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CHICAGO -- An enzyme that breaks down beta-lactam antibiotics -- but only in the small intestine -- protected hospital patients from Clostridium difficile infection (CDI), a researcher said here.
In a Phase IIb randomized clinical trial, the drug ribaxamase reduced the incidence of CDI by more than 70% compared with placebo, according to , of Synthetic Biologics Inc., of Rockville, Md., which is developing the compound.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
At the same time, there was no effect on outcomes for the primary disease -- lower respiratory tract infections treated with intravenous ceftriaxone, Kokai-Kun said at Digestive Disease Week (DDW) 2017.
He also reported that the drug appeared to protect the diversity of the gut microbiome, whose disruption by antibiotics is thought to be a key factor in rendering hospital patients susceptible to C. diff colonization and infection.
CDI is a major health issue, commented Curtis Wray, MD, of UT Health in Houston, who was not part of the study but who co-moderated the DDW session.
"People die ... 30,000 potentially preventable deaths a year," he told ľֱ.
The question is how to prevent those deaths, and the study showed a potentially useful benefit, he said. But the benefit is roughly the same as what has been seen in studies with probiotics, so it will be important to compare efficacy and cost before clinicians can make choices, he added.
"It's yogurt versus a pill," he said.
It might be the case that for a selected population -- perhaps older patients with weakened immune systems -- the drug would be the right choice, he said, but more research will be needed to pin that down.
Kokai-Kun described a vicious circle of events that begins with IV antibiotics in hospital, leads to gut dysbiosis, and in many cases CDI, which is responsible for 29,000 deaths a year in the U.S. as well as extended hospital stays and increased treatment expense.
"But what if we could simply block the initial insult that leads to this cascade?" he asked.
Ribaxamase, he said, is designed to do just that -- it's an engineered enzyme that breaks down penicillins and cephalosporins, but is released in the acidic environment of the intestines and not in the blood or elsewhere.
To test the effect, his group enrolled 412 patients admitted to hospital for a lower respiratory tract infection and expected to need at least 5 days of ceftriaxone. Eligible patients were older than 50 and had high pneumonia severity indices.
They were randomly assigned to get ceftriaxone IV with daily ribaxamase or a placebo, and could also be given a macrolide antibiotic at the treating physician's discretion. The antibiotic treatment period was 5 to 14 days, and the ribaxamase/placebo was continued for 2 days after the end of antibiotic treatment.
The primary endpoint was the proportion of patients in each arm who developed CDI while the secondary endpoint was the prevention of other forms of antibiotic-associated diarrhea. The investigators also explored the effect of the drug on the gut microbiome.
The drug met the primary endpoint, Kokai-Kun said: Of the 206 patients in the placebo arm, seven (or 3.4%) developed CDI, compared with two in the ribaxamase arm, a relative risk reduction of 71.4%.
Importantly, the beta-lactamase activity of the drug in the gut did not interfere with the treatment effect of ceftriaxone: the respiratory infections were cured in 99% of patients in both arms 72 hours after the end of therapy and 2 weeks later, Kokai-Kun said.
For the secondary endpoint of all-cause diarrhea, there was a trend in favor of the drug (driven by the CDI diarrhea) but it did not reach statistical significance.
On the other hand, by a number of measures, the effect of ceftriaxone on gut bacteria was mitigated in patients who also got ribaxamase, he said. For instance, alpha-diversity -- a measure of how varied the microbiome is in a single sample -- was significantly reduced in patients who got placebo, but not in those taking ribaxamase, he said.
He said treatment-emergent adverse events and serious adverse events were similar between the arms with no trend pointing to ribaxamase.
Disclosures
The study was supported by Synthetic Biologics. Kokai-Kun and co-authors are company employees.
Wray disclosed no relevant relationships with industry.
Primary Source
Digestive Disease Week
Kokai-Kun JF "SYN-004 (ribaxamase), an oral β-lactamase, prevented Clostridium difficile infection and protected patients from colonization by antimicrobial resistant pathogens by preserving gut microbiome diversity in a Phase 2b clinical trial" DDW 2017; Abstract 874j.