Fecal microbiota transplantation for the treatment of recurrent or drug-resistant Clostridium difficile infections in inflammatory bowel disease

This is an automatically translated article.

Posted by Master, Doctor Mai Vien Phuong - Department of Examination & Internal Medicine - Vinmec Central Park International General Hospital
A recent multicenter study demonstrated the safety and efficacy of fecal microbiota transplantation (FMT) for the treatment of recurrent or refractory Clostridium difficile infections in patients with inflammatory bowel disease at a rate of cured equal to the general population.
Over the past decade, the rate of infections caused by Clostridium difficile has more than doubled. Fecal microbiota transplantation (FMT) has emerged as a guideline-based treatment for recurrent and refractory disease. However, the role of fecal microbial transplantation in the treatment of Clostridium difficile infections in patients with inflammatory bowel disease (IBD) is controversial despite the high rate of complications associated with Clostridium difficile infections. higher in this group of subjects including mortality, resection and recurrent infections. A recent multicenter study demonstrated the safety and efficacy of fecal microbiota transplantation in the treatment of recurrent or refractory Clostridium difficile infections in patients with inflammatory bowel disease with similar cure rates. comparable to the general population, but questions remain regarding the impact of fecal microbial transplantation on inflammatory bowel disease and its place in the treatment paradigm.

1. Introduction

Clostridium difficile infection is the most common cause of hospital-acquired diarrhea in developed countries. Over the past decade, its incidence has doubled, a phenomenon attributed to the emergence of an epidemic strain of C. difficile bacteria known as North American C. difficile strain type 1, PCR ribotype 027 (NAP1/ BI/ 027), this strain increases toxin production rate associated with greater disease severity, higher relapse rate and its significantly financial burden of mortality. healthcare is estimated at $3.2 billion per year in the United States. The impact of Clostridium difficile infection on patients with inflammatory bowel disease is even more pronounced. Over the past decade, the incidence of infections caused by Clostridium difficile has doubled in Crohn's disease (Crohn's disease) and tripled in ulcerative colitis (ulcerative colitis). More importantly, the prevalence of Clostridium difficile infections in the inflammatory bowel disease (Clostridium difficile) population is estimated to be 2.5 to 8 times higher than in the general population, with 10 % lifetime risk of infection. In 2007, 2.9% of all IBD hospitalizations in the US were due to complicated Clostridium difficile infections. Length of hospital stay and hospital-related costs were also significantly higher when Clostridium difficile infection in patients with inflammatory bowel disease was compared with inflammatory bowel disease or hospital-associated Clostridium difficile infection.

2. Faecal Microbial Transplantation Technique (FMT)

Fecal microbiota transplantation (FMT) has emerged as a highly effective therapy for recurrent Clostridium difficile infections. There is also solid evidence that fecal microbial transplantation is safe and rarely associated with adverse events even in immunosuppressed populations. Treatment guidelines published in 2013 by the American College of Gastroenterology recommend fecal microbiota transplantation for the third recurrence of Clostridium difficile infection. This is predicted based on treatment success rates in excess of 90% for recurrent and refractory Clostridium difficile infections after only one fecal microbial engraftment delivered via colonoscopy to the colon. ascending colon or cecum. Fecal microbiota transplantation through other routes has also demonstrated an efficacy rate of approximately 85% when administered via a nasopharyngeal tube or via enema. More recent studies have shown the role of fecal microbial transplantation in hospitalized patients with severe and complicated Clostridium difficile infections; cure rates are as high as 88% after a single inoculation of fecal microorganisms 25 and over 90% when used in a sequential manner.
Despite the high morbidity and poor outcome associated with Clostridium difficile infections in patients with inflammatory bowel disease, only a few studies have described outcomes after treatment with fecal microbial cultures. in this population. Among inflammatory bowel disease patients receiving immunosuppressive therapy (N = 36), Kelly et al demonstrated resolution of Clostridium difficile infections in 86% of patients after a single microtransplant. single fecal organism, with an overall cure rate of 94%. More recently, Khoruts et al showed that patients with inflammatory bowel disease were more likely to fail a single fecal microbiota transplant and that immunosuppressive therapy had no effect on outcomes. In their study, a single endoscopic fecal microbiota implant cleared Clostridium difficile infection from 74% of patients with inflammatory bowel disease compared with 92% of patients without inflammatory bowel disease (P = 0, 0018). A multicenter study on the use of fecal microbial transplantation specifically in patients with inflammatory bowel disease with recurrent or refractory Clostridium difficile infections, the largest study on the topic to date, has The primary objective was to evaluate treatment success rates for Clostridium difficile infections in this single population and to characterize safety and efficacy-related secondary outcomes for IBD activity. .

3. Study method to evaluate the role of fecal microbiota in the treatment of recurrent Clostridium difficile infections

In this retrospective study, patients from seven medical centers with a history of recurrent or refractory Clostridium difficile inflammatory bowel disease and infection were treated with a microbiological implant in the colonoscopy distribution. colonoscopy or sigmoidoscopy. Procedures for donor selection and faecal disposal were followed as outlined by the Faecal Microbiome Transplantation Working group. Inflammatory bowel disease activity and severity were assessed based on the treating physician's assessment, endoscopic findings, and clinical disease activity score. The results of these assessments were recorded at 1 month before fecal microbiota inoculation, at fecal microbiota inoculation and 3 months after fecal microbiota inoculation. Changes in the clinical course of inflammatory bowel disease after fecal microbiota transplantation were classified by the treating physician as improving, unchanged, or worsening.
Outcomes of Treatment of Clostridium difficile infections A total of 67 patients, 35 with Crohn's disease, 31 with ulcerative colitis, and 1 with unspecified colitis, of which 64% were being treated. treated with immunosuppressants at the time of fecal microbiota transplantation. All patients in this group had a history of recurrent or refractory Clostridium difficile infections with a median of 4 episodes. The majority of patients (94%) had previously been treated with vancomycin. Indications for fecal transplantation are recurrent Clostridium difficile infections in 80% and severe or complicated Clostridium difficile infections in 9%. Overall, 79% were successfully treated after a single fecal microbial engraftment, while 90% achieved success after up to three fecal microbial inoculations. The only independent predictor for repeated fecal microbial engraftment was low serum albumin levels.

4. Impact of fecal microbiota transplantation on inflammatory bowel disease

Seventy-six percent of the population infected with Clostridium difficile have concomitant inflammatory bowel disease, (hereinafter referred to as: Clostridium difficile) with endoscopic evidence of active inflammatory bowel disease in microbial cultures. in feces. After 3 months, the majority of patients are “progressing well”; The clinical course of inflammatory bowel disease improved in 46.3% and remained unchanged in 35.8% of patients. Clinical disease activity scores (Harvey-Bradshaw index) were available for 23 Crohn's disease patients and significantly decreased from a mean of 7 before fecal microbiota transplantation to 2 after fecal microbiota transplantation (P = 0.004). However, a significant number of patients (17.9%) had clinical worsening of inflammatory bowel disease. Of the patients considered more severe, three had extensive colitis at the time of fecal transplantation and were hospitalized for an inflammatory bowel disease flare 2 weeks after fecal transplantation. , but responded promptly to a short course (10-30 days) of systemic steroids. Two patients underwent surgical resection within 1 month, both for severe Crohn's colitis and for treatment-resistant Clostridium difficile infections. Two other ulcerative colitis patients underwent colectomy, but were found to be negative for Clostridium difficile infection by PCR at the time of surgery. Nineteen patients were initiated on new inflammatory bowel disease during a 12-week follow-up period.

5. Side effects of this method

Overall, 12% (8/67) of patients experienced serious adverse events (SAEs), two of which were flare-ups of inflammatory bowel disease requiring hospitalization. Only one patient experienced SAE directly induced by fecal microbial inoculation; This immunocompromised Crohn's disease patient was in clinical and endoscopic remission at the time of fecal microbiota transplantation, developed a 1-week post-implantation flare, and was found to have active inflammation. and CMV cells were positive on subsequent colon biopsies. CMV may have been transmitted through a fecal transplant; neither the donor nor the recipient were tested for CMV prior to fecal microbiota transplantation. Notably, no other infectious complications associated with fecal microbiota transplantation were reported.

6. How will fecal microbiota transplantation change the treatment paradigm for Clostridium difficile infections in patients with inflammatory bowel disease?

This study demonstrated the efficacy of fecal microbiota transplantation as an adjunct to medical therapy for the treatment of Clostridium difficile infections in the inflammatory bowel disease population. The majority of patients have an improved or unchanged inflammatory bowel disease course following fecal microbiota transplantation, but a significant few develop flare-ups of inflammatory bowel disease or present more severe disease. These findings are consistent with a previous study in immunocompromised patients, where 14% of patients in the inflammatory bowel disease group experienced exacerbations of inflammatory bowel disease following fecal microbial transplantation. More recently, Khoruts et al. reported that 25% of inflammatory bowel disease patients with flare-ups required systemic steroid therapy following fecal microbiota transplantation. Importantly, the majority of these patients had severe colitis at the time of fecal microbiota transplantation. With the majority of patients experiencing flares of inflammatory bowel disease following fecal microbial transplantation, the authors applied the practice of enhanced anti-inflammatory/immunosuppressive therapy in patients with myositis. to reduce the risk of inflammatory bowel disease outbreaks following fecal microbiota transplantation. In another study, Chin and colleagues administered fecal microbial cultures to 35 patients with Clostridium difficile infections in patients with predominantly oral capsule inflammatory bowel disease. Although fecal microbial transplantation was well tolerated by all patients, a large proportion (54%) required increased therapy for fecal inflammatory bowel disease following fecal microbial transplantation. Interestingly, two patients developed disease in the form of perianal fistula and abscess following fecal microbial transplantation. The cause of inflammatory bowel disease outbreaks following fecal microbial transplantation and worsening disease activity are unknown. Conceivably, outbreaks could end with the Clostridium difficile infection itself rather than the spontaneous inflammatory bowel disease progression, and or an immune response triggered by the use of fecal microbial cultures. . Potential studies on temporal changes in gut microbiota composition are needed to gain mechanistic insights.

7. Risk factors for Clostridium difficile infection in patients with inflammatory bowel disease

Inflammatory bowel disease patients have multiple risk factors for Clostridium difficile infection including dysbiotic gut flora and higher rates of exposure to immunosuppressants, antibiotics, and hospitalization. lead to significantly worse morbidity and mortality outcomes. However, patients with Clostridium difficile infection in patients with inflammatory bowel disease were treated according to the same guidelines as their patients without Clostridium difficile infection. There is a role for a more aggressive treatment.

8. Role of Vancomycin in the treatment of infections caused by Clostridium difficile in patients with inflammatory bowel disease

Mounting evidence supports the use of vancomycin in Clostridium difficile infections in patients with inflammatory bowel disease as first-line therapy even for non-severe Clostridium difficile infections. In one study, patients with ulcerative colitis and non-severe Clostridium difficile infections had fewer readings and shorter hospital stays with vancomycin-containing regimens than those on metronidazole alone. Lower rates of colectomy have been reported when patients with Clostridium difficile infections in patients with inflammatory bowel disease were treated with oral vancomycin. There is a need to stratify the severity of Clostridium difficile infections specifically for the inflammatory bowel disease population. Both elevated white blood cell counts (WBCs) and serum albumin levels below 3g/dL are characteristic of severe disease and are independently associated with resection and mortality in the general population. In the Clostridium difficile-infected population with inflammatory bowel disease, serum albumin below 3g/dL was associated with a threefold increase in the primary resection outcome and death, regardless of white blood cell count.
Improved outcomes in patients with Clostridium difficile infections in patients with inflammatory bowel disease after vancomycin use even in non-severe cases. Disease severity may be masked by concomitant use of immunosuppressants and delayed recognition of Clostridium difficile infection due to similarity in patient symptoms during flare-ups of inflammatory bowel disease and infections caused by Clostridium difficile.

9. When to use fecal microbiology in the treatment of Clostridium difficile infections?

There may be a role in the earlier localization of fecal microbiota in the treatment of Clostridium difficile infections in the inflammatory bowel disease population despite current evidence for fecal microbial engraftment. for the treatment of inflammatory bowel disease without concomitant Clostridium difficile infection is best. The rate of hospitalization for recurrent Clostridium difficile infections in IBD patients was much higher (8.7%) than in the general population (0.1%). However, it still seems unpredictable in response to fecal microbial transplantation in the inflammatory bowel disease population. Long-term studies are needed to determine the optimal timing of fecal microbial transplantation for the treatment of Clostridium difficile infections in patients with inflammatory bowel disease, to ensure the best outcome while limiting Inflammatory bowel disease activity worsened following fecal microbiota transplantation.

CONCLUSION

Current data suggest that fecal microbiota transplantation for the treatment of recurrent or refractory Clostridium difficile infections is effective and safe in patients with inflammatory bowel disease. The overall cure rate in patients with Clostridium difficile infection in patients with inflammatory bowel disease is comparable to that in patients without inflammatory bowel disease, however, patients with inflammatory bowel disease may require more than one microorganism transplant. fecal matter to cure. While the majority of the clinical course of patients with Clostridium difficile infections in patients with inflammatory bowel disease improved following fecal transplantation, some remained unchanged despite clearance of Clostridium difficile infections. and a significant number may have flare-ups of inflammatory bowel disease. Hospitalizations associated with Clostridium difficile infection in patients with inflammatory bowel disease have been shown to have much higher mortality, colectomy, and length of hospital stay than Clostridium difficile infection or inflammatory bowel disease alone. therefore, fecal microbial transplantation may need to be considered earlier in this population. In order to effectively treat these patients and determine the location of fecal microbial transplantation in the therapeutic model, further studies of fecal microbial transplantation on the outcome of Clostridium difficile infections are needed. and inflammatory bowel disease.

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