A new treatment for recurrent Clostridium difficile infection provides significant benefit when added to standard antibiotic treatment, according to data from two clinical trials published in the New England Journal of Medicine today.
The findings come from two large phase 3 clinical trials—MODIFY I and MODIFY II—designed to determine the efficacy of the drug bezlotoxumab alone or in combination with the drug actoxumab for the treatment of recurrent C difficile infection, which occurs in up to 35% of patients who get initial infections. C difficile, a bacterium that causes inflammation of the colon, is the most common cause of infectious diarrhea in hospital patients.
While antibiotics are the standard treatment for primary and recurrent C difficile, they can also contribute to relapse by wiping out the normal gut flora that helps keep the bacterium in check. That's one of the reasons non-antibiotic therapies have been sought.
Bezlotoxumab is a human monoclonal antibody that provides passive immunity to toxin B, one of the two toxins that attack the lining of the intestine. Actoxumab, also a monoclonal antibody, works by neutralizing toxin A. Bezlotoxumab was approved by the Food and Drug Administration (FDA) in October for use in patients with recurrent C difficile infection who are receiving antibiotic treatment.
Bezlotoxumab shines in both trials
In the two randomized, double-blind, placebo-controlled trials, 2,655 patients from 30 countries with primary or recurrent C difficile were randomly assigned to four treatment groups. One group received a single-dose transfusion of bezlotoxumab, and one group was treated with a single dose of actoxumab. A third group received a single dose of bezlotoxumab plus actoxumab. The final group was treated with a placebo (saline). All patients were also being treated with standard-of-care oral antibiotics (metronidazole, vancomycin, or fidaxomicin).
The primary end point of the trial was to see how many patients developed a recurrent C difficile infection in the 12 weeks following the infusion.
The results of the MODIFY I trial showed that the percentage of patients who had a recurrent infection was significantly lower among those who had been treated with bezlotoxumab than those who received the placebo (17% vs. 28%). In the actoxumab group, by contrast, 26% of patients suffered a relapse. As a result, it was discontinued after the first trial.
In the MODIFY II trial, bezlotoxumab again showed greater efficacy than the placebo, with only 16% of the treatment group getting another infection, compared with 26% of the placebo group. The rate of recurrent infection was also lower in the bezlotxumab-plus-actoxumab group than the placebo group (16% vs. 28%), but the authors concluded that the addition of actoxumab provided no additional benefit.
In a pooled analysis of the data, the rate of sustained cure was 64% with bezlotxumab, 58% with actoxumab-bezlotoxumab, and 54% with placebo. In addition, bezlotoxumab alone and in combination with actoxumab was significantly more effective than the placebo in patients at high risk for recurrent infection. All groups had similar rates of adverse events, the most common of which were diarrhea and nausea.
"In summary, a single intravenous dose of bezlotoxumab against C. difficile toxin B, when given with standard-of-care antibiotics, provided protection against recurrent C. difficile infection for up to 12 weeks that was superior to that provided by treatment with standard-of-care antibiotics alone," the authors write.
Is it cost-effective?
Lead author Mark Wilcox, MD, a professor of medical microbiology at the University of Leeds, said the finding that bezlotoxumab reduces recurrent infection by nearly 40% compared with standard treatment could have far-reaching impacts, given the number of people who suffer recurrent infections.
"It is important to treat the first episodes of C. diff infection optimally, as each recurrence increase the chance of another episode even more," Wilcox said in a university press release. "Fewer recurrent infections would mean less need to use antibiotics, fewer hospital admissions, reduced costs for NHS [Britain's National Health Service], and possibly a reduction in deaths."
But in a related editorial in the New England Journal of Medicine, John Bartlett, MD an infectious disease expert and professor emeritus at the Johns Hopkins University School of Medicine, says the next question that needs to be asked is how bezlotoxumab compares, in terms of relative relapse risk and cost, with other treatments for recurrent C difficile. One of those treatments is fidaxomicin, which is also associated with lower relapse rates.
"The cost issue obviously looms large, given the realities of contemporary medical care and specifically the experience with fidaxomicin," Bartlett writes. "Thus, determining the cost-effectiveness of bezlotoxumab as compared with alternative treatment strategies will be important."
Other strategies for recurrent C difficile infection include fecal microbiota transplantation (FMT), in which stool from a healthy donor is transplanted to the upper or lower part of the gastrointestinal tract of an infected patient. In addition, vaccines for C difficile infection are in phase 2 trials.
The study was supported by Merck, which owns the license to bezlotoxumab.
See also:
Jan 26 N Engl J Med study
Jan 25 University of Leeds press release
Jan 26 N Engl J Med editorial
