Tag Archives: C. difficile research community

Researchers From Loyola Medicine Retrospectively Studied 100 Vancomycin Taper and Pulse Treatment Patients Treated For Recurrent C. difficile Infection

A tapered and pulsed regimen with vancomycin — with diligent follow-up — can achieve significant cure rates in recurrent Clostridium difficile (C. difficile) infected patients, according to a new study.

Researchers from Loyola Medicine retrospectively studied 100 vancomycin taper and pulse treatment patients treated for recurrent C. difficile infection between January 1, 2009 and December 31, 2014. Their clinic, the study authors wrote, has been a referral center for the infection for the past decade.

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

http://www.mdmag.com/medical-news/pulsed-and-tapered-vancomycin-likely-route-to-recurrent-clostridium-difficile-cure

However, despite the guidelines for treatment of recurrent C. difficile infection being not too different than recurrent episodes – except for the use of vancomycin when the case is severe – there have not been many studies on this vancomycin taper and pulsed dosing. 

The researchers observed that after a referral, the confirmed recurrent C. difficile patients were treated with a vancomycin taper and pulse regimen: a taper of vancomycin to once-daily, followed by alternate day dosing; or once-daily followed by alternate day dosing; followed by every third day, for at least 2 weeks. After this regimen, all patients had 90-day follow-up documentation.

On average, the patients in the clinic were on their third C. difficile diarrhea episode. Half of the patients had also received a standard course of vancomycin, while another third had received some type of vancomycin taper regimen, the researchers said.

Despite the fact that many of these patients were a “treatment experienced” population, 75% of the patients who received a supervised vancomycin taper and pulsed regimen achieved a cure,  study author Stuart Johnson  MD, . He added that the results were further improved for patients who received the expended pulse phase: 81% achieved a cure.

“The findings were not unexpected to us, but I think that many clinicians will be surprised how well a deliberate, prolonged vancomycin taper and pulse regimen – with careful follow up – works,” Johnson said.

There were no significant differences among the patients in terms of gender, age, concomitant antibiotics, proton pump inhibitor use, histamine receptor-2 blocker use, or patients with a regimen greater than 10 weeks in length, the researchers continued.

The researchers added that their finding of improved cure rates with alternate-day dosing plus every third day dosing over strictly alternate-day dosing is consistent with the hypothesis that pulsed dosing can promote a cyclical decrease in spore burden, they wrote. This can also permit the resetting of normal microbiota in the gut.

Johnson concluded that the clinical implications of the study show most recurrent C. difficile patients do not need fecal microbiota transplant (FMT).

“FMT has received an enormous amount of press and this procedure is now widely available throughout the US,” Johnson said. “FMT is attractive because it addresses one of the primary mechanisms involved with recurrent C. difficile infection, a marked disruption of the resident bacteria that populate the intestine and provide an important host defense against C. difficile.

Although physicians screen donor feces for “known pathogens,” not all is known of the potential complications to come from FMT, Johnson said.

“In addition, it appears that efficacy with a carefully supervised vancomycin taper and pulse regimen compare to that achieved with FMT,” Johnson said.

The study, “Vancomycin Taper and Pulsed Regimen with careful Follow up for Patients with Recurrent Clostridium difficile Infection,” was published in the journal Clinical Infectious Diseases.

The Latest Developments in C. diff Research and Treatment

 

 

 

 

 

The Program Podcast is Now Available —

Listen at your leisure as our guest, Dr Mary Beth Dorr, PhD, Clinical Director, Clinical Research, Infectious Diseases, and he product development team lead for bezlotoxumab, Merck & Co., Inc.  provided us with an overview of a C. diff. infection, the challenges of recurrence, the latest clinical research overview, current treatment landscape, and pending new C. diff infection treatment guidelines from the Infectious Diseases Society of America (IDSA) that are anticipated to be released fall of 2017.

Click on the C. diff. Spores and More Logo to be connected to the podcast

Researchers Find Key Role of Excess Calcium In the Gut In C. difficile infections (CDI)

New research shows, it can’t make this last, crucial move without enough of a humble nutrient: calcium.

And that new knowledge about Clostridium difficile (a bacterium also known as “C. diff“) may lead to better treatment for the most vulnerable patients.

The discovery, made in research laboratories at the University of Michigan Medical School and the U.S. Food and Drug Administration, is published in the online journal PLoS Pathogens.

It helps solve a key mystery about C. diff: What triggers it to germinate, or break its dormancy, from its hard spore form when it reaches the gut.

Though the findings were made in mice, not humans, the researchers say the crucial role of calcium may help explain another mystery: Why some hospital patients and nursing home residents have a much higher risk of contracting C. diff infections and the resulting diarrhea that carries its spores out of the body.

That group includes people whose guts are flooded with extra calcium because they’re taking certain medications or supplements, have low levels of Vitamin D in their blood or have gut diseases that keep them from absorbing calcium.

The new discovery shows that C. diff can recognize this extra calcium, along with a substance called bile salt produced in the liver, to trigger its awakening and the breaking of its shell.

Previous research had suggested it couldn’t do this without another key component, an amino acid called glycine. But the new findings show calcium and the bile salt called taurochlorate alone are enough. Mouse gut contents that were depleted of gut calcium had a 90 percent lower rate of C. diff spore germination.

“These spores are like armored seeds, and they can pass through the gut’s acidic environment intact,” says Philip Hanna, Ph.D., senior author of the new paper and a professor of microbiology and immunology at U-M. “Much of the spore’s own weight is made of calcium, but we’ve shown that calcium from the gut can work with bile salts to trigger the enzyme needed to activate the spore and start the germination process.”

Ironically, the researchers say, one way to use this new knowledge in human patients might be to add even more calcium to the system.

That could awaken all the dormant C. diff spores in a patient’s gut at once, and make them vulnerable to antibiotics that can only kill the germinated form. That could also prevent the transmission of more spores through diarrhea to the patient’s room. That could slow or stop the cycle of transmission that could threaten them or other patients in the future.

Hanna’s graduate student, Travis Kochan, made a key observation that led to the discovery. He noted that the fluid “growth medium” that the researchers typically grow C. diff in for their studies had calcium in it. He realized this could artificially alter the results of their experiments about what caused C. diff spores to germinate.

So, he used a chemical to remove the calcium while leaving all the other nutrients that                  keep C. diff growing. The result: no new spore germination happened in the calcium-free growth medium.

FDA’s Center for Biologics Evaluation and Research conducted further research in laboratory dishes and in the guts of mice. FDA’s Paul Carlson, Ph.D., a former U-M research fellow, and fellow FDA scientists in his laboratory found that C. diff spores that were mutated so that glycine couldn’t act on them could still germinate and colonize mice. This suggested that calcium, and not glycine, was critical for this process.

Both mutant and regular forms of the bacteria could still activate an enzyme inside the C. diff spore that led the bacteria to start dissolving their hard shell. This released the store of calcium that the spore had been harboring inside itself, and increases the local level of the nutrient even further.

“These spores don’t want to germinate in the wrong place,” says Kochan, whose grandfather suffered from a severe C. diff infection which ultimately led to his death. “C. diff spores have specialized to germinate in the gut environment, especially in the environment of the small intestine, where calcium and the bile salt injection from the liver comes in.”

Hanna notes that the bile salt connection to C. diff spore germination was first discovered at U-M in 1982 by a team led by Ken Wilson, M.D.

Calcium and the gut

Certain ailments and treatments cause defects in calcium absorption, but are also risk factors for C. diff infections. For example, patients with vitamin D deficiency are five times more likely to get C. diff.

Medications aimed at calming acid reflux – such as proton pump inhibitors – and steroids can increase the amount of calcium in the gut. A Vitamin D deficiency can keep the body from reabsorbing calcium through the gut wall, allowing it to build up.

And people with inflammatory bowel diseases such as Crohn’s and colitis also have a harder time absorbing calcium from food through their gut walls.

Older adults are also often counseled to take calcium supplements to compensate for lower calcium levels and protect their bones from fracturing.

Hanna cautions that the new findings should not cause any patients to stop taking their medications or doctor-recommended supplements, or to start taking new ones. But he hopes to work with clinicians at U-M and beyond to test the new knowledge in a clinical setting. Meanwhile, he and Kochan and their FDA and U-M colleagues will continue to study C. diff germination in mice and look for ways to block the enzymes crucial to spore germination.

 

To read the article in its entirety – please click on the following link to be re-directed:

http://www.news-medical.net/news/20170713/Scientists-reveal-key-role-of-excess-gut-calcium-in-C-diffc2a0infections.aspx?utm_source=dlvr.it&utm_medium=twitter

Researchers Suggest a Portion Of C. diff. Cases In Europe Involve Infections Associated With Other Sources Outside of Healthcare-Associated Infections

As part of a multicenter study, investigators from the University of Oxford, the University of Leeds, Astellas Pharma Europe, and elsewhere used a combination of ribotyping, sequencing, phylogenetics, and geographic analyses to retrace the genetic diversity and potential sources of C. difficile isolates involved in infections in European hospitals.

Recent research suggests a proportion of Clostridium difficile cases in Europe involve not only hospital-acquired infections but also infections associated with other sources, such as food.

As stated in the article:

https://www.genomeweb.com/sequencing/clostridium-difficile-genetic-patterns-europe-point-possible-infection-sources-beyond?utm_source=Sailthru&utm_medium=email&utm_campaign=GWDN%20Mon%20PM%202017-04-24&utm_term=GW%20Daily%20News%20Bulletin

David Eyre, a clinical lecturer at the University of Oxford, was slated to present the work at the European Congress of Clinical Microbiology and Infectious Diseases annual 2017 meeting in Vienna this past weekend. The study was funded by Astellas Pharma’s Europe, Middle East, and Africa (EMEA) program.

“We don’t know much about how C. difficile might be spread in the food chain, but this research suggests it may be very widespread,” Eyre said in a statement. “If that turns out to be the case, then we need to focus on some new preventative strategies such as vaccination in humans once this is possible, or we might need to look at our use of animal fertilizers on crops.”

“This study doesn’t give us any definitive answers,” he explained, “but it does suggest other factors [than hospital infections] are at play in the spread of C. difficile and more research is urgently needed to pin them down.”

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Some of the strains clustered by locale, consistent with spread from one individual to the next, for example in a healthcare setting. But more unexpectedly, the team also saw strains smattered across seemingly unconnected sites. And because at least one of those strains had previously been linked to pig farming, the researchers speculated that some infections may have been transmitted through food sources.

 

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

https://www.genomeweb.com/sequencing/clostridium-difficile-genetic-patterns-europe-point-possible-infection-sources-beyond?utm_source=Sailthru&utm_medium=email&utm_campaign=GWDN%20Mon%20PM%202017-04-24&utm_term=GW%20Daily%20News%20Bulletin

C. difficile Researcher Kirk Hevener Of ISU And Research Group At Texas A&M University and University of Hawaii Work On A New Way To Treat Clostridium difficile

Kirk Hevener of the ISU Department of Biomedical and Pharmaceutical Sciences is part of a group that is working on a new way to treat Clostridium difficile, commonly called
C. difficile or C. diff. Working with researchers from Texas A&M University and the University of Hawaii, Hevener is researching a new target that could change the way C. diff is treated through a $415,000 grant from the National Institute of Health.

C. diff  is a bacteria that commonly causes infection of the colon and can lead to severe damage, and in some cases can even be fatal. It is also highly drug-resistant and extremely transmittable.

Hevener identified C. diff as a possible candidate for research while working with a completely different bacteria during his postdoctoral fellowship in Chicago.

Porphyromonas gingivalis is a bacteria that causes disease in the mouth.

While these two bacteria are unrelated, they have two common traits. Both are pathogenic, meaning they cause disease, and contain an enzyme called FabK.

FabK is not found in many other bacteria, so Hevener decided that C. diff would be a good candidate to extend his work in Chicago to, with FabK being the focus of his current work.

This enzyme is part of the fatty acid synthesis pathway. This creates lipids that are used to create the cell membrane, among other functions of the cell. Within C. diff, it is also is part of the mechanism that creates the bacteria’s spores. These spores are inactive forms of the bacteria and are extremely difficult to kill.  They are the reason that recurrence and transmission rates are so high inside of hospitals.

Hevener is studying ways this enzyme can be targeted specifically, with molecules known as inhibitors.

If he and his team can prove that FabK is targetable, it could lead to the development of new medications specific to the treatment of C. diff.

Hevener wanted to make clear that he is currently working on target validation, and not drug development. He and his team are validating that by inhibiting this enzyme, the bacteria would not be able to able to reproduce and create spores, which would then allow others to develop a medication to leverage this mechanism.

By targeting FabK specifically, Hevener’s team would create a narrow spectrum method of treatment, as opposed to the more common broad spectrum approach.

Broad spectrum antibiotics affect all bacteria, regardless if they are pathogenic or beneficial.

There are many bacteria found inside of the human body that aid in different ways from digestion to preventing harmful organisms causing infection.

This narrow spectrum approach has two benefits for a medication developed using it: it does not kill helpful organisms and it helps slow the development of resistance.

Hevener explained that it is impossible to create an antibiotic that is immune to the development of resistance, but because a medication of this type would affect only C. diff, other bacteria would not develop resistance and transfer that genetic mutation to other bacteria. This would slow the progress of a medication becoming less effective or possibly obsolete over time.

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

http://isubengal.com/narrowing-c-difficile/

Belgian Nursing Home Survey of Clostridium difficile Presence and Gut Microbiota Composition

  • Cristina Rodriguez+
  • Bernard Taminiau†,
  • Nicolas Korsak,
  • Véronique Avesani,
  • Johan Van Broeck,
  • Philippe Brach,
  • Michel Delmée and
  • Georges Daube
†Contributed equally
BMC MicrobiologyBMC series – open, inclusive and trusted201616:229

DOI: 10.1186/s12866-016-0848-7

The Author(s). 2016m,Received: 13 April 2016,Accepted: 23 September 2016

Published: 1 October 2016

Abstract

Background

Increasing age, several co-morbidities, environmental contamination, antibiotic exposure and other intestinal perturbations appear to be the greatest risk factors for C. difficile infection (CDI). Therefore, elderly care home residents are considered particularly vulnerable to the infection. The main objective of this study was to evaluate and follow the prevalence of C. difficile in 23 elderly care home residents weekly during a 4-month period. A C. difficile microbiological detection scheme was performed along with an overall microbial biodiversity study of the faeces content by 16S rRNA gene analysis.

Results

Seven out of 23 (30.4 %) residents were (at least one week) positive for C. difficile. C. difficile was detected in 14 out of 30 diarrhoeal samples (43.7 %). The most common PCR-ribotype identified was 027. MLVA showed that there was a clonal dissemination of C. difficile strains within the nursing home residents. 16S-profiling analyses revealed that each resident has his own bacterial imprint, which was stable during the entire study. Significant changes were observed in C. difficile positive individuals in the relative abundance of a few bacterial populations, including Lachnospiraceae and Verrucomicrobiaceae. A decrease of Akkermansia in positive subjects to the bacterium was repeatedly found.

Conclusions

A high C. difficile colonisation in nursing home residents was found, with a predominance of the hypervirulent PCR-ribotype 027. Positive C. difficile status is not associated with microbiota richness or biodiversity reduction in this study. The link between Akkermansia, gut inflammation and C. difficile colonisation merits further investigations.

Keywords

C. difficile Elderly care home residents 16S rRNA gene analysis

Background

Clostridium difficile is a Gram-positive, anaerobic, spore-forming, rod-shaped bacterium that has been widely described in the intestinal tract of humans and animals. In 1978, C. difficile was recognized as a major cause of antibiotic associated diarrhoea and, in the most serious cases pseudomembranous colitis [1, 2, 3]. Since then, many outbreaks have been reported; most of them were associated with the emergence of a specific subtype, hyper-virulent PCR-ribotype 027 [4]. Nowadays, C. difficile is a worldwide public health concern as it is considered the major cause of antibiotic-associated infections in healthcare settings [5]. A recent report of C. difficile infection (CDI) cost-of-illness attributes a mean cost ranging from 8,911 to 30,049 USD for hospitalised patients (per patient/admission/episode/infection) in the USA [6] and annual economic burden estimated around 3,000 million euro in Europe [7].

CDI is more commonly diagnosed among older people in nursing homes. High isolation frequencies have been described in USA, with up to 46 % of elderly residents testing positive for C. difficile, while in Europe or Canada the reported rates are much lower, varying between 0.8 and 10 % [8]. This is partly because elderly people are more commonly in hospitals, have an antibiotic treatment and age-related changes in intestinal flora and host defences, as well as the presence or other underlying health problem [8, 9, 10]. These factors can have an impact on the intestinal microbiota, which may promote C. difficile colonisation and the development of the infection [11]. Therefore, a new concern of several studies has been the identification of the microbial communities implicated in the CDI through the use of new sequencing techniques, like metagenomics [12].

The aim of this study was to evaluate and follow the prevalence of C. difficile among the residents of a Belgian nursing home. Multilocus variable number of tandem repeats analysis (MLVA) was performed to determine the genetic diversity of the C. difficile isolates and possible cross-infection between patients. Additionally, 16S rRNA gene sequencing was used to characterise the faecal microbiota of the elderly residents, to evaluate the global evolutions of the total microbiota and to identify possible relationships between certain bacteria populations and C. difficile colonisation, diarrhoea and antibiotic treatment.

Results

Prevalence of C. difficile

A total of 242 faecal samples were collected from 23 residents in seventeen consecutive weeks (resident number 11 was excluded from the study as he finally did not agree to participate in the survey). Two subjects passed away within the four-month study period. Seven out of 23 monitored residents were positive for C. difficile at least once (Table 1).
TO READ THE ARTICLE IN ITS ENTIRETY AND VIEW TABLES
please click on the following link:
http://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-016-0848-7

University of Leicester Researchers Identified the Potential Of Using A Bacteriophage Cocktail To Eradicate C. difficile Infection (CDI)

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University of Leicester scientists have previously identified the potential of using a bacteriophage cocktail to eradicate Clostridium difficile infection (CDI)

 

and in this research, using an insect model, they show that their prophylactic use can prevent infection forming in the first place.

The data, which is the result of research conducted by University of Leicester researchers Dr. Janet Nale, and Professor Martha Clokie, both from the Department of Infection, Immunity and Inflammation, demonstrated that C. difficile phages are particularly effective when used to prevent infection, but they are also good at targeting harmful bacterial infections once biofilms have formed.

Using biofilm and waxworms as models, these phages reduced C. difficile bacterial counts when administered as a preventative measure. Furthermore, combinations of phages and vancomycin led to a marked decrease in C. difficile colonization in the waxworms.

The fact that this was an experimental lab study in waxworms means that conclusions can be made about cause and effect in this species.

Phages have not been used in humans to treat CDI and to see whether these results apply to people, an experimental trial with people would be necessary. However, work with insect models is crucial to our understanding of how best to exploit them. They have shown that these new models are useful tools in which to investigate the timings and dose regimens of phage treatment.

The paper is now published online and is expected to be published in a hard copy special issue of Frontiers in Microbiology.

The study was funded by AmpliPhi Biosciences Corporation, a developer of bacteriophage-based antibacterial therapies to treat drug-resistant infections.

Professor Martha Clokie has been investigating an alternative approach to antibiotics, which utilises naturally occurring viruses called bacteriophages, meaning ‘eaters of bacteria’, for nearly a decade at Leicester.

She said: “The results suggest that it may be possible to reduce the threat of C. difficile, and potentially other bacterial infections, through the use of phages both prophylactically to prevent infection, and as therapy once an infection is established. Phage therapy targets specific pathogenic bacterial populations while sparing patients’ beneficial microbiome.”

M. Scott Salka, CEO of AmpliPhi Biosciences, said: “The data support our products’ great potential in addressing antibiotic resistant and difficult to treat infections, including C. difficile. I would like to commend Dr. Nale and Professor Clokie for their exciting and insightful research demonstrating the immense promise of phage therapeutics. Their findings underscore our enthusiasm for the potential of our proprietary platform to enable the development of therapeutics to treat a broad range of bacterial infections that are resistant or have suboptimal responses to current antibiotic therapies.”

 

Source:

http://journal.frontiersin.org/article/10.3389/fmicb.2016.01383/full