Fecal Microbiota Transplantation in Recurrent Clostridium Difficile Infection: Is it Superior to Other Conventional Methods?

Clostridium difficile (C. difficile) is a gram-positive species of spore-forming bacteria. C. difficile infection (CDI) is one of the most common hospital-acquired infections in the United States, mainly caused by the use of recent antibiotics that leads to intestinal dysbiosis. Recurrent C. difficile infection (rCDI) often occurs after the successful treatment of CDI. Approximately, 30% of patients experience a clinical recurrence of prior symptoms within eight weeks of antibiotic cessation. This present literature review covers the current pathophysiology of CDI, risk factors for infection, diagnostic methods, several treatment modalities, and the potential use of fecal microbial transplant (FMT) for patients with multiple recurrent CDIs. Recent studies have focused on FMT, with an efficacy rate of nearly 90% in multiple recurrent CDI settings. Despite its efficacy, it is not commonly used as first-line treatment. More studies are needed to establish this therapy as the first option in patients with rCDI.


Introduction And Background
Clostridium difficile (C. difficile) is a gram-positive, anaerobic, spore-forming bacillus that was retitled to Clostridioides difficile in 2016 [1]. C. difficile infection (CDI) is one of the most common nosocomial diseases in the United States, with approximately 453,000 infections and 29,000 deaths in 2011 [2]. It has been a big problem for U.S healthcare systems, leading to roughly $5 billion in healthcare costs [3].
The incidence and fatality rate of recurrent C. difficile infection (rCDI) have been escalating worldwide due to an increase in drug-resistant strains [4]. rCDI is generally described as an episode of CDI that occurs within eight weeks of the previous event [5,6], which can be due to relapse of the same strain or a different strain [7]. In some reported studies, rCDI occurred in approximately 15-30% of patients who initially responded to antibiotic therapy [8,9].
The pathogenesis of CDI supports the hypothesis that antibiotic use can change the constitution and homeostasis of intestinal microbiota, which leads to pathogenic toxinproducing C. difficile strains to inhabit the intestine, causing illness ranging in severity from mild diarrhea to pseudomembranous colitis, toxic megacolon, and sepsis [10,11]. 1 2, 3 4 5 1 Over the last few years, fecal microbiota transplantation (FMT), which consists of fecal microbiota infusion from a healthy donor into a recipient subject, has been more successful and durable than conventional therapy for rCDI patients. Particularly fresh donor FMT can reconstitute the standard composition of intestinal microbiota in patients and restore their function to protect against further CDI recurrence and colonization [12][13][14][15]. FMT was conducted in hundreds of patients, and the findings have been published in the medical literature. Besides, FMT is successfully treated in 87% of rCDI patients [16].
Our article aims to include high-quality papers on this topic for more detailed research to be updated to contribute to some significant assistance for clinical practice.

Review Method
Data is collected from PubMed using regular keywords and MeSH strategy and subheadings. Table 1 demonstrates regular and MeSH keywords for the literature search.

Total records 34805
Records selected 1753

Total records 20622
Records selected 2149

Total records 668
Records selected 263  Table 2 indicates the total number of articles after inclusion/exclusion criteria have been used in the following order:

2: Total number of articles after applying inclusion/exclusion criteria
A total of 1490 articles from keyword search "CDI were removed due to lack of outcome of interest in "CDI treatment" and the elimination of duplicates. After a detailed search, the total number of articles collected was 263 free full texts. All 263 free full texts were reviewed, and 233 were removed due to one of the following reasons: (1) not specifying the disease of interest (those which did not assess CDI separately but were instead a composite assessment of CDI with other Clostridium species); (2) case report or case series studies (as it only assessed for a particular patient in focus; (3) meta-analysis.
Finally, 30 publications in PubMed (with free full text available online) were included in the final selection, including 12 review articles, 11 clinical trials, five randomized control trials, one observational study and one cohort study.
The maximum number of subjects in a study was 232, and the minimum was 14, and the total number of subjects included in all 30 studies was 951. All the documents reviewed were readily accessible for analysis, and the citations for the borrowed definitions were valid. A qualitative analysis was conducted on the existing data after inclusion/exclusion to provide the relevant disease and population with the necessary result.

Discussion
In the presented literature review, we found that FMT is helpful in treating patients with rCDIs. Moreover, studies have proved that FMT has provided an initial cure rate of nearly 90% in patients with rCDI [17,18]. Nonetheless, the optimal treatment option is still depending on the severity of the disease.
The normal intestinal microflora is a significant protective barrier against CDI. Bile acids play an essential part in the induction of C. difficile spore colonization in the intestine. Generally, primary bile acids stimulate C. difficile spores colonization, and the secondary bile acids inhibit this process. Typically, a greater level of secondary bile acids is present in the feces of healthy individuals compared to CDI. In contrast, primary bile acid level was more elevated in patients with recurrent CDIs compared to patients with their first episode of CDI. FMT induces the restoration of the intestinal microbiota that metabolizes the primary bile acids and the normalization of the secondary bile acids. Various cytokines such as IL-8, IL-1β, IL-6, TNFα, INFγ, and leukotriene B4 play a role in the pathogenesis of CDI. Moreover, C. difficile produces toxin A, "enterotoxin A" and toxin B, "cytotoxin B." In severe situations, microulcerations are seen on the intestinal mucosa surface, covered with pseudomembranes [19,20].
Symptoms of rCDIs appear mostly during the first week after completion of the first episode of CDI treatment [21]. The clinical features of CDI range from the asymptomatic carrier state to life-threatening fulminant colitis. In addition to watery diarrhea, other features include fever, nausea and vomiting, abdominal pain, weakness, and anorexia. Although there is no active bleeding, stool for occult blood is usually positive. The symptoms vary according to the severity of the disease. Other serious complications include toxic megacolon, intestinal perforation and ileus, renal failure, systemic inflammatory response syndrome, septicemia, and death [22]. Following the initial diagnosis and the treatment of CDI, the diagnosis of recurrent CDI is challenging. It requires the gathering of a detailed and complete clinical history of antibiotic use and symptom response. Patients should express a clinical response to antibiotics against C. difficile, then encounter a recurrence of prior symptoms within eight weeks of antibiotics cessation [23].  The three main indications for treatment with FMT are: 1. Recurrent C. difficile infection where there were (a) three or more episodes of mild to moderate C. difficile infection and failure of a six-to eight-week cycle with vancomycin, with or without an alternative antibiotic (rifaximin, nitazoxanide, or fidaxomicin), or (b) at least two episodes of C. difficile infection resulting in hospitalization 2. Moderate C. difficile infection not responding to standard therapy (vancomycin or fidaxomicin) for at least one week 3. Severe C. difficile infection (including fulminant) with no response to standard treatment after two days [24].
The routes of FMT administration are heterogeneous and include the upper GI tract (via esophagogastroduodenoscopy, nasogastric, or nasojejunal catheter or by ingestion of oral capsules) and the lower GI tract (by colonoscopy in the proximal colon, by enema and rectosigmoidoscopy in the distal colon, or a combined approach). The nasogastric route is efficient and safe for patients with contraindications to the colonoscopic route, which is well acknowledged. The massive burden is the vomiting and aspiration of the infused fecal contents. The enema route granted a significant degree of symptoms resolution. Nonetheless, it was mandatory to repeat the procedure in most cases until securing clinical improvement. Although the efficacy of retention enema had been in a dilemma, Orenstein et al. have demonstrated that retention enema is more effective and safer than placebo in phase I and phase II recurrent CDI clinical trials [25]. FMT via colonoscopy has superiority in allowing direct visualization of the entire colon, infusion of a large volume of fecal material, and better retention than the enema. Still, it is relatively risky of perforation, expensive, and invasive procedures. Oral capsules can have the same resolution rate compared with other routes, but they need a longer time to clinical improvement. The pros of the oral capsules are cost-effective, secure storage, proven efficacy, few side effects, easy administration, patient comfort, noninvasiveness, and safety for critically ill patients [26]. Kao et al. demonstrated that FMT via oral capsules had comparable outcomes of administering by colonoscopy in recurrent CDI patients [27]. There have been an enormous number of studies to evaluate the different methods of FMT administration.
Youngster et al. conducted a randomized pilot study comparing upper and lower GI routes of FMT, and found a non-significant difference in clinical resolution rate between those two routes [28]. In a nutshell, currently, there is no firm evidence of the most favorable FMT administration method in the clinical setting, and the appropriate way should rely on the condition of the individual.
Even though the adverse reactions to FMT are rare, there are three adverse events of fecal microbiota transplantation.
1. Minor: Gastrointestinal adverse reactions such as abdominal discomfort, nausea/vomiting (especially with oral FMT route), diarrhea/constipation, bloating, flatulence, and transient fever 2. Severe: bleeding and perforation due to complications of endoscopy, aspiration due to sedation, pneumonia, infection, and sepsis 3. Additionally, the risk of potential transmission of blood-borne pathogens (e.g., hepatitis B & C, HIV), induction of chronic diseases due to alterations in the gut microbiota (e.g., obesity, diabetes, atherosclerosis, IBD, IBS, and colon cancer) [25].

Conclusions
The current literature review concluded that the treatment of recurrent CDI is still challenging even though many treatment options are being researched and tested. Nevertheless, FMT is one of the most effective approaches and is becoming a more commonly used therapeutic option for managing multiple rCDIs. Currently, there is no firm evidence of the most favorable FMT administration method in the clinical setting, and the appropriate practice should be focused solely on the individual's condition. Therefore, more research is required in this area before it can be recommended on a routine basis.

Conflicts of interest:
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