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“C. diff. Spores and More,” Global Broadcasting Network – innovative and educational interactive healthcare talk radio program discusses
“Taking aim at “super-bugs” and the latest CDC Vital Signs Report results”
With Our Guest, Dr. Clifford McDonald, MD, — Senior Advisor for Science and Integrity Division of Healthcare Quality Promotion at the CDC
Tuesday, March 22nd at the following times
10 a.m. Pacific Time 11 a.m. Mountain Time 12 p.m. Central Time 1 p.m. Eastern Time
The Centers for Disease Control and Prevention (CDC) sounds the alarm on the danger of modern medicine returning to a time when simple infections were often fatal. As the latest Vital Signs Report shows, much progress has been made in our hospitals and healthcare facilities to protect patients from healthcare-associated infections. But, more work needs to be done, because many of these infections are caused by antibiotic-resistant bacteria which are difficult, if not impossible to treat. The CDC believes clinicians are key to national progress in preventing infections. They have the power to change the direction of antibiotic resistance each and every time they care for their patients. It requires taking the appropriate steps every time.
We are in a race to slow resistance, and we can’t afford to let the “superbugs” outpace us, especially in healthcare settings.
Dr. McDonald graduated from Northwestern University Medical School, completed his Internal Medicine Residency at Michigan State University, and an Infectious Diseases Fellowship at the University of South Alabama, following which he completed a fellowship in Medical Microbiology at Duke University. Past positions have included Associate Investigator at the National Health Research Institutes in Taiwan and Assistant Professor in the Division of Infectious Diseases at the University of Louisville. Dr. McDonald is a former officer in the Epidemic Intelligence Service and former Chief of the Prevention and Response Branch in the Division of Healthcare Quality Promotion at the CDC where he currently serves as Senior Advisor for Science and Integrity in the same division. He is the author or co-author of over 100 peer-reviewed publications with his main interests in the epidemiology/prevention of HAI’s, especially Clostridium difficile infections, and prevention of antimicrobial resistance.
C. diff. Spores and MoreGlobal Broadcasting Network – producing educational programs dedicated to C. difficile Infections and more — brought to you by VoiceAmerica and sponsored by Clorox Healthcare
Merck known as MSD outside the United States and Canada, announced that the two pivotal Phase 3 clinical studies for bezlotoxumab, its investigational antitoxin for prevention of Clostridium difficile (C. difficile) infectionrecurrence, met their primary efficacy endpoint: the reduction in C. difficile recurrence through week 12 compared to placebo, when used in conjunction with standard of care antibiotics for
the treatment of C. difficile.
Based on these results, the company plans to submit new drug applications seeking regulatory approval of bezlotoxumab in the U.S., EU and Canada in 2015. Currently, there are no therapies approved for the prevention of recurrent disease caused by C. difficile.
“These results were also demonstrated in patient subgroups known to be at
high risk for C. difficile recurrence.”
Results from the studies were presented for the first time at the Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and International Congress of Chemotherapy and Infection (ICC) joint meeting in San Diego, Sept. 17-21.
“Results of these studies showed that a single, one-time infusion of the antitoxin bezlotoxumab given with standard of care C. difficile antibiotic treatment significantly reduced the recurrence of C. difficile infection compared to standard of care alone, and demonstrated this benefit over a 12-week period,” said Dr. Mark Wilcox, Leeds Teaching Hospitals and University of Leeds, U.K., and a lead investigator for the studies. “These results were also demonstrated in patient subgroups known to be at high risk for C. difficile recurrence.”
Bezlotoxumab is not an antibiotic. It is a selective, fully-human, monoclonal antibody designed to
neutralize C. difficile toxin B, a toxin that can damage the gut wall and cause inflammation, leading to the symptoms of C. difficile enteritis, which include abdominal pain and watery diarrhea.
Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb), and licensed to Merck in 2009 for development as a potential
therapeutic for C. difficile infection.
“Recurrence is a major challenge with C. difficile infection, and novel approaches are
needed to help prevent the cycle of C. difficile recurrence,” said Dr. Dale Gerding, professor of medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Ill., and a lead investigator for the studies.
About the pivotal Phase 3 studies
Two global, Phase 3, double-blind studies were conducted to evaluate bezlotoxumab, either alone or in combination with actoxumab (a fully human monoclonal antibody against C. difficile toxin A), compared to placebo for the prevention of recurrent C. difficile infection in patients on standard of care antibiotics for a primary or recurrent C. difficile infection. The MODIFY I study (MONOCOLONAL ANTIBODIES FOR C. DIFFICILE THERAPY) enrolled 1452 patients (median age 65 years) in 19 countries and the MODIFY II study enrolled 1203 patients (median age 67 years) in 17 countries. The studies were conducted in both hospital and outpatient settings, and the primary endpoint for each study was evaluated through 12 weeks following study drug administration.
In the MODIFY I study, patients receiving standard of care antibiotics for C. difficile were randomized to receive a single, one-time infusion of either bezlotoxumab (10 mg/kg) (n=403), actoxumab (10 mg/kg) (n=242), the combination of bezlotoxumab and actoxumab (10 mg/kg each) (n=403) or placebo (n=404). The actoxumab arm was stopped for efficacy and safety reasons after an interim analysis. In the MODIFY II study, patients receiving standard of care antibiotics for C. difficile were randomized to receive a single, one-time infusion of either bezlotoxumab (10 mg/kg) (n=407), bezlotoxumab and actoxumab (10 mg/kg each) (n=397) or placebo (n=399).
In both MODIFY I and MODIFY II, the rate of C. difficile infection recurrence through week 12, the primary efficacy endpoint, was significantly lower in the bezlotoxumab arms (17.4%, p=0.0003) and (15.7%; p=0.0003), and the combination bezlotoxumab and actoxumab arms (15.9%, p<0.0001) and (14.9%, p<0.0001), compared to the placebo arms (27.6%) and (25.7%), respectively. In MODIFY I and MODIFY II, 1396 and 1163 patients were evaluated in the full analysis sets, respectively.
In both studies, the rate of C. difficile infection recurrence was lower in the bezlotoxumab arms compared to the placebo arms in patient subgroups known to be at high
risk for C. difficile recurrence, including patients with any prior
episode(s) of C. difficile infection within the previous six months, patients infected with the BI/NAP1/027 strain, patients with severe C. difficile infection (Zar score ≥ 2), patients 65 years of age or older, and patients with compromised immunity. These subpopulation analyses were pre-specified in the protocol for each study.
In the studies, the adverse reaction rates were comparable across the bezlotoxumab and placebo arms. In MODIFY I, the most common adverse reactions through four weeks after infusion (nausea, diarrhea and pyrexia) occurred at similar rates in the bezlotoxumab group (7.4%, 6.7% and 5.6%) and the placebo group (6.5%, 5.0% and 2.8%). In MODIFY II, the most common adverse reactions through four weeks after infusion (nausea, diarrhea and urinary tract infection) occurred at similar rates in the bezlotoxumab group (5.8%, 5.3% and 4.5%) and the placebo group (3.4%, 6.6% and 4.2%). Additionally, rates of serious adverse reactions and deaths assessed through 12 weeks after infusion were comparable across these treatment arms.
Treatment with the combination of bezlotoxumab and actoxumab did not provide added efficacy over bezlotoxumab alone. Furthermore, actoxumab alone provided no benefit in the prevention of C. difficile recurrence compared with placebo. Based on these results, bezlotoxumab alone was selected for the marketing authorization application.
Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside of the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.
To read the article in its entirety click on the following link:
The gastrointestinal tract harbors a complex community of bacteria, known as the microbiota, which plays an integral role preventing its colonization by gut pathogens. This resistance has been shown to be crucial for protection against Clostridium difficile infections (CDI), which are the leading source of hospital-acquired infections in the United States. Antibiotics are a major risk factor for acquiring CDI due to their effect on the normal structure of the indigenous gut microbiota. We found that diverse antibiotic perturbations gave rise to altered communities that varied in their susceptibility to C. difficile colonization. We found that multiple coexisting populations, not one specific population of bacteria, conferred resistance. By understanding the relationships between C. difficile and members of the microbiota, it will be possible to better manage this important infection.
The spore-associated protein BclA1 affects the susceptibility of animals to colonization and infection by Clostridium difficile
The paper shows that so-called “hypervirulent” strains of C. difficile, such as the 027 ribotype strains, are actually less infectious than the existing strains of C. difficile carried in humans and animals. We were able to show this by characterizing one gene of C. difficile that encodes the BclA1 protein. BclA1 is involved in the early stages of colonization and its presence enables spores of C. difficile to colonise the host. When this protein is removed or truncated the ability of spores to colonise is much reduced. This then raises the question of how hypervirulent strains are more efficient at infecting a host, in other words, how they can be more virulent. The answer is probably the hypervirulent strains are able to produce more toxins. This work raised the concept that C. difficile is similar to influenza. For example, with influenza the most infectious influenza strains do not normally cause fatality (ie, the seasonal flu strains). On the other hand, the pandemic strains (avian influenza) are not very infectious (that is, they spread poorly) yet when they do infect they cause a dangerous infection more likely to lead to fatality. C. difficile we reason behaves in a similar way, the hypervirulent strains are poorly infectious yet cause a more potent infection while highly infectious strains cause a less potent infection. We plan to use this knowledge to type new isolates of C. difficile and assess their risk to humans.
Professor Simon M. Cutting
School of Biological Sciences,
Bourne Laboratories, 4-26,
Royal Holloway, University of London
Surrey TW20 OEX