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Lani · 01-18-2013, 09:25 AM

C difficile: Synthetic Stool Substitute Clears Infection

Jenni Laidman

Jan 10, 2013

A synthetic stool substitute successfully ended bouts of recurrent antibiotic-resistant Clostridium difficile in a proof-of-principle study published January 9 in the inaugural issue of Microbiome.

The study, which involved just 2 patients, suggests the promise of an off-the-shelf alternative to the transplantation of donor stool to control antibiotic-resistant intestinal bacteria.

Elaine O. Petrof, MD, assistant professor, Department of Medicine, Infectious Diseases, Kingston General Hospital, Queen's University, Ontario, Canada, and colleagues created the human synthetic stool mixture by culturing the stool microbial diversity of a healthy 41-year-old woman and brewing a mixture of 33 different intestinal bacteria isolated in pure culture. They named the synthetic stool mixture RePOOPulate.

The bacterial mixture was infused into the colon of 2 patients in their 70s, both of whom were infected with a hypervirulent strain of C difficile, ribotype 078, and who had failed at least 3 courses of antibiotic therapy.

Both patients returned to normal bowel patterns in 2 or 3 days and remained symptom-free for 6 months. At that time, rRNA sequences representing the RePOOPulate mixture made up 25% of the gut bacterial population.

"It's an interesting paper and pretty exciting," Colleen Kelly, MD, a gastroenterologist from the Center for Women's Gastrointestinal Medicine at the Women's Medicine Collaborative, Providence, Rhode Island, told Medscape Medical News in an email. Dr. Kelly was not involved in the current study.

"I've been doing fecal transplants for nearly 5 years and have treated 90 patients with about a 94% success rate. Identifying a suitable donor can be difficult in some patients. Also, the cost of donor screen labs (which is not always covered by insurance) is expensive. The process of donor eligibility determination is time consuming, and some doctors face institutional barriers that prevent them from offering [fecal microbiota transplantation]. If a safe, effective product was available, many more patients could be treated with [fecal microbiota transplantation]. Additionally, this compound would make the necessary clinical trials much easier to do." Dr. Kelly is involved in what is considered the first randomized trial of fecal transplant for recurring C difficile.

C difficile, a Gram-positive, anaerobic bacillus that produces a toxin, is the source of 15% to 25% of antibiotic-associated diarrhea.

Researchers in the Canadian study cultured 62 different bacterial isolates from donor stool, identifying them by 16S rRNA gene sequencing and profiling them for antibiotic susceptibility. Any isolate resistant to antibiotics was eliminated. The result was 33 isolates sensitive to a range of antibiotics and relatively easy to culture under anaerobic conditions. The researchers used the profile of a healthy donor as a guide to relative abundances of species to include in the probiotic mixture. The purified intestinal bacterial cultures were grown in "Robo-gut" equipment that mimics the environment within the large intestine.

The authors note that the creation of a synthetic mixture allows for control of the composition of the bacteria the patient will receive in a reproducible species mix. It also eliminates the worry of viruses or other pathogens that can ride along in donor stool.

In the past, researchers have tried single probiotics in attempts to clear C difficile infection. "They have not really ever [been] shown to manage multiply recurrent C diff," said Cliff McDonald, MD, chief, Prevention and Response Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia. "I think it's conceivable [to use] a cocktail or several cocktails — there might be quite a few that work pretty well. It might be hard to say which cocktail works better than the other. It may depend upon the people treated, too," Dr. McDonald told Medscape Medical News. He was not involved in the Microbiome study.

Dr. McDonald also noted that a group from the Sanger Institute published a paper in October 2012 in PLoS Pathogens reporting the successful use of a cocktail of 6 bacteria to clear C difficile infection in mice.

The results of the Canadian study are "fantastic," said Mayur Ramesh, MD, senior staff physician in infectious disease, Henry Ford Hospital, Detroit, Michigan. "That's what everybody's looking for, including our own team." Dr. Ramesh has developed a simplified method of preparing donor stool for transplant and treatment of C difficile infection, but was not involved in the current study.

A synthetic substance could resolve the significant "yuck" factor that makes physicians unwilling to perform stool transplants, according to Dr. Ramesh. "Nobody wants to do it," he said.

Patients, in contrast, accept the treatment easily. "I have not a single patient refuse. I have people fly in from California, and I'm in Detroit," he said. "American doctors are shunning things like this, even though it saves lives. This is the best treatment for C difficile."

The newly published study included a 74-year-old white woman who suffered 6 episodes of recurrent C difficile infection during 18 months after orthopedic surgery and preoperative treatment with cefazolin, and a 70-year-old white woman who had 3 episodes of recurrent C difficile infection after treatment with cefazolin for cellulitis. Both women received additional antibiotics after the probiotic transfer. One patient received several courses for recurrent urinary tract infection and the second for recurrent cellulitis. Still, by the end of 6 months they had no return of C difficile infection symptoms and maintained a diverse population of gut bacteria.

Recurrent C difficile infection is largely a result of the inability of normal intestinal flora to recover from antibiotic treatment.

This work was supported by the Southeastern Ontario Academic Medical Association and the Physicians’ Services Incorporated Foundation, as well as a University of Western Ontario Academic Development Fund grant. Dr. Petrof and 2 coauthors have a provisional patent together. The other authors, Dr. Kelly, Dr. McDonald, and Dr. Ramesh have disclosed no relevant financial relationships.

Microbiome. 2013;1:3.

01-18-2013, 09:25 AM	#4
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	Re: C-diff-- "Repoopulate"--I kid you not! C difficile: Synthetic Stool Substitute Clears Infection Jenni Laidman Jan 10, 2013 A synthetic stool substitute successfully ended bouts of recurrent antibiotic-resistant Clostridium difficile in a proof-of-principle study published January 9 in the inaugural issue of Microbiome. The study, which involved just 2 patients, suggests the promise of an off-the-shelf alternative to the transplantation of donor stool to control antibiotic-resistant intestinal bacteria. Elaine O. Petrof, MD, assistant professor, Department of Medicine, Infectious Diseases, Kingston General Hospital, Queen's University, Ontario, Canada, and colleagues created the human synthetic stool mixture by culturing the stool microbial diversity of a healthy 41-year-old woman and brewing a mixture of 33 different intestinal bacteria isolated in pure culture. They named the synthetic stool mixture RePOOPulate. The bacterial mixture was infused into the colon of 2 patients in their 70s, both of whom were infected with a hypervirulent strain of C difficile, ribotype 078, and who had failed at least 3 courses of antibiotic therapy. Both patients returned to normal bowel patterns in 2 or 3 days and remained symptom-free for 6 months. At that time, rRNA sequences representing the RePOOPulate mixture made up 25% of the gut bacterial population. "It's an interesting paper and pretty exciting," Colleen Kelly, MD, a gastroenterologist from the Center for Women's Gastrointestinal Medicine at the Women's Medicine Collaborative, Providence, Rhode Island, told Medscape Medical News in an email. Dr. Kelly was not involved in the current study. "I've been doing fecal transplants for nearly 5 years and have treated 90 patients with about a 94% success rate. Identifying a suitable donor can be difficult in some patients. Also, the cost of donor screen labs (which is not always covered by insurance) is expensive. The process of donor eligibility determination is time consuming, and some doctors face institutional barriers that prevent them from offering [fecal microbiota transplantation]. If a safe, effective product was available, many more patients could be treated with [fecal microbiota transplantation]. Additionally, this compound would make the necessary clinical trials much easier to do." Dr. Kelly is involved in what is considered the first randomized trial of fecal transplant for recurring C difficile. C difficile, a Gram-positive, anaerobic bacillus that produces a toxin, is the source of 15% to 25% of antibiotic-associated diarrhea. Researchers in the Canadian study cultured 62 different bacterial isolates from donor stool, identifying them by 16S rRNA gene sequencing and profiling them for antibiotic susceptibility. Any isolate resistant to antibiotics was eliminated. The result was 33 isolates sensitive to a range of antibiotics and relatively easy to culture under anaerobic conditions. The researchers used the profile of a healthy donor as a guide to relative abundances of species to include in the probiotic mixture. The purified intestinal bacterial cultures were grown in "Robo-gut" equipment that mimics the environment within the large intestine. The authors note that the creation of a synthetic mixture allows for control of the composition of the bacteria the patient will receive in a reproducible species mix. It also eliminates the worry of viruses or other pathogens that can ride along in donor stool. In the past, researchers have tried single probiotics in attempts to clear C difficile infection. "They have not really ever [been] shown to manage multiply recurrent C diff," said Cliff McDonald, MD, chief, Prevention and Response Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia. "I think it's conceivable [to use] a cocktail or several cocktails — there might be quite a few that work pretty well. It might be hard to say which cocktail works better than the other. It may depend upon the people treated, too," Dr. McDonald told Medscape Medical News. He was not involved in the Microbiome study. Dr. McDonald also noted that a group from the Sanger Institute published a paper in October 2012 in PLoS Pathogens reporting the successful use of a cocktail of 6 bacteria to clear C difficile infection in mice. The results of the Canadian study are "fantastic," said Mayur Ramesh, MD, senior staff physician in infectious disease, Henry Ford Hospital, Detroit, Michigan. "That's what everybody's looking for, including our own team." Dr. Ramesh has developed a simplified method of preparing donor stool for transplant and treatment of C difficile infection, but was not involved in the current study. A synthetic substance could resolve the significant "yuck" factor that makes physicians unwilling to perform stool transplants, according to Dr. Ramesh. "Nobody wants to do it," he said. Patients, in contrast, accept the treatment easily. "I have not a single patient refuse. I have people fly in from California, and I'm in Detroit," he said. "American doctors are shunning things like this, even though it saves lives. This is the best treatment for C difficile." The newly published study included a 74-year-old white woman who suffered 6 episodes of recurrent C difficile infection during 18 months after orthopedic surgery and preoperative treatment with cefazolin, and a 70-year-old white woman who had 3 episodes of recurrent C difficile infection after treatment with cefazolin for cellulitis. Both women received additional antibiotics after the probiotic transfer. One patient received several courses for recurrent urinary tract infection and the second for recurrent cellulitis. Still, by the end of 6 months they had no return of C difficile infection symptoms and maintained a diverse population of gut bacteria. Recurrent C difficile infection is largely a result of the inability of normal intestinal flora to recover from antibiotic treatment. This work was supported by the Southeastern Ontario Academic Medical Association and the Physicians’ Services Incorporated Foundation, as well as a University of Western Ontario Academic Development Fund grant. Dr. Petrof and 2 coauthors have a provisional patent together. The other authors, Dr. Kelly, Dr. McDonald, and Dr. Ramesh have disclosed no relevant financial relationships. Microbiome. 2013;1:3.