THE C DIFF FOUNDATION
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/.