The beta-lactamase ribaxamase reduces the incidence of Clostridium difficile infections in hospitalized patients treated with intravenous ceftriaxone for lower-respiratory-tract infections, researchers report.
Intravenous beta-lactam antibiotics are associated with a high risk of C. difficile infections because of their disruption of the gut microbiome. Ribaxamase, an orally administered beta-lactamase, is designed to degrade excess beta-lactam antibiotics in the upper gastrointestinal tract before they disrupt the gut microbiome and lead to C. difficile infection (CDI).
Phase 2a studies have demonstrated that ribaxamase degrades ceftriaxone excreted into the intestine without affecting the plasma pharmacokinetics of the antibiotic. In the new work, a placebo-controlled phase 2b study, Dr. John F. Kokai-Kun from Synthetic Biologics, in Rockville, Maryland, and colleagues investigated whether ribaxamase could also prevent C. difficile infection in patients treated with IV ceftriaxone for a lower-respiratory-tract infection.
Of the 512 pati
ents included in the study (206 each in the ribaxamase and placebo groups), about half received other antibiotics in addition to ceftriaxone. Ten patients (4.9%) in the ribaxamase group and 14 patients (6.8%) in the placebo group received probiotics during the study, and none of these patients developed C. difficile infection.
As reported in The Lancet Infectious Diseases, online March 15, two patients (1.0%) in the ribaxamase group and seven (3.4%) in the placebo group met the criteria for C. difficile infection at or before the four-week follow-up visit (P=0.045, but the 95% confidence interval was -0.6 to 5.9 percentage points).
There were no additional cases of C. difficile infection after the four-week follow-up visit.
There was no significant difference between the ribaxamase and placebo groups in new colonization with C. difficile at the end of treatment or at the end of the four-week follow-up. But there was a significant reduction in the risk of new colonization by vancomycin-resistant enterococci (VRE) and the ribaxamase group.
The risk of colonization by extended-spectrum beta-lactamase (ESBL) producing Gram-negative bacilli remained fairly constant at about 20% across all time points in both groups.
The percentage of patients experiencing serious adverse events was higher in the ribaxamase group (16.0% vs. 10.2% in the placebo group), as well as the percentage experiencing fatal adverse events (5.3% vs. 2.4%, respectively).
Most such events appeared to be related to the patient's medical history, an identified malignancy, or progression of the original respiratory infection. None was considered to be drug related by the investigators, medical monitors, or non-affiliated third-party reviewer.
"Our study supports the continued clinical development of ribaxamase for prevention of C. difficile infection in at-risk patients treated with intravenous beta-lactam antibiotics, especially those being treated for extended durations for serious infections or who have other underlying risk factors for C. difficile infection," the researchers conclude.
Dr. Simon D. Goldenberg from Guy's and St. Thomas' NHS Foundation Trust, King's College, in London, who wrote an accompanying editorial, told Reuters Health by email, "Co-administration of ribaxamase with beta-lactam antibiotics may be a more elegant and targeted solution, although it is only relevant to patients who receive this class of drug; there are many more patients who are prescribed other classes of antibiotic, for which ribaxamase would be ineffective."
"UK practice for treatment of lower-respiratory-tract infection (including severe pneumonia) is generally for a total of 5 days of amoxicillin or co-amoxiclav (rather than a third-generation cephalosporin, which has significantly more excretion into the gastrointestinal tract)," he explained. "The median length of ceftriaxone therapy in the study was 8 days; thus, its relevance to UK practice may be limited."
"It is also not clear how the strategy of performing an intravenous to oral switch would be affected," Dr. Goldenberg said. "In its current formulation, ribaxamase would render any orally administered beta-lactam ineffective. I am not convinced that physicians would be willing to keep patients in hospital (or enroll into an outpatient antibiotic therapy (OPAT) service) in order to prevent C. difficile infection."
"The other interesting finding from the study was the significant reduction in risk of colonization by VRE in the ribaxamase treated group," he added. "Unfortunately, this was not seen for Gram-negative organisms such as ESBLs, which one might argue are a more significant threat in terms of currently available effective treatments."
Dr. Rafael Mendo from Beth Israel Deaconess Medical Center, in Boston, told Reuters Health by email, "The 95% confidence interval includes zero, which means that there is not a significant difference between the placebo and ribaxamase groups. This finding demonstrates that there is a possibility that ribaxamase does not show a significant difference compared to placebo, and future studies utilizing larger sample size are required to determine ribaxamase's efficacy."
"Ribaxamase's future randomized control trials should consider balancing patients' comorbidities, particularly cardiovascular, between treatment and placebo groups to determine its efficacy and safety in CDI precisely," said Dr. Mendo, who was not involved in the study.
"On the other hand, it may be interesting to explore if ribaxamase could have a role as a preventive measure in high-risk patients for vancomycin-resistant enterococci (VRE) infection," Dr. Mendo added.
Synthetic Biologics, which funded the study and employed most of the authors, has said that is working closely with the U.S. Food and Drug Administration to complete the protocol for a phase 3 trial.
Dr. Kokai-Kun did not respond to a request for comments.
SOURCE: https://bit.ly/2CMBz3i and https://bit.ly/2OF9wHL
Lancet Infect Dis 2019.
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