About 500,000 Americans fall ill from Clostridium difficile infections every year.
A multinational, double-blind, placebo-controlled phase 2b study conducted at 84 sites in Europe and North America has demonstrated the ability of ribaxamase to reduce the risk of opportunistic Clostridium difficile infections (CDI) in hospital patients. The findings from researchers at Synthetic Biologics, Inc., Rockville, Maryland, were presented today at IDWeek 2017 being held in San Diego, California.
“Ribaxamase reduced the incidence of new target CDI by 71% as compared with placebo, protected the diversity of the gut microbiome and reduced the emergence of antibiotic resistance in ceftriaxone-treated patients,” said lead study author John Kokai-Kun, PhD.
The findings are good news. CDI is an “urgent threat," according to Dr. Kokai-Kun. No drugs or vaccines aimed at preventing CDI have been approved by the United States Food and Drug Administration.
CDI produces symptoms that range from diarrhea to colon inflammation that can be life-threatening. About 500,000 Americans fall ill from CDIs every year. More recently, the numbers have been increasing and the symptoms have become more severe and harder to treat. The increased prevalence and severity of the infections coincide with the emergence of a more aggressive strain of C. difficile that produces more toxins and which can be more antibiotic resistant.
CDI is spread by spores of the bacterium that can persist on surfaces for a prolonged time. They can be transferred to the hands and, if personal hygiene is lax, can be ingested. Toxins produced by the germinated bacteria attack the intestinal wall.
SYN-004 (ribaxamase) is a beta-lactamase that was designed to be orally administered with intravenous beta-lactam antibiotics and remain localized in the intestine to degrade antibiotics including penicillins and cephalosporins excreted into the intestine. “SYN-004 is designed to prevent disruption of the gut microbiome and thus protect from opportunistic gastrointestinal pathogens like C. difficile,” explained Dr. Kokai-Kun.
The study enrolled 412 patients who were at least 50 years of age (mean age 70 years). Two-thirds of the patients were male, one-third had received macrolides, and one-third were receiving drugs to relieve stomach acidity. The intention-to-treat population who were “enriched for higher risk for CDI”, according to Dr. Kokai-Kun, were hospitalized for ≥5 days of intravenous ceftriaxone for treatment of lower respiratory tract infections. Half the patients were randomized to oral ribaxamase 150 mg, 4 times a day during the period of intravenous ceftriaxone treatment, and for another 72 hours. The other group received placebo along with ceftriaxone for the same times. Fecal samples were collected at randomization, at the end of the treatment period, and the end of the 6-week follow-up to determine the fecal microbiome by 16s ribosomal RNA sequencing.
The primary endpoint was prevention of CDI. The secondary endpoint was prevention of non-C- difficile antibiotic-associated diarrhea. Exploratory endpoints evaluated the ability of the treatment regimen to curb the disruption of the gut microbiome.
In the placebo group, alpha and beta diversity analyses showed that the gut microbiome was significantly changed, while no appreciable change was evident in the ribaxamase group. The primary endpoint was met, with the ribaxamase group displaying a 71.4% relative risk reduction concerning CDI (P = .045). There was a statistically significant 44% relative risk reduction in new colonization by vancomycin-resistant enterococci at 72 hours (P = .0001) and 4 weeks (P = .0002). New C. difficile colonization was also reduced, but not significantly, in the ribaxamase group at 72 hours (P = .059) and 4 weeks (P = .088).
Respiratory infection was cleared in nearly all (~99%) cases, indicating that the activity of ceftriaxone was not lessened by the presence of ribaxamase. Less diarrhea was evident in the ribaxamase group, but the change compared to the placebo group was not significant (P = .113).
“These data support that ribaxamase can maintain the balance of the gut microbiome and thereby prevent opportunistic infections like CDI during intravenous beta-lactam treatment,” said Dr. Kokai-Kun.
John Kokai-Kun, PhD; Synthetic Biologics, Inc.: Employee, Salary
Kokai-Kun J, Roberts T, Coughlin O, Whalen H, Le C, Da Costa C, Sliman J. SYN-004 (ribaxamase) prevents New Onset Clostridium difficile Infection by Protecting the Integrity Gut Microbiome in a Phase 2b Study
Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at email@example.com.