Tag: Clostridioides difficile

Categories : Antibiotics Diseases, Syndromes and ConditionsTags :

Faulty ‘Fight or Flight’ Drives C. Diff Infections

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Clostridioides difficile. Credit: CDC

The portion of our nervous systems responsible for the “fight or flight” response can shape the severity of potentially deadly Clostridioides difficile infections, new research from the School of Medicine reveals in Cell Reports Medicine.

The findings suggest that doctors may be able to save patients from the infections – a plague for hospitals and nursing homes – by using drugs to quiet the hyperactive nervous system response, the researchers say.

“Compared to how much we know about immune system influences in C. difficile infections, the field is just scratching the surface in understanding neuronal contributions to disease,” said researcher William A. Petri Jr., MD, PhD, of UVA Health’s Division of Infectious Diseases and International Health. “Newly identifying components of the nervous system that worsen inflammation will allow us to determine potential therapeutic targets and biomarkers for patients at risk of severe disease.”

C. difficile, is a perpetual burden for healthcare facilities. Extensive antibiotic use, particularly among patients who are hospitalised or in nursing care, can allow it to establish dangerous infections. Further, patients who make it through the severe diarrhoea, nausea, fever and colitis C. difficile can cause are not necessarily in the clear: One in six will develop another C. diff infection within eight weeks, according to the federal Centers for Disease Control and Prevention.

The new UVA research reveals the critical role the nervous system plays in severe C. difficile infections. The researchers found that the “sympathetic” nervous system – the branch that responds to dangerous situations – can be a key driver of serious C. diff.

Normally, our “fight or flight” response is helpful for avoiding danger. It helps us respond quickly, improves our eyesight, boosts our strength. It also can stimulate our immune system and help us recover from injury. But in C. difficile cases, the nervous system can have a hyperactive response that becomes part of the problem, and UVA’s new research explains why.

“Neurons are the first responders that coordinate defences against toxic attacks. Sometimes those responders don’t recruit the right size and kind of artillery and that can make things worse,” said researcher David Tyus, a neuroscience graduate student at UVA. “Interestingly, the receptor we identified as important in C. difficile infection [the alpha 2 adrenergic receptor] has also been linked to irritable bowel syndrome. I’m curious to know if there could be a unifying underlying mechanism between the two disease contexts.”

Promisingly, the researchers found that targeting the receptor in lab mice reduced intestinal inflammation and decreased C. difficile severity and mortality. That suggests that, with further research, doctors may be able to take a similar tact to better treat severe C. diff infections in patients. For example, they may be able to surgically remove a portion of nerves in the gut, or they may be able to develop medicines to target the alpha 2 receptor – as Petri and Tyus are attempting to do.

“Our next step is to determine which cells with the alpha 2 receptor are receiving signals from the sympathetic nervous system and play a role in C. difficile-mediated disease,” Petri said. “We are very excited to think about how our findings translate to clinic and how the sympathetic nervous system might play a role in recurrent infection. I hope that this study sets the foundation for future findings of how neurons affect the course of C. difficile infection outcomes.”

Source: University of Virginia Health System

Categories : AntibioticsTags :

First-line Antibiotic for C. Diff may be Weakening

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Clostridioides difficile. Credit: CDC

The antibiotic vancomycin, recommended as first-line treatment for infection caused by the deadly superbug Clostridioides difficile, may not be living up to its promise, according to new US-based research.

C. diff infection is the leading cause of death due to gastroenteritis in the US. It causes gastrointestinal symptoms ranging from diarrhoea and abdominal pain to toxic megacolon, sepsis and death.

Based on 2018 clinical practice guidelines, the use of oral vancomycin has increased by 54% in the past six years, but the clinical cure rates have decreased from nearly 100% in the early 2000’s to around 70% in contemporary clinical trials.

“Despite the increasing prevalence of data showing reduced effectiveness of vancomycin, there is a significant lack of understanding regarding whether antimicrobial resistance to these strains may affect the clinical response to vancomycin therapy,” reports Anne J. Gonzales-Luna, research assistant professor in the Department of Pharmacy Practice and Translational Research, UH College of Pharmacy, in the journal Clinical Infectious Diseases. “In fact, the prevailing view has been that antibiotic resistance to these strains are unlikely to impact clinical outcomes, given the high concentrations of vancomycin in stools.”

But the University of Houston College of Pharmacy team arrived at a different conclusion after sifting through research included in a multicentre study, which included adults treated with oral vancomycin between 2016-2021 for C. diff infection.

“We found reduced vancomycin susceptibility in C. difficile was associated with lower 30-day sustained clinical response and lower 14-day initial cure rates in the studied patient cohort,” said Gonzales-Luna.

The finding is cause for concern.

“It’s an alarming development in the field of C. diff as there are only two recommended antibiotics,” said Kevin Garey, professor of pharmacy practice and translational research. “If antimicrobial resistance increases in both antibiotics, it will complicate the management of C. diff infection leading us back to a pre-antibiotic era.”

Source: University of Houston

Categories : Diseases, Syndromes and Conditions HospitalsTags :

Chlorine Disinfectant no Better than Water at Eliminating C. Diff

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Clostridioides difficile. Credit: CDC

One of the primary chlorine disinfectants currently used for hospital infection control does not kill off spores of the notorious cause of hospital-acquired infection Clostridioides difficile, according to a new study published in the journal Microbiology.

Research by the University of Plymouth has shown that C. Diff spores are completely unaffected despite being treated with high concentrations of bleach used in many hospitals.

In fact, the chlorine chemicals are no more effective at damaging the spores when used as a surface disinfectant – than using water with no additives.

The study’s authors say susceptible people working and being treated in clinical settings might be unknowingly placed at risk of contracting the superbug.

As a result, and with incidence of biocide overuse only serving to fuel rises in antimicrobial resistance (AMR) worldwide, they have called for urgent research to find alternative strategies to disinfect C. diff spores in order to break the chain of transmission in clinical environments.

Dr Tina Joshi, Associate Professor in Molecular Microbiology at the University of Plymouth, carried out the study with Humaira Ahmed, a fourth year Medicine student from the University’s Peninsula Medical School.

Dr Joshi, said: “With incidence of anti-microbial resistance on the rise, the threat posed by superbugs to human health is increasing. But far from demonstrating that our clinical environments are clean and safe for staff and patients, this study highlights the ability of C. diff spores to tolerate disinfection at in-use and recommended active chlorine concentrations. It shows we need disinfectants, and guidelines, that are fit for purpose and work in line with bacterial evolution, and the research should have significant impact on current disinfection protocols in the medical field globally.”

C. diff causes diarrhoea, colitis and other bowel complications, causing around 29 000 deaths per year in the USA, and almost 8500 in Europe, with the most recent data showing that, in the UK, incidence of C. diff infection was increasing prior to the start of the COVID pandemic.

Previously, Dr Joshi and colleagues had demonstrated the ability of C. diff spores to survive exposure to recommended concentrations of sodium dichloroisocyanurate in liquid form and within personal protective fabrics such as surgical gowns.

The new study examined spore response of three different strains of C. diff to three clinical in-use concentrations of sodium hypochlorite. The spores were then spiked onto surgical scrubs and patient gowns, examined using scanning electron microscopes to establish if there were any morphological changes to the outer spore coat.

Dr Joshi, who is on the Microbiology Society Council and Co-Chairs their Impact & Influence Committee, added: “Understanding how these spores and disinfectants interact is integral to practical management of C. diff infection and reducing the burden of infection in healthcare settings. However, there are still unanswered questions regarding the extent of biocide tolerance within C. diff and whether it is affected by antibiotic co-tolerance. With AMR increasing globally, the need to find those answers – both for C. diff and other superbugs – has never been more pressing.”

Source: University of Plymouth

Categories : Diseases, Syndromes and Conditions HospitalsTags :

The Greater Clostridioides Difficile Threat may Come from Within

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Clostridioides difficile. Credit: CDC

Despite strenuous control efforts, hospital-acquired infections still occur – the most common of which is caused by the bacterium Clostridioides difficile, which creates lingering spores and resists alcohol-based hand sanitisers. Surprising findings from a new study in Nature Medicine suggest that the burden of C. diff infection may be less a matter of hospital transmission and more a result of characteristics associated with the patients themselves.

The study team, led by Evan Snitkin, PhD; Vincent Young, MD, PhD; and Mary Hayden, MD, leveraged ongoing epidemiological studies focused on hospital-acquired infections that enabled them to analyse daily faecal samples from every patient within the intensive care unit at Rush University Medical Center over a nine-month period.

Arianna Miles-Jay, a postdoctoral fellow in Dr Snitkin’s lab, analysed 1141 eligible patients, and found that a little over 9% were colonised with C. diff. Using whole genome sequencing at U-M of 425 C. difficile strains isolated from nearly 4000 faecal specimens, she compared the strains to each other to analyse spread. But she found that, based on the genomics, there was very little transmission.

Essentially, there was very little evidence that the strains of C. diff from one patient to the next were the same, which would imply in-hospital acquisition. In fact, there were only six genomically supported transmissions over the study period. Instead, people who were already colonised were at greater risk of transitioning to infection.

“Something happened to these patients that we still don’t understand to trigger the transition from C. diff hanging out in the gut to the organism causing diarrhoea and the other complications resulting from infection,” said Snitkin.

Hayden notes this doesn’t mean hospital infection prevention measures are not needed. In fact, the measures in place in the Rush ICU at the time of the study – high rates of compliance with hand hygiene among healthcare personnel, routine environmental disinfection with an agent active against C. diff, and single patient rooms were likely responsible for the low transmission rate. The current study highlights, though that more steps are needed to identify patients who are colonised and try to prevent infection in them.

Where did the C. diff come from? “They are sort of all around us,” said Young. “C. diff creates spores, which are quite resistant to environmental stresses including exposure to oxygen and dehydration…for example, they are impervious to alcohol-based hand sanitiser.”

However, only about 5% of the population outside of a healthcare setting has C. diff in their gut – where it typically causes no issues.

“We need to figure out ways to prevent patients from developing an infection when we give them tube feedings, antibiotics, proton pump inhibitors – all things which predispose people to getting an actual infection with C. diff that causes damage to the intestines or worse,” said Young.

The team next hopes to build on work on AI prediction for patients at risk of C. diff infection to identify patients more likely to be colonised and who could benefit from more focused intervention.

Said Snitkin, “A lot of resources are put into gaining further improvements in preventing the spread of infections, when there is increasing support to redirect some of these resources to optimise the use of antibiotics and identify other triggers that lead patients harbouring C. diff and other healthcare pathogens to develop serious infections.”

Source: Michigan Medicine – University of Michigan

Categories : Diseases, Syndromes and ConditionsTags :

Scientists Unravel The Reason Why NSAIDs Exacerbate C. Diff Infections

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Clostridioides difficile. Credit: CDC

Nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate gastrointestinal infections by Clostridioides difficile, the leading cause of antibiotic-associated diarrhoea worldwide – but the reason why has long eluded medical science. In a new paper published in Science Advances, researchers have begun to answer that question, showing that NSAIDs disrupt the mitochondria of cells lining the colon, sensitising them to damage by pathogenic toxins.

C. difficile is a bacterium that leads to a wide range of symptoms, from mild diarrhoea to complex infection and death. The factors that influence this wide spectrum of clinical outcomes remain largely unclear, but emerging evidence suggests that factors like diet and pharmaceutical drugs influence both susceptibility to infection and disease progression. However, little is known about how these factors impact the course of C. difficile infection.

Prior studies have shown that NSAIDs like indomethacin, aspirin, and naproxen negatively affect the gut, both in patients with C. difficile infection and other conditions like inflammatory bowel disease (IBD). Long-term NSAID use can lead to stomach ulcers and intestinal injuries. One hypothesis that this is due to the effects of NSAIDs on cyclooxygenase (COX) enzymes; a process that helps reduce inflammation and pain but also impairs mucosal function in the upper gastrointestinal tract. NSAIDs also have off-target effects and have been shown to affect cellular mitochondria by uncoupling cellular mitochondrial functions, but these had not been studied in C. difficile infections.

To define these effects, Children’s Hospital of Philadelphia (CHOP) researchers, led by graduate student Joshua Soto Ocaña, used in vitro and mouse models of C. difficile infection to test how permeable colonic epithelial cells are in the presence of the NSAID indomethacin. The researchers observed that both indomethacin and C. difficile toxins increased epithelial cell barrier permeability and inflammatory cell death. They also found that the effect was additive: the combined effect on cell permeability of both toxins and indomethacin was increased compared to each independently, suggesting a synergistic effect of NSAIDs and C. difficile in increasing this pathogen’s virulence.

Surprisingly, the researchers found that NSAIDs exacerbate C. difficile infection independent of COX inhibition and instead through off-target effects on mitochondria. They did so by treating colonic epithelial cells with a precursor molecule that is similar in structure to indomethacin but lacks the ability to inhibit the COX enzyme. Not only did they find that this NSAID-like molecule induced cell death, but they also found that adding selective COX inhibitors did not increase cell death, demonstrating that COX enzyme inhibition is not required to induce epithelial cell damage during C. difficile infection and that, instead, this damage occurs through off-target effects of NSAIDs.

To test the role of off-target effects during C. difficile infection, the researchers used mice pretreated either with indomethacin or the NSAID-precursor molecule. When exposed to C. difficile, both groups of mice showed equal enhancement in disease severity and mortality compared to untreated control mice infected with C. difficile only. The researchers also observed a similar effect in mice who were pretreated with the NSAID aspirin. To further define the specific mechanisms driving these off-target effects of NSAIDs, researchers looked at mitochondrial functions in colonic epithelial cells in vitro and in mice. They observed that the combination of NSAIDs and C. difficile toxins increased damage to colonic epithelial cell mitochondria and disrupted several important mitochondrial functions.

“Our work further demonstrates the clinical importance of NSAIDs in patients with C. diff infection and sheds light on why the combination of these two may be so detrimental,” said senior author Joseph P. Zackular, PhD, Investigator and Assistant Professor of Pathology and Laboratory Medicine at CHOP. “Our mechanistic findings are a starting point for further research that aims to understand the impact of mitochondrial functions during C. diff infection. These data could also inform how NSAID-mediated mitochondrial uncoupling affects other diseases, such as small intestinal injury, IBD, and colorectal cancer.”

Source: Children’s Hospital of Philadelphia

Categories : Diseases, Syndromes and ConditionsTags :

The Metabolic ‘Jump Start’ Behind C. Difficile’s Rapid Colonisation Ability

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C difficile. Source: CDC

A team of investigators has identified metabolic strategies used by Clostridioides difficile to rapidly colonise the gut, which involve a metabolic ‘jump start’. In addition, the findings identify methods to better prevent and treat the most common cause of antibiotic-associated diarrhoea and healthcare-acquired infections (HAIs). The team’s results are published in Nature Chemical Biology and have important implications for antibiotics and the study of metabolites.

“Investigating real-time metabolism in microorganisms that only grow in environments lacking oxygen had been considered impossible,” said co-corresponding author Lynn Bry, MD, PhD, director of the Massachusetts Host-Microbiome Center. “Here, we’ve shown it can be done to combat C. difficile infections – and with findings applicable to clinical medicine.”

“C. difficile is the leading cause of hospital-acquired infections and a leading cause of antibiotic-associated diarrhoea. Understanding its metabolic mechanisms at a cellular level may be useful for preventing and treating infections,” said co-senior author Leo L. Cheng, PhD, an associate biophysicist in Pathology and Radiology at MGH and an associate professor of Radiology at Harvard Medical School.

The anaerobic C. difficile causes infections by releasing toxins that allow the pathogen to obtain nutrients from damaged gut tissues. Understanding how C. difficile metabolises nutrients while colonising the gut could inform new approaches to prevent and treat infections.

To complete their study, Bry and Cheng used a technology called high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HRMAS NMR) to study real-time metabolism in living cells under anaerobic conditions. The team incorporated computational predictions to detect metabolic shifts in C. difficile as nutrient availability decreased, and then developed an approach to simultaneously track carbon and nitrogen flow through anaerobe metabolism. The researchers identified how C. difficile jump-starts its metabolism by fermenting amino acids before engaging pathways to ferment simple sugars such as glucose. They found that critical pathways converged on a metabolic integration point to produce the amino acid alanine to efficiently drive bacterial growth.

The study’s findings identified new targets for small molecule drugs to counter C. difficile colonisation and infection in the gut and provide a new approach to rapidly define microbial metabolism for other applications, including antibiotic development and the production of economically and therapeutically important metabolites.

Source: Mass General Brigham

Categories : UncategorizedTags :

Treatment for Resolving C. Diff Infection ‘So Effective’ that Trial Discontinued

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Clostridioides difficile. Source: CDC

In a clinical trial, researchers found that, after a course of vancomycin, faecal microbiota transplantation (FMT) resolved Clostridioides difficile infections significantly more effectively than standard care alone. The treatment was so effective that further participant recruitment was halted. The findings were published in The Lancet Gastroenterology and Hepatology.

The results of the randomised, double-blind, placebo-controlled trial are extremely encouraging, said Simon Mark Dahl Baunwall, a PhD student at the Department of Clinical Medicine and a doctor at Aarhus University Hospital.

“Our new study shows that we can effectively cure the infection through the early use of faecal microbiota transplantation (FMT) after completing the standard treatment, to prevent relapses,” he said.

Few treatment options are available for the urgent threat of C. diff infections. Microbiota restoration with faecal microbiota transplantation is an effective treatment option for patients with multiple recurring episodes of C. diff. The researchers compared the efficacy and safety of faecal microbiota transplantation compared with placebo after vancomycin for first or second C. diff infection.

At a Danish hospital, 42 eligible patients with first or second C. difficile infection were randomly assigned to either faecal microbiota transplantation or placebo administered on day 1 and between day 3 and 7, after they had received 125mg oral vancomycin four times daily for 10 days. The primary endpoint was resolution of C difficile-associated diarrhoea (CDAD) eight weeks after treatment, with patients followed for eight weeks or until recurrence.

Due to the efficacy The primary outcome and safety outcomes were analysed in the intention-to-treat population, which included all randomly assigned patients.

Findings

The trial was stopped after the interim analysis done on April 7, 2022 for ethical reasons because the placebo group had a much lower rate of resolution at week 8 (33%) than the treatment group (90%). The absolute risk reduction was 57%.

“In rare cases, it can happen that you discover that the treatment you are investigating is so effective that it is ethically indefensible to continue,” said Baunwall.

“Our study is one example, in that the new FMT treatment is so much better than the standard treatment with antibiotics that it would be unethical to continue, because the patients in the control group would risk not receiving the FMT treatment.”

Overall, 204 adverse events occurred, with one or more adverse events being reported in 20 of 21 patients in the FMT group and all 21 patients in the placebo group, with the most common being diarrhoea and abdominal pain.

Interpretation

The study authors concluded that FMT in patients with first or second C. diff infection, is highly effective and superior to the standard of care vancomycin alone in achieving sustained resolution from C. diff.

Source: Aarhus University