For example, new data published in The New England Journal of Medicine underscore the shortcomings of advances in testing technology, suggested Sahil Khanna, MBBS, an associate professor of medicine at Mayo Clinic College of Medicine and Science, in Rochester, Minn. (2020;382:1320-1330).
At first glance, the study, which used data from 10 sites nationwide to derive a national estimate of the incidence of CDI, reported a relatively unchanged rate of the disease over a six-year period: 476,400 cases in 2011 and 462,100 cases in 2017. However, Dr. Khanna noted that after adjusting for the increasing use of nucleic acid amplification testing (NAAT), the researchers concluded that the incidence of CDI had actually decreased by 24% during the study period, including a 36% drop in healthcare-acquired CDI cases.
The study highlights a problem with NAAT, according to Khanna.
“NAAT is approximately 95% sensitive in detecting the C. difficile gene, but it cannot determine if the gene is active and toxin-producing, so it has the potential for overdiagnosis and for producing clinical false positives,” he explained. “Because of this, it’s important that we interpret NAAT results in the context of patient symptoms.”
Clinicians must be selective when deciding which patients should be tested, he said, only using it in patients who have acute diarrhea with no obvious alternative explanation, and who have the risk factors for CDI. These include older age, longer hospitalization, immunosuppression, use of antibiotics, gastric acid-suppressing agents, gastrointestinal surgery, manipulation of the gastrointestinal tract, and tube feeding.
“Patients not experiencing an active infection can be colonized with C. difficile, in which case there is a risk of a clinical false positives and unnecessary treatment,” Khanna emphasized.
An alternative testing approach now recommended by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) is the use of a multistep algorithm including glutamate dehydrogenase (GDH) to identify pathogenic bacteria and enzyme immunoassay (EIA) to detect C. difficile toxin (Clin Infect Dis 2018;66:e1-e48). NAAT should be reserved for instances in which results from GDH and EIA are inconclusive, the guidelines recommend.
“Unfortunately, NAAT remains the most commonly used test method,” Khanna said, adding that laboratories are increasingly adopting a two-step protocol of GDH and EIA.
Recurrent CDI mostly occurs in people:65 and older who take antibiotics and receive medical care
staying in hospitals and nursing homes for a long time with weakened immune systems
The treatment landscape for CDI also has changed over the past few years, noted Kim Ly, PharmD, a clinical pharmacy specialist in critical care and infectious diseases at Sunrise Hospital and Medical Center, in Las Vegas. Bezlotoxumab (Zinplava, Merck), a monoclonal antibody, is now approved for combination treatment of toxin B–producing CDI, along with an established antibiotic. Additionally, metronidazole, while still approved for the treatment of CDI, is no longer recommended by IDSA/SHEA as a first-line agent for primary CDI in adults.
“For severe initial episodes of CDI, oral vancomycin and fidaxomicin [Dificid, Merck] are now the preferred agents, and metronidazole is only recommended for nonsevere initial episodes when patients are unable to be treated with oral vancomycin or fidaxomicin,” Kim explained.
For a first recurrence of CDI, the IDSA/SHEA guidelines recommend administering oral vancomycin as a tapered and pulsed regimen or fidaxomicin, rather than a standard 10-day course of vancomycin. For subsequent recurrences, clinicians can use the same regimen, with the addition of a standard course of oral vancomycin followed by rifaximin or fecal microbiota transplantation (FMT).
Metronidazole comes into play again in the management of fulminant CDI, Ly noted.
“The IDSA/SHEA guidelines recommend treating this with oral or rectal vancomycin 500 mg four times daily along with intravenous metronidazole,” she explained.
Given that antibiotic-induced microbiota disruption “is far and away the number one precipitant for getting recurrent CDI,” selecting the CDI treatment with the least impact on the microbiota is important, said former IDSA president Cynthia Sears, MD, a professor in the Department of Medicine, Division of Infectious Diseases, at the Johns Hopkins University School of Medicine, in Baltimore.
“Vancomycin is the most commonly used therapy for CDI and its recurrences, but it decreases intestinal diversity and so impedes the recovery of the normal microbiota after CDI, setting the stage for CDI recurrence,” Sears said. “We have learned that vancomycin hits the colon with full force when taken orally because it is not absorbed, and it has off-target effects on lots of anaerobic bacteria that are essential to intestinal resistance of CDI.”
Fidaxomicin has less of an effect on the microbiota and has been shown to sometimes decrease the risk for CDI recurrence when compared with vancomycin (N Engl J Med 2011;364:422-431), but it can be expensive, she said.
Fecal Microbiota Transplantation
FMT is a less expensive, highly effective treatment that has received increasingly widespread attention, specifically for the management of recurrent CDI. Despite the enthusiasm surrounding the treatment, Sears expressed significant reservations about employing it.
“While there’s no question that FMT benefits patients with recurrent CDI, I feel we don’t yet have a quality-controlled product that we know is safe as well as being effective,” she said.
Sears pointed to two recent FDA safety alerts that warned of the harm that FMT can cause. The first, from 2019, reported that stool from a single donor had not been thoroughly screened before FMT and contained extended-spectrum ss-lactamase–producing Escherichia coli. The specimen had been used in separate FMTs for two immunocompromised patients, leading to infection with the pathogen and death in one case.
In another FDA safety alert from earlier this year, the organization said a stool bank specimen that had undergone comprehensive screening nevertheless contained enteropathogenic E. coli and Shiga toxin-producing E. coli. Transfer of the stool for the treatment of recurrent CDI resulted in one nonfatal infection and one death.
“Stool banks try very hard to be sure their specimens are free of disease-causing microbes, but if you have very low-level colonization, molecular diagnostics can miss this,” Sears said. More recently, she noted, the FDA has also raised concerns about the possibility of transferring SARS-CoV-2 through FMT, given that the virus can be present in the stool of infected individuals.
What would a safer and equally effective microbiota-based treatment look like? According to Sears, while microbial diversity seems to be protective against recurrent CDI, there are suggestions that the administration of specific strains may be able to treat CDI and can be produced under the same strict quality control manufacturing processes as other FDA-approved drugs. One study published in 2015 using human and mouse samples found that colonization with Clostridium scindens, a strain of Firmicutes, increased resistance to CDI (Nature 2015;517:205-208). Many microbiota-based therapeutics are in the research pipeline as well.
“I am optimistic that we will see something emerge that’s safer and still as effective as FMT for patients, whether it’s an orally or rectally administered product,” Sears said.
An accurate diagnosis via laboratory testing is critical for effectively treating persistent diarrhea lasting more than 2 weeks, as the often poorly recognized syndrome can be caused by different pathogens than acute diarrhea, according to a clinical review recently published in JAMA.
“I’d like to educate doctors about the importance of taking the history and assessing duration of illness,” Herbert L. DuPont, MD, Director of the Center for Infectious Diseases at The University of Texas Health Science Center at Houston School of Public Health, said in a press release. “For acute diarrhea, the lab has a minimal role, restricted to patients passing bloody stools. If a patient has had diarrhea for 2 weeks or more, the doctor should focus on the cause of the disease through laboratory testing, with an emphasis on parasites.”
DuPont performed a review of relevant literature published up to February 2016 to provide an overview of the epidemiology, etiology, diagnosis and management of persistent diarrhea in immunocompetent patients.
Common causes of persistent diarrhea
Although acute diarrhea is usually caused by viruses or toxins, persistent diarrhea is usually caused by bacteria or parasites, DuPont wrote.
Protozoa are the most common parasitic cause of persistent diarrhea, including Giardia, Cryptosporidium and Cyclospora, whereas Entamoeba histolytica, Cystoisospora belli, Dientamoeba fragilis, Strongyloides stercoralis and Microsporidia species are less common.
Bacterial species that may cause persistent diarrhea include enteroaggregative Escherichia coli, Shigella, Campylobacter, Salmonella, Vibrio parahaemolyticus, Arcobacter butzleri and Aeromonas species.
Clostridium difficile can cause recurrent diarrhea in patients receiving antibiotics in health care settings, and viral agents, such as norovirus, and helminths can also cause persistent diarrhea.
“Parasites are more common in the developing world. Consequently, persistent diarrhea is more common in these areas and in local populations or people traveling to these locations,” DuPont wrote. “Persistent diarrhea occurs in approximately 3% of international travelers to developing regions.” Parasitic infection is less common in industrialized regions, where foodborne and waterborne pathogens and C. difficileare more common causes, he added.
Persistent diarrhea can also have noninfectious causes, including lactase deficiency, ingested osmotic substances, postinfectious irritable bowel syndrome, functional bowel diseases, inflammatory bowel disease, celiac disease, ischemic or microscopic colitis, carbohydrate malabsorption, cancer and other idiopathic illnesses.
Complete evaluation, new diagnostic methods
Duration of illness should be determined by health care providers when developing an evaluation plan, and the clinical assessment of patients with persistent diarrhea lasting more than 14 days should include a complete history, physical examination and diagnostic testing for infectious or noninfectious etiologies.
“The longer the duration of illness, the more likely it is that parasitic pathogens or noninfectious causes will eventually be identified,” DuPont wrote.
Previously, bacterial pathogens were identified using stool culture-based methods, and parasites are often identified using commercial enzyme immunoassay tests or microscopy. However, the recent advent of multiplex polymerase chain reaction (PCR) platforms enable simultaneous testing for a number of bacterial, viral and parasitic enteropathogens by identifying their DNA sequences.
The xTAG Gastrointestinal Pathogen Panel (Luminex Corp) tests for 14 viruses, bacteria, and parasites and the FilmArray GI panel (Biofire Diagnostics) tests for 22 viruses, bacteria, and parasites.
“These new tests are easy to use, are capable of detecting a broad range of pathogens and represent a significant improvement over culture-based diagnostic approaches,” DuPont said in the press release. “The technology needs to be more widely available. Diagnosis is critical when treating persistent diarrhea.” However, false positive results are problematic, he wrote.
Treatment depends on diagnosis
After treating any dehydration with oral rehydration therapy, a laboratory test should be performed to determine the cause of persistent diarrhea to determine the appropriate treatment. However, a single 1,000 mg dose of empirical azithromycin is appropriate concurrent to the lab test for adults who have traveled to the developing world, as bacterial causes that lab tests cannot usually identify are common.
Although antimicrobial agents are recommended for a number of pathogens, the antibiotic choice should be optimized based on the pathogen’s susceptibility to prevent antimicrobial resistance.
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INTERNATIONAL RAISING C. diff. AWARENESS CONFERENCE
HIGHLIGHTS — PROMISE & CHALLENGES IN C. diff. TREATMENT
Part 1: Novel Approaches and Therapies in Development
The Centers for Disease Control first recognized C. difficile infection (CDI) as an urgent threat to public health in September 2013. However, I first began to understand the impact on patients in 2008 when I was first diagnosed with Clostridium difficile (C. diff). My journeys, including many months of illness (nine recurrent CDI) which included a referral to hospice care before finally being correctly treated in 2009. Henceforth; I was no stranger to this diagnosis with over two decades of Nursing and witnessing the loss of my Father, whose life was claimed by C. difficile involvement in 2004.
C. diff. has left me with serious health complications. Though I returned to my career as a Nurse for a brief time, I was diagnosed with an entirely new C. diff infection in 2011– enduring nine recurrences through the following year. Another year taken away from C. diff..
Like many other patients, the physical, financial and emotional toll has been great – not only on me, but also on my family. Yet, through my journeys and what I have learned in the process has inspired me to help others affected by C. diff. and share with fellow healthcare professionals through educating and advocating for C. difficile infection prevention, treatments, and environmental safety worldwide.
I was proud to kick off the third annual International Raising C. diff Awareness Conference & Health EXPO in Cambridge, MA last fall. The Annual Conference is one of many important initiatives the C Diff Foundation undertakes to build awareness, advance advocacy and support research to address the public health threat posed by this devastating, life-threatening infection and common healthcare-associated infection.
Through the Conference– the C Diff Foundation offers perspective from world renowned experts on C. difficile infection prevention, treatment and research, with discussions ranging from pharmaceutical options to environmental safety products.
Here are the highlights from our guest speakers
Dr. Mary Beth Dorr, Director of Clinical Research, Infectious Diseases at Merck, presented the most recent data on the company’s C. diff antitoxin, bezlotoxumab. Nearest to potential FDA approval among new options for patients, bezlotoxumab would be used as an adjunct to standard antibiotic regimens for C. diff, with a goal of reducing recurrences—something for which no other drug has been approved.
Merck’s first trial, MODIFY 1 (Monoclonal Antibodies For C. DIFficile Therapy), included 1,412 patients globally. In addition to standard treatment of care, patients received a single intravenous infusion of either the antitoxin actoxumab (binds to the C. diff toxin A) or bezlotoxumab (binds to the C. diff toxin B) alone, or the two in combination, or a placebo.
This study called for a pre-specified interim analysis allowing for modifications in the trial after 40% of patients had completed a 12-week follow-up. As a result, actoxumab alone was dropped from further study as it did not provide added efficacy over bezlotoxumab alone or the combination of bezlotoxumab and actoxumab.
The MODIFY 2 trial evaluated an additional 1,163 patients who received standard antibiotic treatment for C. diff plus either bezlotoxumab alone, or the combination of bezlotoxumab and actoxumab, or placebo. The primary endpoint was prevention of a recurrence of C. diff infection at 12 weeks defined as a new episode of diarrhea and a positive stool test for toxigenic C. diff.
Many of the patients in the trial were quite ill: 17% had severe CDI, 18% had the more virulent PCR ribotype 027 strain, and about 20% were immunocompromised.
For the two studies overall, the rates of recurrent C. diff were significantly less in patients receiving bezlotoxumab alone than placebo (17% vs. 28%). Adverse events were no different in the treatment and placebo groups.
Because there was no benefit to the combination of the two antibodies, bezlotoxumab alone was selected for new drug applications submitted to the US FDA and European Medicines Agency seeking marketing approval.
Ecobiotics — A Novel Approach To Recurrent CDI’s
Fecal microbial therapy, also referred to as FMT or stool transplants, generated much discussion. However; this therapeutic approach aiming to change the gut microbiome, the collection of bacteria and other microorganisms in and on our bodies, is being studied in clinical trials by two of the presenters.
Dr. David Cook, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Seres Therapeutics, spoke about “ecobiotic therapeutic restoration.” He noted that a dysbiotic, or imbalanced microbiome, is increasingly linked to multiple diseases including C. difficile infection, inflammatory bowel disease, and metabolic diseases like diabetes mellitus. ECOSPOR is their current Phase 2 clinical study focused on the safety and efficacy of SER-109, a drug for the potential prevention of recurrent Clostridium difficile infection (CDI) in adults who have had three or more episode of CDI within the previous nine months.
In its Phase 2 study, Seres used spores from the Clostridiales group of organisms, treated to decrease the risk of any pathogen transmission. A small group of patients with > 3 prior CDIs were given two doses of a mixture of strains of spores by mouth and followed up for 8 weeks. In this study, 13 of 15 (87%) patients met the primary endpoint of no recurrent diarrhea associated with a positive test for C. diff.
Another study, using a slightly smaller dose of spores, had the same findings. Overall, 29 of 30 (97%) patients had clinical resolution of their diarrhea; the improvement persisted at 24 weeks. A slightly larger Phase 2 study is underway now and Phase 3 studies are planned for 2016. The drug has received breakthrough and orphan drug designations from the FDA. Seres’ drug also reduced carriage of or colonization by multi-drug resistant organisms (MDRO), including Klebsiella, Providencia, and Vancomycin-resistant enterococci (VRE), all of which are recognized by the CDC as urgent or emerging health threats.
RBX2660 — Therapeutic Microbiota Restoration
Dr. Lee Jones, Foundress and CEO of Rebiotix, presented ongoing studies with RBX2660. Their product, RBX2660, which also aims to restore a gut microbiome altered by CDI, has been designated a drug, rather than a tissue transplant, by the FDA and has received fast track, orphan drug, and breakthrough therapy designations. The liquid microbial suspension packaged for enema delivery is manufactured differently than fecal microbial transplants, and the end-product is standardized and ready for administration.
The initial Phase 2 study, PUNCH, was open-label and included 30 patients with at least two recurrences of C. diff requiring hospitalization. With a 6-month follow-up period, this trial had an 87% efficacy rate and no recurrences. A second 120 patient randomized, placebo-controlled, double-blind trial (PUNCH CD 2) is ongoing. Rebiotix is also developing an oral formulation and planning trials for other indications.
Approaches to vaccination were also discussed at the conference by the companies leading those research initiatives. Mucosal vaccination, to protect people from pathogens that enter or cause harm at the mucosal surface, or lining of our gastrointestinal or respiratory tracts, has been used in developing a variety of vaccines, including polio, typhoid, and experimental influenza vaccinations. Dr. Simon Cutting, PhD, Professor of Molecular Microbiology at
Royal Holloway, University of London, explained the rationale behind this approach and reviewed supporting animal data. If approved, this vaccine would be administered orally.
These studies are still in early development.
Dr. Patricia Pietrobon, Associate Vice President, Research and Development, C. diff Program Leader at Sanofi Pasteur, presented an update on the company’s vaccine, H-030-012, which relies on injection of an inactivated whole toxin to both C. diff toxins A and B. Sanofi’s vaccine showed immunogenicity in patients in Phase 2 studies, and was the first vaccine to be awarded fast track approval by the FDA. Their vaccine showed an antibody response and immunologic boost after a dose at 6 months, suggesting vaccination might confer long-term protection from C. diff. A 15,000 participant, 5-year, global trial is underway, hoping to provide long-term immunity to C. diff.
Several other approaches for C. diff prevention and treatment were presented:
The first, described by Dr. Klaus Gottleib, MD, FACG, Vice President, Clinical Development and Regulatory Affairs, Synthetic Biologics, involves use of a beta-lactamase enzyme given orally in combination with a patient receiving a beta-lactam (penicillin or cephalosporin) antibiotic. The antibiotics would still have full efficacy in the blood or soft tissue, but the company’s hypothesis is that the enzyme will destroy unneeded antibiotic in the gut and will prevent C. diff from developing by reducing alteration in the gut flora.
Their drug, SYN-004, is in Phase 2 trial development.
Dr. Martha Clokie, Ph.D. Leicester UK, Professor in Microbiology. Dr. Cloakie’s research focuses on phages that infect bacterial pathogens of medical relevance and is focusing on targeting C. diff without altering the rest of the microbiome in preclinical studies. Hoping to destroy C. diff with a biological warfare approach, she focuses on phages, tiny virus-like particles that infect bacteria.
Dr. Melanie Thompson, Ph.D. is studying an older drug used for rheumatoid arthritis, auranofin, in Australia. Auranofin targets the selenium metabolism of C. diff, and is likely to be fairly specific treatment against that bacterium.
Part 2 – Challenges in Testing and Infection Management
Among the key presentations, Dr. Mark Wilcox, MD, FRCPath, Head of Microbiology and Academic Lead of Pathology at the Leeds Teaching Hospitals, Professor of Medical Microbiology at the University of Leeds, lead on Clostridium difficile for Public Health England, and Chairman of the conference, addressed the challenges of diagnosing C. diff.. From knowing who to test, to which test to employ, the state of testing poses challenges in accurately determining the number of CDI cases and in comparing rates over time or between locations.
He raised important questions for the medical community to address:
Who should be tested?
Which tests should be used?
How do we measure accuracy between tests in order to compare infection rates over time and by location?
Dr. Wilcox showed data from the Euclid Study in Europe looking at approximately 4,000 stool samples submitted to participating hospital labs on a given day, whether or not a test for C. diff. was ordered. The data shows that about 25% of cases were missed by the hospitals, but were picked up by a centralized reference lab. On a single day, 246 patients (6.3%) received an incorrect result from their hospital. The translates to about 40,000 cases of CDI missed in Europe alone per year and underscoring that CDI is far more common, and commonly missed than appreciated, making it hard to grasp both the magnitude of the problem and the treat individual patients.
Barley Chironda, RPN, CIC, Manager of Infection Prevention and Medical Device Reprocessing at St. Joseph’s Health Centre, Toronto, Ontario, Canada also addressed the topic of testing in acknowledging that some physicians may also be reluctant to order C. diff. tests both because the tests can be hard to interpret, and because there may be perceived disincentives for detecting and reporting the infection . Hospitals can be penalized financially for infections acquired in the hospital as well as receive lower quality of care ratings.
While there is confusion over how to test for C. diff. there is a general understanding as to what we must do to contain the epidemic — use fewer antibiotics. Currently, up to 85% of patients with C. difficile associated diarrhea (CDAD) have received antibiotics in the 28 days before their CDI occurred. More than 1/2 of all hospital patients receive an antibiotic, as do almost all surgical patients. Estimates are that 30 – 50% of antibiotic use is unnecessary or inappropriate.
As Dr. Hudson Garrett, Jr., PhD, MSN, MPH, FNP, CSRN, VA-BC, Vice President, Clinical Affairs, PDI, Nice-Pak, and Sani Professional, explained, education of both healthcare workers and patients is needed. Prescribers need to limit antibiotic use to the most specific or narrowest spectrum antibiotic they can, and patients need to learn that antibiotics are not helpful for colds or viral infections.
If use of broad-spectrum antibiotics in hospitals is reduced by 30%, the CDC has estimated there will be 26% fewer CDI’s. Garrett stressed the importance of good leadership and multidisciplinary approach to the success of an antibiotic stewardship program, emphasizing the need for engagement, education and involvement from the top administrators, physicians, pharmacists, and patients,
Another concern is the overuse of the class of antibiotics called quinolones. An especially toxic and severe strain of C. diff. NAP2/027/B1 has been emerging, seemingly driven by the use of fluoroquinolone antibiotics. Quinolones are a widely prescribed class of antibiotics often used in treating pneumonia.
Limiting antibiotics and more appropriate use is not just for people — it is also important in agriculture. There is a growing concern that contaminated products — both meat and produce — may transmit resistant organisms to people and spread C. diff. outside healthcare facilities.
Controlling the spread of C. diff. is a challenge. While previously believed to be strictly a healthcare-associated infection, recent findings show that many patients acquire C. diff. in the community.
As part of his presentation, “Behind the Scenes; C. difficile Management in Health from the lens of an Infection Preventionist, ” Barley Chronda, also reviewed infection control issues, focusing on the importance of cleaning. He noted that 11% of occupants in a hospital room would acquire C. diff. if a prior patient had the infection.
The issues hospitals face include:
A lack of dedicated equipment which may allow for the spread of C. diff. spores on items like stethoscopes and blood pressure cuffs;
Isolation for patients with diarrhea or incontinence with consideration for patient symptoms, hospital costs and appropriate patient care;
Lack of clarity re: responsibility for cleaning specific items, and what type of cleaning agent to use, as many products do not inactivate spores. Clorox ® and UV-C Xenon, a high-energy, full spectrum pulsed Xenon Ultraviolet Light by Xenex — both sponsors of the Conference, were addressed as options for CDI and a variety of multi-drug resistant organisms.
Hand-washing (Hand Hygiene) as many hospitals lack conveniently placed sinks and rely on alcohol hand sanitize gels and solutions,. While alcohol is great for reducing most bacterial contamination, it is ineffective against C. diff. spores.
The Patient Journey Continues
Nancy Sheridan an Educator and Volunteer Patient Advocate, represented the voice of the many patients who face the challenges of being diagnosed, treated, and surviving a C. diff. infection and shared her experience with the audience. After developing diverticulitis complicated by a perforated colon following an overseas trip. Nancy was treated with antibiotics and developed diarrhea. Though doctors thought she might have a travel – related infection, she insisted on being tested for C. diff. and found C. diff. was causing her severe symptoms. She suffered recurrent C. diff. infections, forcing her to take a leave of absence from her job. In addition to the loss of income and mounting medical bills, she described feeling “defeated and broken.”
Desperate, housebound, in pain, and having a marked weight loss from her recurrent vomiting and bloody diarrhea, she asked for a fecal transplant. Despite multiple refusals, she persisted. Eight months after her ordeal began, Nancy received the stool transplant. She describes her recovery as “miraculous” and within a few weeks, she was back to her teaching and active life. Nancy concluded her story by reminding us that on any given day, 1 of 25 hospitalized patients becomes infected with C. diff. noting “the risk of contracting this deadly infection is too great to remain uninformed.”
That message – from Nancy Sheridan, from the professionals who support us, and the patients who we hear from each day on our U.S. national Hot-Line (1-844-FOR-CDIF) continue to drive us in educating, and advocating for C. diff. infection prevention, treatments, environmental safety, and providing support worldwide.
About The C Diff Foundation The C Diff Foundation is a leading non-profit organization founded in 2012 by Nancy Caralla, a Nurse who was diagnosed and treated for recurrent Clostridium difficile (C. difficile) infections. Through her own journey, and the loss of her father to C. difficile infection involvement, Nancy recognized the need for greater awareness through education about research being conducted by the government, industry and academia and better advocacy on behalf of patients, healthcare professionals and researchers worldwide working to address the public health threat posed by this devastating infection. Follow the C Diff Foundation on Twitter (@cdiffFoundation) or Facebook. For more information, visit: http://www.cdifffoundation.org/.
Patients with recurrent Clostridium difficile infection had distinct bile acid and microbiome profiles compared with healthy controls and patients with first Clostridium difficile infection, according to research published in Alimentary Pharmacology and Therapeutics. These findings led researchers to suggest that secondary bile salts may have potential as a novel biomarker for recurrence.
“The mechanism of recurrent CDI remains unknown, though bile salts have been implicated. The intestinal microbiota metabolizes bile acids, a process that if disrupted by antibiotics may be critical to initiation of CDI,” Jessica R. Allegretti, MD, MPH, from the Crohn’s and Colitis Center and Harvard Medical School, Brigham and Women’s Hospital told Healio Gastroenterology. “This study aimed to assess bile salt profiles in three distinct groups of patients — recurrent CDI, first episode CDI and healthy controls — to better understand the role bile salts play in pathogenesis of recurrent CDI and to gain further understanding as to which bacteria may be responsible for this important function. Additionally, we performed random forest regression to identify predictors of group membership.”
Allegretti and colleagues collected blood and stool samples from 20 patients with first CDI, 19 patients with recurrent CDI being screened for fecal transplantation, and 21 controls. Samples from the first CDI arm were collected before patients received antibiotic treatment, whereas samples from the recurrent CDI arm were collected while they were receiving stable doses of chronic oral vancomycin. Participants in the control arm had not been exposed to antibiotics for at least 3 months.
Researchers then analyzed blood plasma and stool samples for bile salt metabolomics profiles, and performed 16S rRNA amplicon sequencing to determine the microbiota composition of the stool samples.
“We found that secondary bile acids, which are protective, were significantly elevated in controls compared with both CDI groups in stool and blood,” Allegretti said.
The median secondary bile acids lithocholate and deoxycholate were significantly higher in the stool samples of controls compared with both first CDI (P < .0001 and P = .0003, respectively) and recurrent CDI arms (both P < .0001). Deoxycholate was also significantly higher in first vs. recurrent CDI patients (P = .017).
Median deoxycholic acid was significantly higher in the blood samples of controls compared with both first CDI (P < .0001) and recurrent CDI patients (P = .05), and was also significantly higher in the blood samples of first vs. recurrent CDI patients (P = .003).
“Conversely, primary bile acids, which can induce germination, were elevated in the recurrent group,” Allegretti said.
The primary bile acids cholate and chenodeoxycholate were significantly higher in the stool samples of the recurrent CDI arm compared with controls (P = .0002 and P = .02, respectively).
16S rRNA gene analyses showed significant differences in microbial alpha diversity across groups, which were most pronounced in recurrent CDI patients vs. controls (adjusted P < .001), but also significant between first and recurrent CDI patients and between first CDI patients and controls (both adjusted P < .05). There were also significant differences in beta-diversity between all groups (P = .001) and significant differences in relative abundances at the taxa level.
Using PICRUSt analyses, the researchers also found significant differences in predicted abundances of bacterial bile salt hydrolase genes between groups. Finally, using random forest regression, the researchers differentiated recurrent and first CDI patients 84.2% of the time using bile acid ratios, with stool deoxycholate to glycoursodeoxycholate ratio as the best predictor.
“Plasma deoxycholate (a secondary bile acid) was a strong predictor of disease state and may be utilized as a possible biomarker of recurrence,” Allegretti said. “This study further elucidates the role of bile salts in the pathogenesis of recurrent CDI and identifies possible novel biomarkers for recurrent disease.”
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“C. diff. Spores and More,” Global Broadcasting Network – innovative and educational interactive healthcare talk radio program discusses
This episode—— “Understanding IBS”
With Our Guests:
Dr. Caterina Oneto, MD,
Dr. Paul Feuerstadt, MD, FACG
This episode of “C. diff. Spores and More” is focused on “What is IBS?” So you’ve been diagnosed with IBS (Irritable Bowel Sydrome). Now what? Join us for a discussion about the definition, diagnosis, and treatment of the various forms of IBS with our special guests: Dr. Caterina Oneto,, MD and Dr. Paul Feuerstadt, MD, Both professors and physicians specializing in Gastroenterology with a wealth of knowledge and experience treating patients diagnosed with a CDI and through ongoing scientific/medical research.
MORE ABOUT OUR GUESTS:
Dr. Caterina Oneto, MD
Dr. Caterina Oneto is a Clinical Assistant Professor within the NYU Division of Gastroenterology, Board Certified in Gastroenterology and Internal Medicine.
Fluent in Spanish, she graduated with a degree in Medicine and Surgery from the Universidad de Valparaiso in Chile. She completed her residency in Internal Medicine at Cabrini Medical Center, where she served also as Chief Resident, and later completed her Fellowship in Gastroenterology at Montefiore Medical Center, Albert Einstein College of Medicine.
With expertise in endoscopy, colonoscopy, capsule endoscopy, liver and pancreatic diseases, Dr. Oneto’s special interests include IBD (Crohn’s disease and Ulcerative Colitis), IBS (irritable bowel syndrome), microbiota modification, treatment of Clostridium Difficile and FMT (Fecal Microbiota Transplantation).
Dr. Paul Feuerstadt, MD
A native of Long Island, New York, Dr. Feuerstadt attended the University of Pennsylvania where he earned his Bachelor of Arts degree in Biology, with distinction in research and graduated Summa Cum Laude. Following completion of his undergraduate training, Dr. Feuerstadt attended the Weill Medical College of Cornell University in Manhattan, New York where he earned his Medical Doctor degree and stayed at New York Presbyterian Hospital/Weill Cornell medical center for his internship and residency in Internal Medicine. Following completion of his residency Dr. Feuerstadt then moved on to the Montefiore Medical Center in the Bronx, NY for his clinical fellowship training.His areas of interest include ischemic diseases of the gut and chronic diarrheal syndromes with a specific focus on C.diff. infections.Dr. Feuerstadt is affiliated with St. Raphael campus of Yale-New Haven Hospital, Yale-New Haven Hospital and Milford Hospital seeing outpatients in his offices in Hamden and Milford, CT
Both Dr. Oneto and Dr. Feuerstadt preside as Medical Advocates
for the C. diff. Global Community Support Program.
“C. diff. Spores and More “ Global Broadcasting Network spotlights world renowned topic experts, research scientists, healthcare professionals, organization representatives,C. diff. survivors, board members, and their volunteers who are all creating positive changes in the
C. diff. community and more.
Through their interviews, the C Diff Foundation mission will connect, educate, and empower many worldwide.
Questions received through the show page portal will be reviewed and addressed by the show’s Medical Correspondent, Dr. Fred Zar, MD, FACP, Dr. Fred Zar is a Professor of Clinical Medicine, Vice Head for Education in the Department of Medicine, and Program Director of the Internal Medicine Residency at the University of Illinois at Chicago. Over the last two decades he has been a pioneer in the study of the treatment of Clostridium difficile disease and the need to stratify patients by disease severity.
Programming for C. diff. Spores and More is made possible through our official Sponsor; Clorox Healthcare