When it comes to addressing health care-associated infections, Clostridium difficile, remains, well, difficult.
Research suggests that illness due to C difficile is the most common nosocomial infection in the United States, with mortality rates as high as 22%.
Yet, a new study published on September 12 in JAMA Surgery suggests there may be a—relatively—simple and cost-effective solution:
by identifying patients at risk for poor outcomes caused by C difficile infection using serum eosinophil count information collected at hospital admission.
“There’s a frequently obtained, but often underutilized, marker that can predict not only mortality but adverse outcomes in disease,” study co-author David B. Stewart, MD, FACS, FASCRS, associate professor and section chief, colorectal surgery, University of Arizona, told Contagion®.
“Eosinophil count is a marker we often ignore because, in general, it’s relatively unimportant for the bacterial infections we deal with.
However, what our research shows that undetectable levels of eosinophils at the time of admission can be an accurate predictor of disease severity.”
The StoP CDI study will test this idea in a randomized, double-blinded, placebo-controlled trial.
If successful in demonstrating that vancomycin can prevent the disease, the research could save thousands of lives, stop tens of thousands of infections, and save millions of health care dollars.
The Agency for Healthcare Research and Quality recently awarded Dr. Sims with a $2.4 million grant to study a theory that could prevent thousands of C. difficile infections and deaths all over the world. This is one of the largest grants Beaumont Health has ever received.
Ms Post was diagnosed with a Clostridium difficile infection and was treated for it with vancomycin and got better. However, a few days after she stopped the vancomycin, the diarrhea would come back as the infection relapsed. After talking with several doctors she was directed to Matthew Sims, M.D., PhD, director of infectious disease research at Beaumont Hospital, Royal Oak, who enrolled her in a research study and broke the cycle of relapses.
Dr. Sims believes oral vancomycin can keep the C. diff in check when the good bacteria is killed by other antibiotics and should prevent the patient from becoming sick. Participants in the study will be given vancomycin or a placebo along with the antibiotics treating the original infection.
Beaumont Hospital, Royal Oak
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uBiome is a biotechnology company based in San Francisco that gives individuals and organizations access to sequencing technology to sequence their microbiomes with a sampling kit and website. The company was founded by Jessica Richman and Zachary Apte in November 2012,
uBiome plans to announce a collaboration with the Centers for Disease Control and Prevention to analyze over 10,000 stool samples from hospital patients.
As research into the importance of the bacteria living in people’s guts—the microbiome—has become more common, the potential in turning the genetic sequences of those intestinal critters into a useful tool for doctors is obvious—problem is, it’s only potential. No one has quite figured out how. A healthy community of gut microbes isn’t easily reduced to a single metric, like blood sugar or cholesterol levels. So uBiome and the CDC have set out to develop something a “Microbiome Disruption Index”to track how treatments, like antibiotics, alter gut microbes.
CDC will collect the samples, and uBiome will sequence them.
Sequence: uBiome extracts the bacterial DNA out of the sample and identify each of the bacteria that the DNA came from. It’s a little like dusting a scene for fingerprints. *1
The San Francisco-based startup currently sells microbiome sampling kits directly to consumers, who mail the kits back to uBiome for analysis—much like 23andMe with its DNA sequencing kits. uBiome recently started offering grants in the form of $100,000 worth of kits to researchers. The CDC, which has microbiome on the brain (so to speak), decided to apply. “Working with companies developing expertise in this area is something we’re interested in,” says Alison Halpin, a CDC epidemiologist. “And CDC is always looking for partnerships.”
The collaboration, which will begin early next year, is still fairly open-ended. The CDC has only just started thinking about the Microbiome Disruption Index and how to use it to predict things like whether a patient might be at risk for infections that hang out in hospitals. But if sequencing costs continue to fall says Halpin, “It’s possible for [microbiome sequencing] to become a standard tool. We’re trying to anticipate that by understanding how you interpret that information.”
How to interpret sequencing information is a challenge for uBiome, too, which is expanding its business from direct-to-consumer kits to clinical tests ordered by doctors. “We’re moving into the clinical space in a number of ways,” says cofounder and CEO Jessica Richman. “This collaboration helps us figure out what the problems are.” In other words, this is all very early-days. Richman says that uBiome plans to announce its first clinical test next year, but she declined to give details.
Researchers have linked the makeup of the gut microbiome—with varying degree of certainty—to big things like obesity, cancer, and mental illness. But uBiome is more likely to start smaller, with clearer-cut tests like looking for the presence of nasty bugs such as the Clostridium difficile bacteria. (It causes all sorts of nasty gut problems, and can turn pathogenic when a person’s normal, healthy gut flora get wiped out by a course of antibiotics.) The advantage of microbiome sequencing is that uBiome could look test for several different pathogens at once without having to grow any of them in a petri dish first.
uBiome’s lab is currently certified under the Clinical Laboratory Improvement Amendments, which allows approved labs to develop new tests without getting individual approval for each one. That could feel like a red flag. Recent controversy over the blood testing company Theranos has highlighted the sometimes loose regulations, and the Food and Drug Administration has it wants to regulate lab tests more strictly.
For now, says Daniel Almonacid, a senior scientist at uBiome, “We assume we’re in good standing because the CLIA requirements are already met.”1
23andMe famously had a big battle with the FDA over the medical information it offered as results for its genetic tests. If uBiome wants to go in that direction, it may end up running into regulation, too. But in the meantime, 10,000 plus samples could be a significant conversion of poop into data. 1 UPDATE: Correction 8:50pm ET 11/30/2015 This quote has been corrected to more accurately reflect uBiome’s CLIA status.
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.
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People may be more likely to get infected with the sometimes deadly gut infection called “C. diff” during the spring, according to a new study.
Researchers analyzed information from people who were discharged from U.S. hospitals between 2001 and 2010. During this time period, about 2.3 million people were released from a hospital following an infection with Clostridium difficile, which can cause severe diarrhea, and frequently comes back after treatment.
In the spring, there were about 62 cases of C. difficile for every 10,000 people discharged from the hospital, the study found.
In winter and summer, there were 59 C. difficile cases per 10,000 people discharged from the hospital, and the lowest rate was seen in the fall, when there were 56 C. difficile cases per 10,000 hospital discharges.
Most cases of C. difficile occur after people take antibiotics, which disturb the normal balance of gut bacteria, giving harmful bacteria the chance to overgrow. It’s possible that the rates of C. difficile infection are the highest in the spring because people use more antibiotics during the winter months to treat respiratory infections, the researchers said. There can be a one- to two-month lag between the time a person takes antibiotics, or antimicrobials, and when he or she develops a C. difficile infection.
The new finding “emphasizes the importance of antimicrobials’ use as a risk factor” for C. difficile infections, the researchers said. The results also underscore the need to better control infections and use antibiotics only when they are needed,” particularly during high-risk seasons and in high-risk areas, the researchers wrote.
The study also found that, over the 10-year study period, the rates of C. difficile infection were the highest in the Northeast, where the overall rate was 80 cases per 10,000 hospital discharges, followed by the Midwest (64 cases per 10,000 hospital discharges), the South (50 cases per 10,000 hospital discharges) and the West (48 cases per 10,000 hospital discharges).
These regional differences in C. difficile could be partly due to differences in the number of older adults in each area, with the Northeast possibly having a higher proportion of older adults, the researchers said. Older adults are at increased risk for C. difficile infection. In fact, the overall rate of C. difficile infections during the study was 160 cases per 10,000 hospital discharges among adults age 65 and older, compared with 35 cases per 10,000 discharges in adults under 65 and 12 cases per 10,000 discharges in children.
“Our findings indicate the need for additional resources when and where health care burdens are highest,” the researchers said.
The study, conducted by researchers at the University of Texas at Austin, is published in the May issue of the American Journal of Infection Control.
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