adhanom Ghebreyesus, Director-General of WHO, declared last January 17 « Never has the threat of antimicrobial resistance been more immediate and the need for solutions more urgent ».

https://www.who.int/news-room/detail/17-01-2020-lack-of-new-antibiotics-threatens-global-efforts-to-contain-drug-resistant-infections

 

* Source: CDC (US Centers for Disease Control and Prevention)

** ‘Fast Track’ status facilitates the development of the molecule through a faster and more flexible regulatory review of the application. The QIDP designation gives the drug exclusive access to the market for an additional five-year period. These designations are granted by the FDA to drugs under development that meet critical and unmet therapeutic needs.

*** DSMB – Data Safety Monitoring Board: a group of independent experts tasked to review the data generated during the trial and make recommendations on patient safety as well as trial relevance and validity.

**** Standard treatments approved in the United States for the treatment of CDIs include vancomycin, fidaxomicin and metronidazole (all three antibiotics). The choice will be at the discretion of the clinicians. 

Researchers Find C. diff. a Major Cause of Nosocomial Diarrheal Disease Exhibits Phenotypic Heterogeneity Within a Clonal Population As a Result of Phase Variation

Recent work has revealed that Clostridioides difficile, a major cause of nosocomial diarrheal disease, exhibits phenotypic heterogeneity within a clonal population as a result of phase variation.

Many C. difficile strains representing multiple ribotypes develop two colony morphotypes, termed rough and smooth, but the biological implications of this phenomenon have not been explored. Here, we examine the molecular basis and physiological relevance of the distinct colony morphotypes produced by this bacterium. We show that C. difficile reversibly differentiates into rough and smooth colony morphologies and that bacteria derived from the isolates display discrete motility behaviors. We identified an atypical phase-variable signal transduction system consisting of a histidine kinase and two response regulators, named herein colony morphology regulators RST (CmrRST), which mediates the switch in colony morphology and motility behaviors. The CmrRST-regulated surface motility is independent of flagella and type IV pili, suggesting a novel mechanism of cell migration in C. difficile. Microscopic analysis of cell and colony structure indicates that CmrRST promotes the formation of elongated bacteria arranged in bundled chains, which may contribute to bacterial migration on surfaces. In a hamster model of acute C. difficile disease, the CmrRST system is required for disease development. Furthermore, we provide evidence that CmrRST phase varies during infection, suggesting that the intestinal environment impacts the proportion of CmrRST-expressing C. difficile. Our findings indicate that C. difficile employs phase variation of the CmrRST signal transduction system to generate phenotypic heterogeneity during infection, with concomitant effects on bacterial physiology and pathogenesis.

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

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000379

C. difficile clade A, Able to Withstand Modern Diet and Healthcare Facilities Long Before They Existed

Researchers at The Wellcome Sanger Institute and the London School of Hygiene & Tropical Medicine say they found that C. diff bacteria appears to have broken off into another species, reports StudyFinds.

While the researchers just uncovered the strain, it’s likely been around for tens of thousands of years and is probably the cause of the majority of C.diff infections at hospitals today.

The strain, which is being called C. difficile clade A, was built to withstand modern diet and healthcare facilities way before they existed.

Scientists say that Clostridium difficile (C. diff) is evolving, which could make things more difficult for hospitals that have for years struggled with the bacteria.

The newly discovered strain are problematic because they prefer the sugar-rich diet enjoyed in western countries and can tolerate the cleaning procedures typically carried out at the healthcare facilities in these countries. (*?)

Those involved in the study say it has provided scientists with a better understanding of how bacteria evolves over time. They say the discovery further proves the importance of genomic studies of bacteria.

Another study conducted by the American Society for Microbiology recently found that C. diff is doing a good job of sticking to hospital gowns even after they’ve been treated.

Researchers Examined the Effect of Disinfectant on C. difficile Spores and How They Survived Afterwards On Surfaces Including Isolation Gowns, Stainless Steel and Vinyl Flooring

In lab studies, researchers found that C. diff spread easily from disposable gowns often employed in surgery or infection control to stainless steel and vinyl surfaces.

“The [bacteria] also transferred to vinyl flooring, which was quite disturbing. We didn’t realize they would,” said Tina Joshi, a lecturer in molecular microbiology at the University of Plymouth in the United Kingdom and lead author of the new study.

“These bugs evolve. These bugs like to stay one step ahead. And even though we’re using disinfectants and antibiotics appropriately, they still will become resistant in time. It’s inevitable,” Joshi said.

The bacteria, called Clostridioides difficile or C. diff., cause almost a half million infections every year in the United States, according to the Centers for Disease Control and Prevention.

The infection, which is spread by fecal to oral transmission, causes severe diarrhea, and can lead to intestinal inflammation and kidney failure. Those most at risk are people who have been given strong antibiotics, as well as those with long hospital stays, or those living in long-term care facilities like the elderly.

That means that keeping these facilities clean is incredibly important. But new research, published Friday (7/12/19)  in the journal Applied and Environmental Microbiology, shows how difficult that can be.

In lab studies, researchers found that C. diff spread easily from disposable gowns often employed in surgery or infection control to stainless steel and vinyl surfaces.

These bugs evolve. These bugs like to stay one step ahead. And even though we’re using disinfectants and antibiotics appropriately, they still will become resistant in time. It’s inevitable.

What’s more, the bacteria didn’t die when the researchers tried to kill them with concentrated chlorine disinfectant.

“Even if we applied 1,000 parts per million of chlorine, it would allow spores to survive in the gowns,” Joshi told NBC News.

It’s possible that increasing the amount of chlorine might kill the spores, but if the spores are indeed becoming resistant to the disinfectant, it will only be a matter of time before the stronger concentrations can’t kill them.

“These bugs evolve. These bugs like to stay one step ahead. And even though we’re using disinfectants and antibiotics appropriately, they still will become resistant in time. It’s inevitable,” Joshi said.

C. diff infections can occur when a patient is given broad spectrum antibiotics to tackle another infection.

If the bacteria aren’t killed, hospital patients or people in nursing homes can become infected when they come into contact with contaminated surfaces, such as a bedside food tray.

But if traditional disinfectants are ineffective, as the new research suggests, what works?

One option is UV light, which could be useful in killing the bacteria. However, it can be challenging to make sure all surfaces are fully exposed to the light. At this point, Joshi said, highly concentrated bleach appears to be the best option.

For those who care for patients with compromised immune systems at home, the C. Diff Foundation says alcohol-based hand sanitizers are ineffective against the bacteria.

On its website, the group recommends using a cleaning solution of one cup bleach to nine cups of water, and leaving the mixture on surfaces for a minimum of 10 minutes. (Basic & Generic, not EPA registered product).

Meanwhile, if C. diff spores can survive on gowns and other surfaces, it is likely also the case that they can live on doctor’s coats and scrubs worn by hospital personnel all day.  (C Diff Foundation agrees)

“That’s a real infection control hazard, because these spores can stick to fibers. We’ve proven that in this paper,” Joshi said.

Erika Edwards

Erika Edwards is the health and medical news writer/reporter for NBC News and Today.

 

To read the article in its entirety please click on the following link to be redirected:

https://www.nbcnews.com/health/health-news/dangerous-bacteria-can-survive-disinfectant-putting-patients-risk-n1029231

 

 

Researchers Find Sulfated glycosaminoglycans and Low-Density Lipoprotein Receptor Contribute To Clostridioides difficile Toxin A Cell Entry

 

Abstract

Clostridium difficile toxin A (TcdA) is a major exotoxin contributing to disruption of the colonic epithelium during C. difficile infection. TcdA contains a carbohydrate-binding combined repetitive oligopeptides (CROPs) domain that mediates its attachment to cell surfaces, but recent data suggest the existence of CROPs-independent receptors. Here, we carried out genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated screens using a truncated TcdA lacking the CROPs, and identified sulfated glycosaminoglycans (sGAGs) and low-density lipoprotein receptor (LDLR) as host factors contributing to binding and entry of TcdA. TcdA recognizes the sulfation group in sGAGs. Blocking sulfation and glycosaminoglycan synthesis reduces TcdA binding and entry into cells. Binding of TcdA to the colonic epithelium can be reduced by surfen, a small molecule that masks sGAGs, by GM-1111, a sulfated heparan sulfate analogue, and by sulfated cyclodextrin, a sulfated small molecule. Cells lacking LDLR also show reduced sensitivity to TcdA, although binding between LDLR and TcdA are not detected, suggesting that LDLR may facilitate endocytosis of TcdA. Finally, GM-1111 reduces TcdA-induced fluid accumulation and tissue damage in the colon in a mouse model in which TcdA is injected into the caecum. These data demonstrate in vivo and pathological relevance of TcdA-sGAGs interactions, and reveal a potential therapeutic approach of protecting colonic tissues by blocking these interactions.

To view abstract in its entirety please click on the following link to be redirected:  https://www.ncbi.nlm.nih.gov/pubmed/31160825?dopt=Abstract&utm_source=dlvr.it&utm_medium=twitter