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Guest Commentary: Preventing and treating recurrent Clostridium difficile infections
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In this guest commentary, Ciaran Kelly, MD, discusses treatment and prevention of recurrent Clostridium difficile infections following presentations on the topic delivered at the inaugural ASM Microbe 2016 meeting. Kelly is a professor of medicine at Harvard Medical School and director of Gastroenterology Fellowship Training at Beth Israel Deaconess Medical Center in Boston.
Clostridium difficile is the most common cause of nosocomial infectious diarrhea in adults, accounting for about 500,000 cases and 29,000 deaths per year in the United States. Despite the availability of antibiotics such as metronidazole and vancomycin, the recurrence rate for C. difficile infections is 20% to 30%. Recurrent C. difficile infections are associated with higher re-hospitalization and 180-day mortality rates, compared with non-recurrent infections. Moreover, each recurrent C. difficile episode increases the risk for additional recurrences. Sheitoyan-Pesant et al. reported the first recurrence increases the risk for another recurrence to 45% and that additional recurrences push the risk as high as 65%.
Ciaran Kelly
Current practice manages the first recurrence similarly to the primary case, with adjustments based on the severity of the recurrent infection. Subsequent recurrences can be managed with vancomycin taper or pulse regimens, vancomycin chaser regimens or fidaxomicin. Although fidaxomicin is superior to vancomycin regarding cure rate and recurrence rate, it is also more expensive, costing $135 per 200 mg dose. Thus, other approaches are needed to prevent and manage rCDI.
Emerging treatment approaches: Highlights from ASM Microbe 2016
The inaugural ASM Microbe 2016 conference included several presentations on emerging treatment approaches for CDI. Richard J. Vickers, PhD, of Summit, presented additional efficacy and safety data from the phase 2 CoDIFy trial that compared the narrow-spectrum antibiotic ridinilazole with vancomycin in 100 patients. Ridinilazole treatment conferred a sustained clinical response rate of 66.7% compared with 42.4% for vancomycin (difference 21.1%; 90% CI, 3.1-39.1), and a recurrence rate of 14.3% vs. 34.8% for vancomycin. A subgroup analysis favored ridinilazole over vancomycin even in groups at higher risk for rCDI, such as patients older than 75 years, those with severe disease and those with previous CDI episodes. There were no clinically important differences between ridinilazole and vancomycin in adverse or serious adverse events. Furthermore, as reported in a late-breaking poster, ridinilazole did not appear to induce any significant changes in the native microbiome.
Dale N. Gerding, MD, of Loyola University Stritch School of Medicine, noted the phase 3 MODIFY I and MODIFY II trials that showed bezlotoxumab, a monoclonal antibody against C. difficile toxin B, significantly reduced CDI recurrence rates alone or in combination with actoxumab, a monoclonal antibody against C. difficile toxin A. Like ridinilazole, bezlotoxumab also reduced rCDI in several high-risk groups.
Dale N. Gerding
Yoav Golan, MD, MS, of Tufts Medical Center, presented a follow-up study demonstrating that bezlotoxumab treatment significantly reduced 30-day CDI-associated hospital readmission rates (4% vs. 9.6%; difference, –5.7%; 95% CI, –8.8 to –2.7) and rCDI recurrence rates during the 12-week follow-up period (full analysis set: 16.5% vs. 26.6%; difference, –10%; 95% CI, –14 to –6; patients who were inpatients at the time of study randomization: 13.8% vs. 23.1%; difference, –9.3%; 95% CI, –14 to –4.6).
Ellie J.C. Goldstein, MD, of the RM Alden Research Laboratory, presented another follow-up study showing that rCDI rates were lower in the bezlotoxumab and bezlotoxumab/actoxumab groups compared with placebo at 6, 9 and 12 months following treatment. However, this study also found that the overall recurrence rate among patients who showed global cure at 12 weeks was less than 2% and that there were no treatment differences in C. difficile colonization rates at 6, 9 or 12 months after treatment.
Ellie J.C. Goldstein
Fecal microbiota transplant, which aims to restore the gut microbiome, continues to be a promising approach for patients who have experienced at least two or three CDI episodes. Dr. Gerding and Elizabeth Hohmann, MD, of Brigham and Women’s Hospital, discussed systematic analyses of case series and randomized controlled trials that found cure rates of 85% or higher for FMT. They also noted randomized controlled trials demonstrating higher cure rates with repeat FMT administration, compared with one administration alone.
Dr. Hohmann presented data from the Massachusetts General Hospital oral FMT capsule program. Preliminary studies published in JAMA and Clinical Infectious Diseases reported that administration of 15 capsules per day for 2 days resolved multiple-recurrent CDI in 14 of 20 patients and that the response rate increased to 18 of 20 patients with repeated administration. Since then, the Massachusetts General Hospital program has treated more than 200 patients aged 7 to 95 years with cure rates of 82% after one course, 91% after two, and 93% after three.
Dr. Hohmann also described two FMT products on track for FDA approval by the end of 2017. RBX2660, a microbiota enema suspension manufactured by Rebiotix, has shown an 87% cure rate at 8 weeks in a phase 2b trial. SER-109 (Seres Therapeutics), a capsule containing a donor stool spore extract pretreated with ethanol and frozen, conferred clinical cure at 8 weeks in 29 of 30 patients who had experienced more than three CDI episodes during the previous year. The relapse rate among these patients was only 13% during weeks 8 to 24.
Other potential treatment approaches for rCDI include vaccines and replacement with non-toxic C. difficile. Katrin Dubischar, MSc, of Valneva SE, presented a phase 2 study demonstrating a superior immune response to a 200 µg dose of Vla84, a recombinant protein vaccine containing cell-binding domains of toxins A and B, without alum in healthy patients aged 50 to 90 years.
Dr. Gerding noted a phase 2 randomized controlled trial assessing treatment with the non-toxigenic C. difficile strain M3 (NTCD-M3) during the first CDI episode or the first rCDI, following successful treatment with metronidazole or vancomycin. NTCD-M3 treatment had a recurrence rate of 11% overall, 5% for the best dose (107 cells/day for 7 days), and 2% for the best dose if NTCD-M3 was colonized. There were no significant differences in adverse events between NTCD-M3 and placebo.
It is likely that no one approach will be effective against rCDI. Rather, a combination of approaches will be needed to truly tackle this problem. However, with the current approaches in place and new approaches emerging from the pipeline, our armamentarium against rCDI may be growing stronger.
References:
Chang J, et al. Abstract LB-116. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston.
Dubischar K, et al. Slide Session 093. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston.
Golan Y, et al. Abstract 449. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston.
Goldstein E, et al. Abstract 448. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston.
Hohmann E. Symposium 255. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston.
Segreti J, et al. More Than A Gut Reaction: Effective Strategies to Treat and Prevent Recurrent C. difficile Infection. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston.
Sheitoyan-Pesant C, et al. Clin Infect Dis. 2016;62(5):574-80.
Vickers RJ, et al. Abstract 440. Presented at: ASM Microbe; June 16-20, 2016; Boston. Poster Session 417, Abstract 440.
Disclosure: Kelly reports consulting and/or advisory roles with Merck, Sanofi Pasteur, Seres Therapeutics, Summit and Alba.