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Oral enzyme prevents C. difficile infection, VRE colonization
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CHICAGO — SYN-004, or ribaxamase, an oral beta-lactamase given with certain IV antibiotics, prevented Clostridium difficile infection and colonization by antimicrobial-resistant pathogens by preserving gut microbiome diversity, according to the results of a phase 2b proof of concept study presented at Digestive Disease Week.
“What if we could simply block the initial insult that leads to [C. difficile infection, which is] the damage caused to the gut microbiome by these excess antibiotics that really aren’t needed in the intestine. Then we wouldn’t have CDI because any spores that found their way into the intestine would not find an environment that’s conducive to germination of vegetative outgrowth,” John F. Kokai-Kun, PhD, of Synthetic Biologics, said during his presentation. “That’s where our drug ribaxamase comes in, [which] is intended to degrade those excess antibiotics and protect the gut microbiome and thereby prevent opportunistic infections like CDI.”
Investigators performed a phase 2, double blind, placebo-controlled trial at 84 international clinical sites to evaluate the ability of ribaxamase to prevent CDI. They also evaluated secondary endpoints including its effects on antibiotic-associated diarrhea, colonization by opportunistic pathogens, gut microbiota alterations and the appearance of antimicrobial resistant pathogens in the gut.
The researchers identified 412 patients (mean age, 70 years; about two-thirds men) who were at risk for CDI, as they were hospitalized for at least 5 days for lower respiratory tract infections that were treated with IV ceftriaxone, and included them in the modified intent to treat population.
“We used an older ... and sicker patient population,” Kokai-Kun said.
The investigators randomly assigned these patients to receive 150 mg ribaxamase or placebo during their treatment with antibiotics and for 72 hours afterward. They analyzed 652 fecal samples from 229 patients using 16 rRNA sequencing at several pre-specified time points, and monitored all patients for 6 weeks.
Ribaxamase resulted in a 71.4% relative risk reduction in CDI (P = .0454) and a 43.9% relative risk reduction in new colonization by enterococci that were resistant to vancomycin (P = .0002) compared with placebo.
Patients who received ribaxamase also showed fewer alterations and less loss of diversity in their gut microbiota compared with patients who received placebo after receiving antibiotics.
There was also a trend toward reduction in antibiotic-associated diarrhea in the ribaxamase group, Kokai-Kun said.
“Ribaxamase also was well-tolerated and did not affect the cure rate for the primary infection, which is consistent with it not being absorbed,” he said. “Ribaxamase did not significantly reduce antibiotic associated diarrhea as defined in the protocol, however, there was a reduction in all-cause diarrhea as well as in sub-analyses. Ribaxamase reduced new colonization of C. difficile and VRE.”
In conjunction with the CDC, the investigators are also currently analyzing fecal samples from the study “for changes to the gut resistome to look for emergence of antibiotic resistance,” Kokai-Kun added. “In our minds the use of ribaxamase is a paradigm shift in the use of antibiotics that now allows you to take a really highly effective class of antibiotics, the IV beta lactams, and administer those with less concern over their side effects,” he concluded. – by Adam Leitenberger
Reference:
Kokai-Kun JF, et al. Abstract #874j. Presented at: Digestive Disease Week; May 6-9, 2017; Chicago.
Disclosures: Kokai-Kun reports he is employed by Synthetic Biologics.
Perspective
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Colleen R. Kelly, MD, FACG
This data on SYN-004 (ribaxamase) is really interesting. It is clever to design a drug that will enable infections to be treated while limiting the collateral damage to gut microbiota. It’s great that they were able to show a reduction in C. difficile among these high-risk patients.
We know that one C. difficile infection can raise hospital costs by 40% per case. If this drug is again shown to be effective in phase 3 trials and is then priced smartly (so that it would be used), it could become standard for it to be co-administered with beta-lactam antibiotics in high-risk patients.
I wonder whether similar drugs could be designed to counteract the GI effects of other antimicrobials, such as quinolones, which are also used frequently and carry a high risk for causing C. difficile infection.
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