Category Archives: C. diff. Research & Development

Review Article: The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection: Current Understanding and Gap Analysis

The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection: Current Understanding and Gap Analysis

Mark H. Wilcox,1,2 Barbara H. McGovern,3, and Gail A. Hecht4,5

1 Department of Microbiology, Old Medical School, Leeds Teaching Hospitals NHS Trust, Leeds, UK, 2 University of Leeds, Leeds, UK, 3 Seres Therapeutics, Medical Affairs, Cambridge, Massachusetts, USA, 4 Department of Medicine, Division of Gastroenterology, Loyola University Chicago, Chicago, Illinois, USA, and 5 Department of Microbiology and Immunology, Loyola University Chicago, Chicago, Illinois, USA The leading risk factor for Clostridioides

Abstract: The leading risk factor for Clostridioides (Clostridium) difficile infection (CDI) is broad-spectrum antibiotics, which lead to low microbial diversity, or dysbiosis. Current therapeutic strategies for CDI are insufficient, as they do not address the key role of the microbiome in preventing C. difficile spore germination into toxin-producing vegetative bacteria, which leads to symptomatic disease. Fecal microbiota transplant (FMT) appears to reduce the risk of recurrent CDI through microbiome restoration. However, a wide range of efficacy rates have been reported, and few placebo-controlled trials have been conducted, limiting our understanding of FMT efficacy and safety. We discuss the current knowledge gaps driven by questions around the quality and consistency of clinical trial results, patient selection, diagnostic methodologies, use of suppressive antibiotic therapy, and methods for adverse event reporting. We provide specific recommendations for future trial designs of FMT to provide improved quality of the clinical evidence to better inform treatment guidelines.

 

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https://www.scilit.net/article/7444c3597a3c208e70317498502f6beb

Major Article: SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial

SER-109, an Investigational Microbiome Drug to Reduce
Recurrence After Clostridioides difficile Infection: Lessons
Learned From a Phase 2 Trial.

Barbara H. McGovern,1,a,  Christopher B. Ford,1,a , Matthew R. Henn,1,a , Darrell S. Pardi 2
Sahil Khanna,2  Elizabeth L. Hohmann,3  Edward J. O’Brien,1
Christopher A. Desjardins,1, Patricia Bernardo,1, Jennifer R. Wortman,1, Mary-Jane Lombardo,1
Kevin D. Litcofsky,1, Jonathan A. Winkler,1, Christopher W. J. McChalicher,1, Sunny S. Li,1,
Amelia D. Tomlinson,1,Madhumitha Nandakumar,1 David N. Cook1,
Roger J. Pomerantz,1, John G. Auninš,1, and Michele Trucksis1,

1 Seres Therapeutics, Cambridge, Massachusetts, USA, 2 Mayo Clinic, Gastroenterology Division, Rochester, Minnesota, USA, and 3 Massachusetts General Hospital, Infectious Diseases Division, Boston, Massachusetts, USA

Background. Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.

Methods. In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing.

Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.

Results. 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo
(44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years
(45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109
was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed
an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal.

Adverse events were generally mild to moderate in severity.

Conclusions. Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. Clinical Trials Registration. NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw=2&rank=4.

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World Microbiome Day 2020 Information

Microbiome research impacts many facets of life on Earth (and beyond).
In a dedicated page for World Microbiome Day 2020, MicrobiomeAnimal Microbiome and Environmental Microbiome have highlighted some of the many ways microbiome research has benefited us.

 

 

 

Click on the graphic above to access the World Microbiome 2020 Page

World Microbiome Day was founded by APC Microbiome Ireland in 2019. It aims to celebrate all things microbe and to raise awareness of the diverse world of microbiomes and their impact on human, animal, and environmental health.

In honour of the World Microbiome Day 2020  day, the BMC is proud to present this collection of microbiome research specially selected by our editors.

The BMC (Biomed Central) Research In Progress — A pioneer of open access publishing, BMC has an evolving portfolio of high quality peer-reviewed journals including broad interest titles such as BMC Biology and BMC Medicine, specialist journals such as Malaria Journal and Microbiome, and the BMC Series.

https://www.biomedcentral.com/

Expanding beyond biomedicine into the physical sciences, mathematics and engineering disciplines, BMC now offers a wider portfolio of subject fields on a single open access platform.

At BMC, research is always in progress. We are committed to continual innovation to better support the needs of our communities, ensuring the integrity of the research we publish, and championing the benefits of open research. BMC is part of Springer Nature.

BMC has an evolving portfolio of some 300 peer-reviewed journals, sharing discoveries from research communities in science, technology, engineering and medicine. In 1999 we made high quality research open to everyone who needed to access it – and in making the open access model sustainable, we changed the world of academic publishing.

 

Vanderbilt University Medical Center Scientists Demonstrated C. diff. Exposed To Heme Increases Expression of a Protein System Not Previously Studied

 

Vanderbilt University Medical Center scientists have identified a C. diff protein system that senses and captures heme (part of hemoglobin) to build a protective shield that fends off threats from our immune system and antibiotics. The findings, reported in the journal Cell Host & Microbe, reveal a unique mechanism for C. diff survival in the human gut and suggest novel strategies for weakening its defenses.

In a cruel twist, the bacterium Clostridioides difficile (C. diff) makes us bleed and then uses our blood to defend itself against us.

C. diff the most common cause of health care-associated infections (HAI’s) in the United States causes diarrhea and inflammation of the colon (colitis). Individuals taking antibiotics, which disturb the protective gut microbiota, have increased risk for acquiring a C. diff infection, and 20% of patients suffer recurrent C. diff infections despite treatment.

When C. diff colonizes the gut, it produces toxins that cause tissue damage and inflammation. Blood cells burst, releasing heme, the part of hemoglobin that binds iron and oxygen.

Eric Skaar, Ph.D., MPH, Ernest W. Goodpasture Professor of Pathology, Microbiology and Immunology, and colleagues have studied how bacteria respond to heme, which is both a source of the nutrient iron and a reactive, toxic compound.

“Organisms that experience large amounts of heme have to have ways to deal with heme toxicity,” said Skaar, director of the Vanderbilt Institute for Infection, Immunology and Inflammation (VI4). “We wanted to understand how C. diff deals with heme exposure.”

The investigators demonstrated that C. diff exposed to heme increases expression of a protein system that had not been previously studied. They named the system HsmRA (heme sensing membrane proteins R and A) and showed that HsmR senses heme and deploys HsmA to capture it. They also found that the HsmRA system is genetically conserved in many bacterial species.

The binding of heme in the bacterial membrane by HsmA serves a protective purpose first by simply reducing the concentration of free heme, Skaar explained. The researchers also discovered that HsmA uses heme binding to protect C. diff from oxidative stress, including that produced by neutrophils and macrophages from our immune system to kill bacteria.

“C. diff is using cofactors from our own cells as a shield to protect against our innate immune response,” Skaar said.

Oxidative stress also plays a role in antibiotic action.

“Antibiotics have different molecular targets—they may prevent cell wall synthesis; they may prevent protein translation—but the net result of that stress on the cell is often the massive accumulation of oxidative stress that many believe to be a major contributor to why antibiotics kill bacteria,” Skaar said.

The investigators studied whether the HsmRA system protected C. diff against antibiotics.

“We found a really impressive phenotype with vancomycin and metronidazole, two of the front-line antibiotics used to treat C. diff,” Skaar said. “C. diff that expresses HsmA, when HsmA is bound to heme, is much more resistant to vancomycin and metronidazole.”

They also showed that C. diff strains with inactivated HsmR or HsmA had reduced colonization in a mouse model of relapse C. diff infection.

Skaar said it has not been clear why C. diff produces toxins that cause so much tissue damage.

“It’s interesting to speculate that a benefit of toxin-related damage is that C. diff can capture liberated heme and use it as a shield to protect itself against various insults that cause oxidative stress—that would be immune cells, antibiotics and potentially other bacteria.”

The findings suggest that targeting the HsmA-heme shield might increase the sensitivity of C. diff to antibiotics such as vancomycin and metronidazole. It’s not clear that HsmA, a membrane protein, will be a druggable target, Skaar said.

It might be possible, however, to deprive C. diff of heme building blocks by reducing tissue damage or by administering proteins that bind heme, he said. The researchers will explore whether they can increase the sensitivity of C. diff to antibiotics by co-administering a heme-binding protein during infection in an animal model.

“We’re excited about this as a potentially powerful strategy for treating C. diff,” Skaar said.

In other studies, the researchers will explore if the HsmRA system that is genetically conserved in many different organisms has the same functional role to protect against reactive oxygen species. They are also trying to understand the exact mechanism that HsmA-heme uses to detoxify oxidative stress.

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https://phys.org/news/2020-06-clostridioides-difficile-captures-blood-cell.html

Infectious Disease Research Finds the Laundering of Removable Bed Barriers More Effective at Reducing Hospital-Acquired Infections Keeping Patients Safe

Infectious disease research highlights that laundering removable bed barriers is more effective at reducing hospital-acquired infections and keeping patients safe

A new peer-reviewed study published today in Sage Journals’ Infectious Disease Research and Treatment publication, found that cleaning and disinfecting mattresses by using removable, launderable bed barriers is more effective at eliminating bacteria that cause C. diff, MRSA, and E.coli than manual processes using chemical disinfectants. These findings indicate a new, much-needed industry best practice that hospitals must adopt to keep patients safe – especially in today’s COVID-19 reality as more patients begin to re-enter hospitals and resume elective procedures.

Most hospitals currently conduct a manual one-step process of cleaning hospital beds and mattresses, despite being off-label use of the disinfectant and the manufacturer’s multi-step instructions for cleaning and disinfection. Studies have also shown that mattresses, which are difficult to disinfect, contribute to the high rates of hospital-acquired infections (HAIs) in the United States. These concerns prompted ECRI to cite mattress contamination as one of its top health hazards in both 2018 and 2019.

“We evaluated the effectiveness of the commercial laundry process under extreme test conditions, using high concentrations of soilage, blood, and urine. Laundering the removable bed barriers eliminated every major organism that contributes to HAIs—when the fabric was tested both at the beginning and end of life of the barrier,” said Edmond Hooker, MD, DrPH, an epidemiologist and practicing physician who co-authored the study, “The findings are both significant and timely as hospitals grapple with growing concerns about patient safety and how to prevent the spread of COVID-19 and other diseases. The time is now to take action and protect patients with this evidenced-based approach to cleaning and disinfecting.”

The commercial laundry process detailed in the study provides detergent, bleach, agitation, and repeatability. These elements allow bacteria and spores to be physically separated from the barrier surface. The chlorine works to kill residual organisms. Multiple rinse cycles allow the microorganisms to be removed from the washing machine.

“The current state of cleaning and disinfecting beds and mattresses is dangerous because it can leave residual bacteria that can be transmitted from patient to patient. However, laundering removable bed barriers provides an alternative. It eliminates issues with insufficient removal of pathogens from the patient surface, ” said Ardis Hoven, MD, Professor of Medicine at the University of Kentucky and an Infectious Disease consultant to the Kentucky Department for Public Health. “Unlike the commonly used manual process, it exceeded FDA guidance on this type of device. Hospital administrators must translate this new knowledge into action to protect the patients and families they serve.”

Trinity Guardion, the maker of the Soteria Bed Barrier – a removable and launderable bed barrier – sponsored the study. Dr. Hooker is a professor at Xavier University’s Department of Healthcare Administration and associate professor at the University of Cincinnati Medical Center. To view the full study results, please visit the publication website.

 

To read the publication in its entirety please visit

www.trinityguardion.com