Category Archives: C. diff. Research Community

Immuron Announced First Patients Enrolled In Phase 1/2 (first-in-human) Clinical Trials For Immuron’s IMM-529 For Treatment of C.difficile Infections

The Australian biopharmaceutical company Immuron announced that the first patients have enrolled in phase 1/2 (first-in-human) clinical trials for Immuron’s IMM-529, an oral immunotherapeutic medication for treatment of Clostridium difficile infections (CDI).

As published in MD Mag February 16, 2018

To review this publication in its entirety please click on the following link to be redirected:

http://www.mdmag.com/medical-news/a-powerful-new-weapon-in-the-fight-against-clostridium-difficile-infection

According to Dan Peres, MD, senior vice president and head of medical development at Immuron, IMM-529 “has shown promise in successfully treating Clostridium-difficile” through its “unique delivery of antibodies.”

If the trials are successful, IMM-529 may be a powerful new weapon in the global fight against CDI. Peres reports that IMM-529 that has been effective in preclinical studies for prophylactic use, treatment of disease, and the prevention of recurrence in relation to CDI, and that the company is excited to enroll the first patients.

The placebo-controlled study to test the safety, tolerability and efficacy of IMM-529 will take place at Hadassah Medical Center in Jerusalem and include 60 CDI diagnosed patients in the 28 day study.

Patients enrolled in the study, led by Yoseph Caraco, MD, head of the clinical pharmacology unit at Hadassah Medical Center, will receive IMM-529 or a placebo 3 times a day during the 28 -day trial period, and be monitored for 2 additional months, determining any recurrence of the disease.

In a statement, Caraco said that he was optimistic about IMM-529 based on pre-clinical trial results and that IMM-529 could “be the answer we’re all looking for” when it comes to treatment of CDI.

IMM-529 targets CDI in 2 ways: by neutralizing toxin B (TcdB), a cytotoxin responsible for inflammation and diarrhea that characterizes CDI, and by binding Clostridium difficile spores and vegetative cells preventing further colonization. Caraco reported that IMM-529 approaches CDI by “targeting the main virulence factors of the disease with only minor disturbance to the natural biome” which could be extremely valuable in treating CDI.

In the earlier pre-clinical proof-of-concept study by led by Dena Lyras, MD, PhD with Monash University in Melbourne, Australia, IMM-529 was shown to be 80% effective in both the treatment of and prevention of CDI without the use of antibiotics.

In a December 2015 statement from Immuron, Lyras stated that she was “excited by the potential of these therapeutics in treating patients with both the acute and the relapse phase, of the disease.”

According to data supplied by the American Gastroenterological Association, approximately 500,000 people in the US are diagnosed with CDI each year, and CDI-associated deaths range from 14,000 to 30,000 per year.

In the European Union, according to a 2016 study led by Alessandro Cassini, MD, with the European Centre for Disease Prevention and Control in Stockholm, Sweden, more than 150,000 cases of hospital-acquired CDI infections (134,053–173,089; 95% CI) occur each year.

According to Immuron, the cost of CDI globally (calculated by CIDRAP, the Center for Infectious Disease and Policy at the University of Minnesota) is an estimated annual economic burden of more than $10 billion and increases in hypervirulent and antibiotic-resistant strains have led to CDI becoming a major medical concern.

Caraco stated that CDI poses “a growing risk amongst a greater population of patients, including those recently treated with antibiotics, the elderly, institutionalized and hospitalized.”

If IMM-529 is found to be safe and effective in clinical trials, it could prove a significant boon to the global fight against CDI at all 3 stages of the disease.

Surotomycin Failed To Show Benefit Over Vancomycin In a Pivotal Phase 3 Trial To Treat C. difficile Infections

A similar proportion of patients with Clostridium difficile infection showed clinical response at the end of treatment with surotomycin vs. vancomycin in a pivotal phase 3 trial.

However, surotomycin did not demonstrate superiority for key secondary endpoints including sustained clinical response and clinical response over time, and therefore failed to show benefit over vancomycin.

 

As published :  https://www.healio.com/gastroenterology/infection/news/online/%7B3531418d-42aa-4092-a9f2-55ba2ce6dcda%7D/surotomycin-meets-non-inferiority-endpoint-fails-to-show-benefit-over-vancomycin-in-c-difficile

This follows previously reported results of a parallel phase 3 trial in which surotomycin failed to meet non-inferiority criteria relative to vancomycin for primary and key secondary endpoints.

“Surotomycin has a narrow spectrum of activity, demonstrating low resistance rates and rapid activity against C. difficile with similar dose- and time-dependent pharmacodynamics to vancomycin in resolving CDI in a hamster model,” Sahil Khanna, MBBS, of the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., told Healio Gastroenterology and Liver Disease.

In this second phase 3 trial, “surotomycin demonstrated non-inferiority to vancomycin for CDI clinical response at end of treatment. It was similar to vancomycin for sustained clinical cure.”

In this double-blind, international multicenter trial, Khanna and colleagues randomly assigned 285 patients with confirmed CDI to receive 250 mg oral surotomycin twice daily alternating with placebo twice daily, and 292 to receive 125 mg oral vancomycin four times daily for 10 days.

At the end of treatment, clinical response with surotomycin (83.4%) was non-inferior to vancomycin (82.1%), with a difference of 1.4% (95% CI, 4.9-7.6).

Through 30 to 40 days of follow-up, clinical response over time was not superior to surotomycin, nor was sustained clinical response (63.3% vs. 59%; difference, 4.3%; 95% CI, 3.6-12.2).

Both treatments were generally well tolerated, with typical treatment-emergent adverse events occurring in 52.4% of patients treated with surotomycin and 60.1% of those treated with vancomycin.

“Interestingly, in the hypervirulent strain of CDI, recurrence rate was lower for surotomycin vs. vancomycin,” Khanna said, though he and colleagues noted in the study manuscript that “this finding is nominal due to a lack of multiplicity control.”

Based on the results of these trials, the surotomycin development program has been discontinued, but “the non-inferiority of surotomycin to vancomycin observed in the current trial is in contrast with the parallel trial,” investigators wrote. – by Adam Leitenberger

Disclosures: This study was funded by Merck. Khanna reports he has served as an advisor to Summit Pharmaceuticals and serves as a consultant to Rebiotix and Assembly Biosciences. Please see the full study for a list of all other researchers’ relevant financial disclosures.

SOURECE:  https://www.healio.com/gastroenterology/infection/news/online/%7B3531418d-42aa-4092-a9f2-55ba2ce6dcda%7D/surotomycin-meets-non-inferiority-endpoint-fails-to-show-benefit-over-vancomycin-in-c-difficile

Researchers From Loyola Medicine Retrospectively Studied 100 Vancomycin Taper and Pulse Treatment Patients Treated For Recurrent C. difficile Infection

A tapered and pulsed regimen with vancomycin — with diligent follow-up — can achieve significant cure rates in recurrent Clostridium difficile (C. difficile) infected patients, according to a new study.

Researchers from Loyola Medicine retrospectively studied 100 vancomycin taper and pulse treatment patients treated for recurrent C. difficile infection between January 1, 2009 and December 31, 2014. Their clinic, the study authors wrote, has been a referral center for the infection for the past decade.

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

http://www.mdmag.com/medical-news/pulsed-and-tapered-vancomycin-likely-route-to-recurrent-clostridium-difficile-cure

However, despite the guidelines for treatment of recurrent C. difficile infection being not too different than recurrent episodes – except for the use of vancomycin when the case is severe – there have not been many studies on this vancomycin taper and pulsed dosing. 

The researchers observed that after a referral, the confirmed recurrent C. difficile patients were treated with a vancomycin taper and pulse regimen: a taper of vancomycin to once-daily, followed by alternate day dosing; or once-daily followed by alternate day dosing; followed by every third day, for at least 2 weeks. After this regimen, all patients had 90-day follow-up documentation.

On average, the patients in the clinic were on their third C. difficile diarrhea episode. Half of the patients had also received a standard course of vancomycin, while another third had received some type of vancomycin taper regimen, the researchers said.

Despite the fact that many of these patients were a “treatment experienced” population, 75% of the patients who received a supervised vancomycin taper and pulsed regimen achieved a cure,  study author Stuart Johnson  MD, . He added that the results were further improved for patients who received the expended pulse phase: 81% achieved a cure.

“The findings were not unexpected to us, but I think that many clinicians will be surprised how well a deliberate, prolonged vancomycin taper and pulse regimen – with careful follow up – works,” Johnson said.

There were no significant differences among the patients in terms of gender, age, concomitant antibiotics, proton pump inhibitor use, histamine receptor-2 blocker use, or patients with a regimen greater than 10 weeks in length, the researchers continued.

The researchers added that their finding of improved cure rates with alternate-day dosing plus every third day dosing over strictly alternate-day dosing is consistent with the hypothesis that pulsed dosing can promote a cyclical decrease in spore burden, they wrote. This can also permit the resetting of normal microbiota in the gut.

Johnson concluded that the clinical implications of the study show most recurrent C. difficile patients do not need fecal microbiota transplant (FMT).

“FMT has received an enormous amount of press and this procedure is now widely available throughout the US,” Johnson said. “FMT is attractive because it addresses one of the primary mechanisms involved with recurrent C. difficile infection, a marked disruption of the resident bacteria that populate the intestine and provide an important host defense against C. difficile.

Although physicians screen donor feces for “known pathogens,” not all is known of the potential complications to come from FMT, Johnson said.

“In addition, it appears that efficacy with a carefully supervised vancomycin taper and pulse regimen compare to that achieved with FMT,” Johnson said.

The study, “Vancomycin Taper and Pulsed Regimen with careful Follow up for Patients with Recurrent Clostridium difficile Infection,” was published in the journal Clinical Infectious Diseases.

Norman B. Javitt, M.D. Is Welcomed As a Member Of the C Diff Foundation, R & D Committee

We are pleased to welcome
Norman B. Javitt, M.D. to the
C Diff Foundation.

Dr. Javitt has an extensive professional career in health care.  New York University Medical Center: Instructor, then Assistant Professor Medicine where his career was devoted mostly to research in liver disease, specifically in inborn errors of cholesterol metabolism affecting newborns, and to teaching medical students.

Cornell University Medical School-New York Hospital:  Associate Professor of Medicine, then Professor of medicine and Chief, Division of Gastroenterology the research program continued to grow, attracting many fellows from all over the world.  Also provided care for private patients, both children and adults, with difficult liver problems.

New York University Medical Center:  Professor of Medicine and of Pediatrics, Division chairman Hepatic Diseases April, Research professor 2015-presnt.  At NYUMC Dr. Javitt has been focusing on C. difficile research  and teaching medical students and house staff.  His research interest has also expand to many areas of cholesterol synthesis and metabolism other than just liver disease.

Dr. Javitt has published research papers in age-related macular degeneration, in vitro fertilization, and Alzheimer’s disease.  He has also published more than 150 research papers, in addition to several books and review articles, and presented work at numerous professional meetings and symposia throughout the world.  His work has been supported by the National Institutes of Health, by private foundations and Pharmaceutical companies.  Dr. Javitt is welcomed by fellow researchers in the Research and Development Committee Chaired by Professor Simon M. Cutting, Ph.D…

C. diff. May Carry Risks in Preoperative and Postoperative Patients

 

There are risks for acquiring a C. difficile infection (CDI).

The risks range from the overuse of Antibiotics, Immunosuppressed patients, prolonged hospital stays, being a patient in a long-term care facility, and for the senior population.

There may also be a risk for the surgical patients and the following study explains the study and the results:

To read the article in its entirety please click on the following link: https://cdifffoundation.wordpress.com/wp-admin/post-new.php

A lengthy study of four surgical specialties has determined that Clostridium difficile infection (CDI) is a major risk factor for postoperative patients, although incidences varied.

Although it has been shown that CDI is associated with increased cost, morbidity and mortality in patients after surgery, this is the first to examine C. difficile rates across multiple surgical specialties (Infect Control Hosp Epidemiol 2017:1-4. doi: 10.1017/ice.2017.158).

“This study has great importance as the landscape of repayment for elective surgical procedures changes,” said the study’s lead author, James Bernatz, MD, a surgeon with the Department of Orthopedics and Rehabilitative Medicine at University of Wisconsin Hospital and Clinics, in Madison. “With more surgeries being reimbursed as bundled payments, hospitals are pressured to limit costs. As C. diff infection has been found to increase length of stay by one week and double the cost of care, it is clearly a postoperative complication to be avoided.”

Dr. Bernatz and his colleagues conducted the study at a 592-bed tertiary care academic center. They used the hospital’s quality improvement database to review admissions to the orthopedic surgery, neurosurgery, trauma surgery and general surgery units from January 2014 through July 2016. Those patients who underwent an inpatient surgical procedure, and did not meet the exclusion criteria, were surveyed.

Case patients were defined as those who underwent an inpatient procedure and subsequently developed a health care–associated CDI, which was defined as a positive polymerase chain reaction (PCR) test result for C. difficile toxin gene recorded more than 72 hours after admission and within 12 weeks of discharge.

They found 52 cases of CDI among 11,310 surgical admissions to four hospital units: general surgery, neurology, orthopedics and trauma. In all 52 cases, patients had a PCR-positive test result more than 72 hours after admission and within 12 weeks of discharge, making the incidence rate 0.80 cases per 1,000 patient-days. The trauma unit had the highest rate at 9.5 CDI cases per 1,000 admissions (11 cases over 1.160 admissions during the study period). General surgery had 30 cases among 3,447 admissions for a rate of 8.7; orthopedics had six cases among 4,339 admissions for a rate of 1.4; and neurology had five cases among 2,364 admissions for a rate of 2.1.

A number of risk factors were surveyed, including the use of antibiotics.

Regarding antibiotic use, the researchers found that the odds of CDI increased 3.34-fold when the perioperative antibiotic is continued more than 24 hours after surgery, outside of the perioperative window. Antibiotic use, other than the perioperative antibiotic, while in the hospital also was associated with 2.2 times greater odds of CDI. And exposure to antibiotics as long as six months before surgery increases the odds of CDI more than threefold.

“Although the surgeon cannot necessarily control the antibiotics prescribed to their patients in the year leading up to surgery, they can control antibiotic administration in the perioperative and postoperative period,” Dr. Bernatz said. “Antibiotics should be limited to one prophylactic preoperative dose, unless 24 hours of antibiotics are indicated. In the immediate postoperative period, antibiotics should be used judiciously.”

Other significant risk factors included number of hospital admissions in the past year and proton pump inhibitor or histamine type 2 receptor blocker use in the previous six months. “Previous studies have shown a correlation between CDI and hospital admission in the previous 3 months,” the researchers wrote. “Our study reports that this association extends to 12 months. We found that the number of hospital admissions in the past year increases the odds of CDI by 133% for each admission.”

A higher American Society of Anesthesiologists (ASA) physical status classification also was a significant risk factor for CDI; ASA IV or V patients were 15 times more likely to develop CDI than those with ASA class I or II disease, according to the researchers.

Dr. Bernatz said additional research is needed to further reveal these links. “Other studies could examine the rate of C. diff infection between operations within one subspecialty to determine if certain operative variables or patient characteristics affect the postoperative risk of C. diff infection,” he said.

The Latest Developments in C. diff Research and Treatment

 

 

 

 

 

The Program Podcast is Now Available —

Listen at your leisure as our guest, Dr Mary Beth Dorr, PhD, Clinical Director, Clinical Research, Infectious Diseases, and he product development team lead for bezlotoxumab, Merck & Co., Inc.  provided us with an overview of a C. diff. infection, the challenges of recurrence, the latest clinical research overview, current treatment landscape, and pending new C. diff infection treatment guidelines from the Infectious Diseases Society of America (IDSA) that are anticipated to be released fall of 2017.

Click on the C. diff. Spores and More Logo to be connected to the podcast

Researchers Find Key Role of Excess Calcium In the Gut In C. difficile infections (CDI)

New research shows, it can’t make this last, crucial move without enough of a humble nutrient: calcium.

And that new knowledge about Clostridium difficile (a bacterium also known as “C. diff“) may lead to better treatment for the most vulnerable patients.

The discovery, made in research laboratories at the University of Michigan Medical School and the U.S. Food and Drug Administration, is published in the online journal PLoS Pathogens.

It helps solve a key mystery about C. diff: What triggers it to germinate, or break its dormancy, from its hard spore form when it reaches the gut.

Though the findings were made in mice, not humans, the researchers say the crucial role of calcium may help explain another mystery: Why some hospital patients and nursing home residents have a much higher risk of contracting C. diff infections and the resulting diarrhea that carries its spores out of the body.

That group includes people whose guts are flooded with extra calcium because they’re taking certain medications or supplements, have low levels of Vitamin D in their blood or have gut diseases that keep them from absorbing calcium.

The new discovery shows that C. diff can recognize this extra calcium, along with a substance called bile salt produced in the liver, to trigger its awakening and the breaking of its shell.

Previous research had suggested it couldn’t do this without another key component, an amino acid called glycine. But the new findings show calcium and the bile salt called taurochlorate alone are enough. Mouse gut contents that were depleted of gut calcium had a 90 percent lower rate of C. diff spore germination.

“These spores are like armored seeds, and they can pass through the gut’s acidic environment intact,” says Philip Hanna, Ph.D., senior author of the new paper and a professor of microbiology and immunology at U-M. “Much of the spore’s own weight is made of calcium, but we’ve shown that calcium from the gut can work with bile salts to trigger the enzyme needed to activate the spore and start the germination process.”

Ironically, the researchers say, one way to use this new knowledge in human patients might be to add even more calcium to the system.

That could awaken all the dormant C. diff spores in a patient’s gut at once, and make them vulnerable to antibiotics that can only kill the germinated form. That could also prevent the transmission of more spores through diarrhea to the patient’s room. That could slow or stop the cycle of transmission that could threaten them or other patients in the future.

Hanna’s graduate student, Travis Kochan, made a key observation that led to the discovery. He noted that the fluid “growth medium” that the researchers typically grow C. diff in for their studies had calcium in it. He realized this could artificially alter the results of their experiments about what caused C. diff spores to germinate.

So, he used a chemical to remove the calcium while leaving all the other nutrients that                  keep C. diff growing. The result: no new spore germination happened in the calcium-free growth medium.

FDA’s Center for Biologics Evaluation and Research conducted further research in laboratory dishes and in the guts of mice. FDA’s Paul Carlson, Ph.D., a former U-M research fellow, and fellow FDA scientists in his laboratory found that C. diff spores that were mutated so that glycine couldn’t act on them could still germinate and colonize mice. This suggested that calcium, and not glycine, was critical for this process.

Both mutant and regular forms of the bacteria could still activate an enzyme inside the C. diff spore that led the bacteria to start dissolving their hard shell. This released the store of calcium that the spore had been harboring inside itself, and increases the local level of the nutrient even further.

“These spores don’t want to germinate in the wrong place,” says Kochan, whose grandfather suffered from a severe C. diff infection which ultimately led to his death. “C. diff spores have specialized to germinate in the gut environment, especially in the environment of the small intestine, where calcium and the bile salt injection from the liver comes in.”

Hanna notes that the bile salt connection to C. diff spore germination was first discovered at U-M in 1982 by a team led by Ken Wilson, M.D.

Calcium and the gut

Certain ailments and treatments cause defects in calcium absorption, but are also risk factors for C. diff infections. For example, patients with vitamin D deficiency are five times more likely to get C. diff.

Medications aimed at calming acid reflux – such as proton pump inhibitors – and steroids can increase the amount of calcium in the gut. A Vitamin D deficiency can keep the body from reabsorbing calcium through the gut wall, allowing it to build up.

And people with inflammatory bowel diseases such as Crohn’s and colitis also have a harder time absorbing calcium from food through their gut walls.

Older adults are also often counseled to take calcium supplements to compensate for lower calcium levels and protect their bones from fracturing.

Hanna cautions that the new findings should not cause any patients to stop taking their medications or doctor-recommended supplements, or to start taking new ones. But he hopes to work with clinicians at U-M and beyond to test the new knowledge in a clinical setting. Meanwhile, he and Kochan and their FDA and U-M colleagues will continue to study C. diff germination in mice and look for ways to block the enzymes crucial to spore germination.

 

To read the article in its entirety – please click on the following link to be re-directed:

http://www.news-medical.net/news/20170713/Scientists-reveal-key-role-of-excess-gut-calcium-in-C-diffc2a0infections.aspx?utm_source=dlvr.it&utm_medium=twitter