Tag Archives: Microbiome

Minnesota Has Declared November “C. difficile Infection Awareness Month

 

 

 

 

http://www.clipsyndicate.com/video/play/7172019

According to research, C. Diff is the most common infection in U.S. hospitals within the last decade.

The state of Minnesota has declared November C. difficile Infection Awareness Month.” According to research, C. Diff is the most common infection in U.S. hospitals within the last decade.

Doctors at Mayo Clinic want people to know that they can get the infection even outside of hospitals. They also say once you get it, it’s easier to get it each time.

Dr. Sahil Khanna said ways to prevent C. diff is to wash hands and avoid unnecessary antibiotics.

He said Mayo Clinic is also studying whether or not there could be a vaccination for C. Diff.

“So there’s a large multi-center study that’s going on right now in people who may be at risk for C. Diff infection,” Khanna said. “So if you’ve been to the hospital, if you’ve received antibiotics, those patients can be enrolled in a vaccine study to see if this vaccine would prevent C. Diff from happening.”

Mayo Clinic is also working with Minnesota-based company Rebiotix on another form of treatment for the infection where people can simply ingest a tablet.

“Newer studies are being derived where you can actually take material from donor stool, process donor stool in a lab, and derive all the good bacteria that you need from the donor stool and put them in capsule form,” Khanna said.

Khanna said this capsule-based treatment has more advantages than a colonoscopy-based treatment that is currently being used to treat C. Diff.

 

Clifford McDonald, MD and Alison Laufer-Halpin, Ph.D., of the CDC Discuss the Human Microbiome on C. diff. Spores and More

C Diff Foundation’s “C. diff. Spores and More Global Broadcasting Network” is honored to announce Doctors McDonald and Laufer-Halpin as our guest speakers on

Tuesday, July 25, 2017 at 10 a.m. PT / 1 p.m. ET

(www.cdiffradio.com)

These two leading topic experts will be discussing significant ways to unlock the mysteries of the human microbiome; how it affects our health, the immune system, and why it is so important to protect it.

As part of the Centers for Disease Control and Prevention (CDC) efforts to protect patients and slow antibiotic-resistance, the CDC is investing in research to discover and develop new ways to prevent antibiotic-resistant infections.

To Listen To the Podcast – click on the following link:

https://www.voiceamerica.com/episode/100322/the-human-microbiome-how-it-works-how-it-affects-your-health-your-immune-system-and-why-it-is

 

Learn more about C Diff Radio at: http://www.cdiffradio.com/.

Study shows Microbiome Differences Between Intensive Care Unit Patients Hospitalized From Healthy Patients

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The microbiome of patients admitted to the intensive care unit (ICU) at a hospital differs dramatically from that of healthy patients, according to a new study published in mSphere.

 

Researchers analyzing microbial taxa in ICU patients’ guts, mouth and skin reported finding dysbiosis, or a bacterial imbalance, that worsened during a patient’s stay in the hospital. Compared to healthy people, ICU patients had depleted populations of commensal, health-promoting microbes and higher counts of bacterial taxa with pathogenic strains – leaving patients vulnerable to hospital-acquired infections that may lead to sepsis, organ failure and potentially death.

What is dysbiosis?  Pathogens, antibiotic use, diet, inflammation, and other forces can cause dysbiosis, a disruption in these microbial ecosystems that can lead to or perpetuate disease  (1)

What makes a gut microbiome healthy or not remains poorly defined in the field. Nonetheless, researchers suspect that critical illness requiring a stay in the ICU is associated with the the loss of bacteria that help keep a person healthy. The new study, which prospectively monitored and tracked changes in bacterial makeup, delivers evidence for that hypothesis.
“The results were what we feared them to be,” says study leader Paul Wischmeyer, an anesthesiologist at the University of Colorado School of Medicine. “We saw a massive depletion of normal, health-promoting species.”
Wischmeyer, who will move to Duke University in the fall, runs a lab that focuses on nutrition-related interventions to improve outcomes for critically ill patients.

He notes that treatments used in the ICU – including courses of powerful antibiotics, medicines to sustain blood pressure, and lack of nutrition – can reduce the population of known healthy bacteria. An understanding of how those changes affect patient outcomes could guide the development of targeted interventions to restore bacterial balance, which in turn could reduce the risk of infection by dangerous pathogens.
Previous studies have tracked microbiome changes in individual or small numbers of critically ill patients, but Wischmeyer and his collaborators analyzed skin, stool, and oral samples from 115 ICU patients across four hospitals in the United States and Canada. They analyzed bacterial populations in the samples twice – once 48 hours after admission, and again after 10 days in the ICU (or when the patient was discharged). They also recorded what the patients ate, what treatments patients received, and what infections patients incurred.
The researchers compared their data to data collected from a healthy subset of people who participated in the American Gut project dataset. (American Gut is a crowd-sourced project aimed at characterizing the human microbiome by the Rob Knight Lab at the University of California San Diego.) They reported that samples from ICU patients showed lower levels of Firmicutes and Bacteroidetes bacteria, two of the largest groups of microbes in the gut, and higher abundances of Proteobacteria, which include many pathogens.
Wischmeyer was surprised by how quickly the microbiome changed in the patients. “We saw the rapid rise of organisms clearly associated with disease,” he says. “In some cases, those organisms became 95 percent of the entire gut flora – all made up of one pathogenic taxa – within days of admission to the ICU. That was really striking.” Notably, the researchers reported that some of the patient microbiomes, even at the time of admission, resembled the microbiomes of corpses. “That happened in more people than we would like to have seen,” he says.
Wischmeyer suggests the microbiome could be tracked like other vital signs and could potentially be used to identify patient problems and risks before they become symptomatic. In addition, now that researchers have begun to understand how the microbiome changes in the ICU, Wischmeyer says the next step is to use the data to identify therapies – perhaps including probiotics – to restore a healthy bacterial balance to patients.
Everyone who collaborated on the project – including dietitians, pharmacists, statisticians, critical care physicians, and computer scientists – participated on a largely voluntary basis without significant funding to explore the role of the microbiome in ICU medicine, says Wischmeyer.

 

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

https://www.asm.org/index.php/journal-press-releases/94540-icu-patients-lose-helpful-gut-bacteria-within-days-of-hospital-admission?platform=hootsuite

Sources:

(1)  http://www.serestherapeutics.com

 

Thanks and Appreciation To Our Guests For Joining Us On C. diff. Spores And More Season II

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As Season II concludes, we wish to take this opportunity to sincerely thank each
and every guest for taking time out of their
busy schedule and joining us on Tuesday’s at
10:00a Pacific Time / 1:00p Eastern Time over the past seven months.

C. diff. Spores and More Global Broadcasting Network will be taking a break and will return to live broadcasting on  January 17th, 2017 with the Centers for Disease Control and Prevention (CDC) leading the way with our guest
Dr. Katherine Fleming-Dutra, Medical Officer, CDC’s Office of Antibiotic Stewardship.

A Prescription for Over-Prescribing: The Key to Fighting
Antibiotic Resistance

Dr. Fleming-Dutra is a medical epidemiologist with the Office of Antibiotic Stewardship in the Division of Healthcare Quality Promotion at the Centers Disease Control and Prevention (CDC).

Dr. Fleming-Dutra is a pediatrician and pediatric emergency medicine physician and has focused on infectious diseases epidemiology and antibiotic stewardship in the outpatient setting in her career at CDC.

Join Dr. Fleming-Dutra as she discusses a recent study published by the Journal of the American Medical Association, was released showing that at least 30 percent of all prescriptions written in doctors’ offices and emergency rooms are completely unnecessary. So how do we use these alarming results to transform the culture of over-prescribing Dr. Katherine Fleming-Dutra, M.D., will:

  • Give a detailed explanation of the study results, and provide an in-depth review of specific findings;
  • Highlight what CDC is doing to promote antibiotic stewardship across healthcare settings, and
  • Identify what clinicians, other health care professionals, and patients can do to improve antibiotic prescribing, therefore fighting antibiotic resistance.

 

C diff Radio™ Live Broadcast AND Podcasts

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  brought to you by VoiceAmerica and
sponsored by Clorox Healthcare

An educational program that is dedicated to  C. difficile Infections  and more–

 

Click On The LOGO  Above And Enjoy Listening To the Live Broadcasts In the C. diff. Spores and More Podcast Library.

 

Live Broadcast airs
on Tuesdays at:    10a PT,    11a MT,   12p CT,    1p ET

We are pleased to share  “C. diff. Spores and More ™”  with you because, as advocates of  C. diff.,  we know the importance of this cutting-edge new weekly radio show  and what it means for our Foundation’s community worldwide.–

Hard Facts: Deaths and illnesses are much higher than reports have shown. Nearly half a million Americans suffered from Clostridium difficile (C. diff.) infections in a single year according to a study released today, February 25, 2015, by the Centers for Disease Control and Prevention (CDC).

• More than 100,000 of these infections developed among residents of U.S. nursing homes.

Approximately 29,000 patients died within 30 days of the initial diagnosis of a C. diff. infection. Of these 29,000 – 15,000 deaths were estimated to be directly related to a
C. diff. infection. Therefore; C. diff. is an important cause of infectious disease death in the U.S.

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Previous studies indicate that C. diff. has become the most common microbial cause of Healthcare-Associated Infections found in U.S. hospitals driving up costs to $4.8 billion each year in excess health care costs in acute care facilities alone. Approximately
two-thirds of C. diff. infections were found to be associated with an inpatient stay in a health care facility, only 24% of the total cases occurred in patients while they were hospitalized. The study also revealed that almost as many cases occurred in nursing homes as in hospitals and the remainder of individuals acquired the
Healthcare-Associated infection, C. diff., recently discharged from a health care facility.

This new study finds that 1 out of every 5 patients with the Healthcare-Associated Infection (HAI), C. diff., experience a recurrence of the infection and 1 out of every 9 patients over the age of 65 diagnosed with a HAI – C. diff. infection died within 30 days of being diagnosed. Older Americans are quite vulnerable to this life-threatening diarrhea infection. The CDC study also found that women and Caucasian individuals are at an increased risk of acquiring a C. diff. infection. The CDC Director, Dr. Tom Frieden, MD, MPH said, “C. difficile infections cause immense suffering and death for thousands of Americans each year.” “These infections can be prevented by improving antibiotic prescribing and by improving infection control in the health care system. CDC hopes to ramp up prevention of this deadly infection by supporting State Antibiotic Resistance Prevention Programs in all 50 states.”

“This does not include the number of C. diff. infections taking place and being treated in other countries.”  “The  C Diff Foundation supports hundreds of communities by sharing the Foundation’s mission and  raising C. diff. awareness to healthcare professionals, individuals, patients, families,  and communities working towards a shared goal ~  witnessing a reduction of newly diagnosed C. diff. cases by 2020 .”   ” The C Diff Foundation volunteer Advocates are greatly appreciated and continue to create positive changes by sharing their time  aiding in the success of our mission “Raising C. diff. awareness ™”  worldwide.

C. diff. Spores and More ™“ 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 listeners 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 HeZarPhotoWebsiteTop (2)ad 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.

 

Take our show on the go…………..download a mobile app today

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Programming for C. diff. Spores and More ™ is made possible through our official Corporate Sponsor;  Clorox Healthcare

We look forward to sharing time with our worldwide listeners when we return in January, Season III. 

Until then………………

We send out get-well wishes to everyone being treated for and recovering from a C. difficile infection and all wellness draining illnesses worldwide.

“None of us can do this alone – All of us can do this together!”

Summit Therapeutics Announces Additional Positive Data From the CoDIFy Phase 2 Clinical Trial That Show Narrow Spectrum Antibiotic ridinilazole Preserves Gut Microbiome in C.diff. Infection Patients

In The News *

Summit Therapeutics , the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and Clostridium difficile infection (‘CDI’), announces additional positive data from the CoDIFy Phase 2 clinical trial that show the narrow spectrum antibiotic ridinilazole preserves the gut microbiome in CDI patients while the standard of care, vancomycin, inflicts substantial and long-lasting damage on the gut microbiome.

About Ridinilazole
Ridinilazole (SMT19969) is an orally administered small molecule antibiotic that Summit is developing specifically for the treatment of CDI. In preclinical efficacy studies, ridinilazole exhibited a narrow spectrum of activity and had a potent bactericidal effect against all clinical isolates of C. difficile tested. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In this trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy.  Ridinilazole has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track status by the US Food and Drug Administration.  The QIDP incentives are provided through the US GAIN Act and include an extension of marketing exclusivity for an additional five years upon FDA approval.

“CDI results from damage to the microbiome, and patients experience further collateral damage through the use of broad spectrum antibiotics to treat CDI, leaving them vulnerable to recurrent disease,” commented David R. Snydman, MD, FACP, FIDSA, Chief, Division of Geographic Medicine and Infectious Diseases and Hospital Epidemiologist of Tufts University School of Medicine. “New, selective antibiotics are needed to minimise these high recurrence rates, and ridinilazole demonstrates an exceptional ability to preserve a patient’s microbiome and allow the growth of protective bacteria, which are vital to protecting against CDI.”

Preliminary analysis of these new data show ridinilazole to be highly preserving of the gut microbiome. Ridinilazole treated patients in CoDIFy exhibited no further damage to their microbiome during therapy with a proportion of patients showing initial evidence of recovery of key bacterial groups with roles in protecting from CDI. In stark contrast, vancomycin treated patients suffered substantial damage to their gut microbiome during treatment and this persisted in many patients during the 30-day post treatment period.

“These new results from the Phase 2 trial show ridinilazole preserves the patients’ microbiome while simultaneously working to eradicate the C. difficile bacteria. The clinical data strongly suggest that ridinilazole treatment may be better able to protect against recurrent disease than the current standard of care,” commented Glyn Edwards, Chief Executive Officer of Summit Therapeutics. “We believe this approach offers a clear advantage over conventional broad spectrum antibiotics currently used to treat CDI that cause substantial damage to the gut microbiome or approaches that aim to artificially re-establish a damaged gut microbiome following antibiotic treatment.”

“As evidenced by our growing body of clinical and preclinical data, we believe ridinilazole has the ideal profile to become a single therapeutic approach capable of both treating the initial infection and reducing the high rates of recurrent disease.”

These key microbiome findings strongly support recently reported results from the Phase 2 CoDIFy trial that showed ridinilazole to be statistically superior to vancomycin in sustained clinical response (‘SCR’), a combined endpoint capturing both initial cure and rates of recurrent CDI, with the improved SCR rate following ridinilazole treatment being driven by a large numerical reduction in recurrence. Full microbiome data are expected to be published at a scientific conference in due course.

About CoDIFy
CoDIFy was a double blind, randomized, active controlled, multi-centre, Phase 2 clinical trial that evaluated the efficacy of ridinilazole against vancomycin in a total of 100 patients. Half of the patients received ridinilazole for ten days (200 mg, twice a day), and the remaining half received vancomycin for ten days (125 mg, four times a day). The results of the trial showed ridinilazole achieved statistical superiority in SCR with rates of 66.7% compared to 42.4% for vancomycin.  SCR is defined as cure at the end of therapy and no recurrent disease 30 days post end of therapy. The primary analysis was conducted on the modified intent-to-treat (‘mITT’) population that comprised subjects with CDI confirmed by the presence of free toxin. These additional data on the preserving effect ridinilazole had on the gut microbiome support the top-line Phase 2 data and improvement observed in rates of recurrent disease.

 

About Ridinilazole
Ridinilazole (SMT19969) is an orally administered small molecule antibiotic that Summit is developing specifically for the treatment of CDI. In preclinical efficacy studies, ridinilazole exhibited a narrow spectrum of activity and had a potent bactericidal effect against all clinical isolates of C. difficile tested. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In this trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy.  Ridinilazole has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track status by the US Food and Drug Administration.  The QIDP incentives are provided through the US GAIN Act and include an extension of marketing exclusivity for an additional five years upon FDA approval.

About Summit Therapeutics
Summit is a biopharmaceutical company focused on the discovery, development and commercialisation of novel medicines for indications for which there are no existing or only inadequate therapies. Summit is conducting clinical programs focused on the genetic disease Duchenne muscular dystrophy and the infectious disease C. difficile infection.

Further information is available at www.summitplc.com and Summit can be followed on Twitter (@summitplc).

To read the article in its entirety:

http://www.econotimes.com/Summit-Announces-Ridinilazole-Preserves-the-Gut-Microbiome-of-Patients-With-C-difficile-Infection-in-Phase-2-Trial-173750

*Please note – The C Diff Foundation does not endorse this product or any product and this posting is strictly for informational purposes only.

C. diff. Spores and More Global Broadcasting Network Welcome Guests; Dr. David Cook, Ph.D., and Dr. Michele Trucksis, Ph.D., M.D. Of Seres Therapeutics, Inc.

“Ecobiotics: A Novel Approach to Recurrent C. difficile infections”

Tuesday, February 23rd — Live Broadcast

PODCAST IS NOW AVAILABLE, PLEASE CLICK ON THE SERES THERAPEUTICS LOGO BELOW

10 a.m. Pacific Time,,   11 a.m. Mountain Time,
12 p.m. Central Time,    1 p.m. Eastern Time

We invite you to  listen to the live broadcast and archived programs by clicking on the
Cdiff radio logo displayed below:

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This episode introduces Seres Therapeutics, a leading microbiome therapeutics company, which recently published in the Journal of Infectious Diseases positive results from an open-label Phase 1b/2 study of SER-109 for the treatment of patients with recurrent
C. difficile infections (CDI).  Seres Therapeutics is creating a new class of medicines to treat diseases resulting from functional deficiencies in the microbiome, a condition known as dysbiosis.

TO LISTEN TO THIS EPISODE – PLEASE CLICK ON THE SERES THERAPEUTICS LOGO BELOW

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New insights into the human microbiome are fundamentally reshaping how we understand and treat a wide range of diseases, creating new possibilities for patients not served by current therapeutic approaches. Ecobiotics are ecological compositions of beneficial organisms that are designed to reestablish a healthy microbiome. The discovery efforts at Seres Therapeutics currently span metabolic, inflammatory, and infectious diseases.

Join Guests;  
Dr. David Cook, Ph.D., Executive Vice President of R&D and Chief Scientific Officer
And
Dr. Michele (Shelley) Trucksis, Ph.D., M.D., Executive Vice President and Chief Medical Officer

As we discuss the microbiome, CDI, clinical studies SER-109, Probiotics, ECOSPOR, and much more

 

C. diff. Spores and More™  Global Broadcasting Network –  producing educational programs dedicated to  C. difficile Infections and more —  brought to you by VoiceAmerica and sponsored by Clorox Healthcare

 

Seres Therapeutics Disclaimer:
“This interview will include forward-looking statements on Seres Therapeutics’ current expectations and projections about future events. These statements are based upon current beliefs, expectations and assumptions, and are subject to a number of important risks and uncertainties, including those set forth in Seres Therapeutics’ filings with the SEC, many of which are difficult to predict. Actual results may differ materially from such statements. The information included in this interview is provided only as of the date of this interview, and Seres Therapeutics undertakes no obligation to update any forward-looking statements stated in this interview on account of new information, future events, or otherwise, except as required by law. Seres Therapeutics has provided financial support to the C Diff Foundation.”

Seres Therapeutics, Inc., A Leading Microbiome Therapeutics Company, Announced Positive Results From the Phase 1b/2 Study of SER-109 In Recurrent Clostridium difficile infections (CDI)

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“The impressive level of efficacy observed with SER-109 treatment is striking when compared with the high rate of recurrence expected in this population,” said Dr. Stuart H. Cohen, MD, Chief, Division of Infectious Diseases, University of California, Davis. “These results demonstrate the potential of SER-109 to effectively treat recurrent CDI. With current treatment approaches having significant limitations, SER-109 has the potential to fundamentally change the management of this urgent health issue.”

Abstract

Background. Patients with recurrent Clostridium difficile infection (CDI) have a ≥60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI.

Methods.  Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 × 109 spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 × 108 spores). The primary efficacy end point was absence of C. difficile–positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed.

Results.  Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile–positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non–spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea.

Conclusions.  SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI.

 

Clostridium difficile infection (CDI) and its attendant complications, including diarrhea, pseudomembranous colitis, and toxic megacolon, are associated with an estimated 29 000 annual deaths in the United States and is recognized by the Centers for Disease Control and Prevention as an urgent public health priority [1]. Antibiotic exposure is the leading risk factor for CDI, and the risk of recurrent disease is increased among elderly patients and following antibiotic reexposure. Antibiotic therapy for recurrent CDI contributes to persistent disruption of the gut microbiome, which is the first-line defense against colonization and infection by pathogens, including C. difficile [25]. The risk of recurrence increases to >60% following a second episode [3, 6, 7].

Research has focused on the potential role that the human microbiome plays in health and disease. In 2008, the National Institutes of Health supported the creation of the Human Microbiome Project to characterize the species composition and function of the healthy microbiome. In the gut, the 2 dominant phyla are Firmicutes (ie, gram-positive organisms, including Bacilli and Clostridia) and Bacteroidetes (ie, gram-negative anaerobes, including Bacteroides, Parabacteroides, and Prevotella) [8, 9]. In contrast, gram-negative Enterobacteriaceae, such as Escherichia coli, make up only a fraction of the healthy microbiome [8]. There is also significant intersubject variability at both the genus and species level, suggesting that the bacterial communities in any one individual are unique, mirroring the complex interplay of diet, host genetics, immune response, and microbial coadaptation. Despite this variation, there are common core species found in a majority of healthy individuals, and metabolic pathways are preserved due to functional redundancy [10]. Thus, a wide range of microbiomes defines a healthy state.

In states of disease, there are also broad patterns that define gut dysbiosis, such as a loss of microbial diversity and increasing representation of gram-negative facultative anaerobes, such as Enterobacteriaceae [11, 12]. Antibiotic-induced dysbiosis underlies colonization and invasion by C. difficile, while repair of the microbiome, through fecal microbiota transplantation (FMT), is associated with efficacy rates of 81%–90% for those with recurrent CDI [1316]. FMT involves transferring minimally processed, uncharacterized fecal material from a healthy donor to a recipient [17].

FMT administration is often invasive and requires donor screening and stool preparation. Despite donor screening, stool preparations for FMT have the potential to transmit infections due to pathogens that are present at times outside the period of detectability or for which diagnostic tests are unavailable; there is also the possibility of unwitting transmission of emerging pathogens that have not been identified to date [18, 19]. While there have been recent reports of stool delivered via oral encapsulated FMT or stool enemas, the data demonstrate first-dose efficacy of approximately 52%–70%, which is significantly lower than that for other modes of administration, such as colonoscopy [14, 20, 21]. In recognition of FMT as an experimental biologic, the Food and Drug Administration issued guidance that this intervention should only be used for prevention of recurrent CDI and after receipt of informed consent. An alternative approach for achieving improved safety and convenience with comparable efficacy is urgently needed [22].

SER-109 is composed of approximately 50 species of Firmicutes spores derived from stool specimens from healthy donors. After demonstrating the preclinical efficacy of SER-109 in rodent CDI models, we formulated it for oral delivery in humans based on the hypothesis that spore-forming organisms would compete metabolically with C. difficile for essential nutrients and/or bile acids [2327]. In addition, spore purification with ethanol reduces the risk of transmission of other potential pathogens [28]. This initial study was designed to evaluate the efficacy and safety profile of SER-109 for CDI prevention in patients with recurrent infections and to measure alterations in the gut microbiota.

METHODS

Study Design

This open-label, single-arm, descending-dose study evaluated the safety, efficacy, and engraftment of SER-109 formulated for oral delivery. The study was sponsored by Seres Therapeutics and conducted at 4 US medical centers: Massachusetts General Hospital (Boston, Massachusetts), Mayo Clinic (Rochester, Minnesota), Miriam Hospital (Providence, Rhode Island), and Emory University Hospital (Atlanta, Georgia). The protocol was developed by investigators at Seres Therapeutics and authors of the current study (E. L. H., D. S. P., and S. K.) and was approved by the institutional review boards of the participating medical centers.

Study Population

Eligible patients were 18–90 years old and had ≥3 laboratory-confirmed CDI episodes in the previous 12 months, had a life expectancy of ≥3 months, and gave informed consent to receive this donor-derived product. Patients were excluded for a history of acute leukemia; hematopoietic stem cell transplantation, chemotherapy within 2 months and an absolute neutrophil count of <1000 neutrophils/mm3, a history of inflammatory or irritable bowel disease, colectomy, cirrhosis, pregnancy/lactation, severe acute illness unrelated to CDI, antibiotic exposure for a non-CDI indication within 14 days of screening, or prior FMT.

Eligible patients had a clinical response to antibiotic therapy for their current CDI episode immediately prior to dosing and were neither anticipated to require admission to an intensive care unit nor expected to need antibiotics within 6 weeks following study entry.

Screening of Donors

Seven adult donors of stool specimens gave informed consent, underwent a complete medical history and laboratory assessment, and were screened for blood-borne and fecal pathogens, consistent with published protocols [29, 30]. Donors were excluded for being older than 50 years, having a body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) of >25, engaging in high-risk behaviors as per a modified American Association of Blood Banks blood donor questionnaire [31], having a history of acute/chronic gastrointestinal disorders, or using antibiotics (in the previous 6 months), immunosuppressive/antineoplastic agents, or cigarettes (Supplementary Materials).

Preparation of SER-109

SER-109 comprises Firmicutes spores fractionated from stool specimens obtained from healthy donors. Donor stool specimens were processed separately to make unique batches of SER-109. Upon collection, stool specimens were frozen at −80°C. Approximately 150 g was suspended and homogenized in normal saline and filtered through mesh screens. The slurry was centrifuged, and supernatant containing bacterial cells and spores was combined with 100% ethanol to 50% (wt/wt) and incubated at room temperature for 1 hour to reduce risk of pathogen transmission to the recipient [28]. The supernatant was pelleted by centrifugation, washed with saline to remove ethanol, resuspended with sterile glycerol, and filled into capsules (hypromellose DRcaps, Capsugel), which were stored at −80°C.

The product was characterized for spore concentration and absence of residual gram-negative bacteria. Spore content was determined by measuring the dipicolinic acid (DPA) content and normalizing against the DPA content of known numbers of spores representing 3 commensal species [32]. The absence of residual gram-negative bacteria was confirmed by selective plating on MacConkey lactose agar and Bacteroides bile esculin agar. No vegetative microbes were found in any SER-109 preparation within the limit of assay detection (<30 colony-forming units/mL).

Treatment Protocol

Two days prior to dosing, patients discontinued antibiotics for CDI. One day prior to dosing, patients underwent a bowel preparation (to minimize residual antibiotic in the gastrointestinal tract), followed by overnight fasting. Two sites used a regimen of 300 mL of magnesium-citrate (one with Dulcolax), and 2 sites used polyethylene glycol.

Part 1 enrolled 15 patients who each received 30 capsules of SER-109 (observed dose of 15 capsules on day 0 and day 1). The dose of spores varied between 3 × 107 and 2 × 1010, based on natural variations in spore concentration among healthy donors. Based on initial efficacy, 15 additional patients were enrolled in part 2 and treated with SER-109 capsules containing a lower fixed dose of 1 × 108 spores (approximately 17-fold lower than the geometric mean dose administered in part 1 and 3-fold above the minimum dose shown to be effective). Depending on spore content, patients received an observed dose of 1–12 capsules on day 0.

Any patient whose diarrhea recurred between 1 and 8 weeks was eligible for another dose of SER-109, based on data from the conventional FMT literature showing efficacy of a second dose [13, 14]. If a patient elected to receive a second dose of SER-109, the time course of study events was restarted concurrent with the second dose of SER-109.

Adverse events and recurrence of CDI symptoms were monitored through phone calls (on day 4 and weeks 1, 2, and 4) and in-clinic visits (on weeks 8 and 24). Patients were asked to provide a stool sample on day 4 and on weeks 1, 2, 4, 8, and 24 after treatment for genomic and culture-based analysis.

Clinical Outcomes

The primary end point was prevention of recurrent CDI during the 8-week follow-up after SER-109. CDI recurrence was defined as a composite end point of >3 unformed bowel movements in a 24-hour period and laboratory confirmation of C. difficile in the stool. Safety was evaluated by monitoring adverse events and assessing changes in laboratory values, vital signs, and physical examination findings over a 24-week period after dosing.

Alterations in Gut Microbiota Composition

The impact of SER-109 on gut microbiota was determined by examining stool samples before and after treatment for (1) engraftment by spore-forming species and (2) augmentation (outgrowth) of commensal bacteria not found in SER-109. Alterations in composition were measured by 16S ribosomal RNA (rRNA) genomic and culture-based analysis of patient fecal samples (Supplementary Materials). Engraftment was defined by newly detected spore formers in the patient after treatment, which were present in SER-109 but not detectable in the patient before treatment. Augmented bacteria were defined as non–SER-109 organisms whose levels increased at least 10-fold after treatment.

RESULTS

Patient Population

Thirty patients were enrolled after therapeutic response to appropriate CDI antibiotics (ie, vancomycin [n = 23], fidaxomicin [n = 5], metronidazole [n = 1], and rifaximin [n = 1]) was documented (Table 1). Patients had a median age of 66.5 years (range, 22–88 years), and the majority of subjects (67%) were female. The median time from the initial C. difficile diagnosis to the most recent recurrence was 23.1 weeks in cohort 1 and 34.3 weeks in cohort 2. In the overall study population, the median number of CDI recurrences was 3 (range, 2–6 recurrences). Infecting C. difficile strains were identified in 10 patients and included types BI, Y, and DH (Supplementary Table 1).

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Table 1.

Patient Demographic Characteristics, by Cohort

Complete blood counts and a chemistry panel (including liver function tests and analysis of albumin and creatinine levels) were performed at week 8 (for 27 of 30 patients) and at week 24 or early termination for 20 of 30 patients. No significant changes in laboratory findings were observed, with the exception of those for 1 patient, who had an elevated white blood cell count at week 8 at the time of diagnosis of a urinary tract infection.

Clinical Outcomes

Of the 30 patients who received SER-109, 26 (86.7%) achieved the primary end point of no C. difficile–positive diarrhea up to 8 weeks following dosing, with similar outcomes in both dosing cohorts (Figure 1). Of the patients who met the primary end point, 1 required a second dose of SER-109 for recurrence of C. difficile–positive diarrhea on day 26, as per protocol. Four patients who did not meet the primary end point had early onset of symptoms at days 3, 5, 7, and 9 after administration of SER-109 and laboratory confirmation of C. difficile. One of these patients declined a second SER-109 dose and chose not to continue participating in the study. Notably, the other 3 patients were determined by their primary investigator to be recovering from a self-limiting diarrheal episode at the time of stool submission for C. difficile testing. In each case, the investigators advised the patients to refrain from antibiotic use, and all symptoms resolved without any therapeutic intervention; stool samples from these 3 patients were negative for C. difficile carriage at 8 weeks, using a sensitive nucleic acid amplification test for detection of toxins A and B. Thus, 29 of 30 patients (96.7%) achieved clinical resolution of recurrent CDI following SER-109 administration.

CdiffSeresTherapeuticsFig1

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