Clostridioides difficile infection (CDI) is a concerning global health issue, and the incidence of hospital-acquired CDI has substantially increased in recent years globally (Wiegand et al., 2012). CDI remains a major contributor to diarrhea in healthcare settings, even with established prevention and treatment protocols (Hensgens et al., 2014). CDI places a major economic burden on the healthcare system due to prolonged hospitalization and on patients due to comorbidities, repeated infections, extended length of stay, increased treatment costs, and indirect societal costs (Gupta and Ananthakrishnan, 2021). In total, 30% of patients with CDI develop recurrence and are associated with 33% higher hazards of death (Olsen et al., 2015). The difficulty of CDI treatment illustrates the need to prevent recurrence and develop effective therapies.

Updated recommendations on CDI treatment and prevention have been issued by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America (IDSA), the American College of Gastroenterology, and the European Society of Clinical Microbiology and Infectious Diseases (Bainum et al., 2023). CDI treatment has progressed, with vancomycin and fidaxomicin being the primary treatments, whereas metronidazole is only recommended for non-severe cases when patients are unable to obtain or to be treated with oral vancomycin or fidaxomicin (Jarmo et al., 2020). Some studies concluded that fidaxomicin has advantages over vancomycin in terms of reducing recurrence and that fidaxomicin is cost-effective as a first-line therapy (Louie et al., 2011; Cornely et al., 2012; Beinortas et al., 2018; Mikamo et al., 2018). The University of Pittsburgh Medical Center released guidelines (2018) to use fidaxomicin for the first recurrence of CDI or subsequent recurrences (Bariola, 2019). However, fecal microbiota transplantation (FMT) has been recommended by many studies for treating CDI recurrence (Bariola, 2019; Jarmo et al., 2020). Recently, some FMT products were approved by the Food and Drug Administration (FDA) for treating recurrent CDI (Aschenbrenner, 2023; Jain et al., 2023). Strict clinical studies, good manufacturing processes, and donor and pathogen screening are important ways that this approach differs from live biotherapeutic products (LBPs) and traditional FMT (Monday et al., 2024). Donor banks are not established to guarantee that the donors' health is in good condition. To prevent CDI recurrence, the FDA approved a live fecal microbiota product called “Rebyota” (Aschenbrenner, 2023). This product was specifically approved after the failure of antibiotic treatment and the recurrence of CDI in adults. This product provides a potential solution to recurrent CDI following the failure of antibiotic treatment (Cornely et al., 2012). A novel FMT product named Vowst was also approved by the FDA as a prophylactic therapy to prevent the recurrence of CDI. Vowst consists of live fecal microbiota spores and works by re-establishing the gut microbiota and providing a better microbiome for the patient (Jain et al., 2023). Although an endoscopic technique is the recommended mode of delivery for FMT, limited research has examined the potential of frozen oral tablets for FMT. FMT formulated as frozen tablets or capsules is not inferior to FMT performed via colonoscopy (Jain et al., 2023). The approval of Vowst represented a major advancement in the prevention of recurrent CDI (Jain et al., 2023). There are uncertainties regarding the effectiveness of this product for CDI patients other than the participants in its clinical trials, and a prior study recommended that the donor screening process should be improved (Jain et al., 2023).

Approved FMT products are the recommended options for recurrent CDI. Current treatment options for CDI include vancomycin and fidaxomicin as the primary treatments (Jarmo et al., 2020). Metronidazole is reserved for mild cases, and bezlotoxumab, a monoclonal antibody against C. difficile toxin B, is used as an additional treatment for recurrent CDI (Jarmo et al., 2020). Fidaxomicin and FMT are more expensive but more effective in preventing recurrences, and thus, they are becoming the standard of care for CDI (Gupta and Ananthakrishnan, 2021). However, there are limited data on the preferred administration route of FMT, the cost-effectiveness of preventing recurrent FMT, and the use of unconventional therapies such as bezlotoxumab. This review explored the latest update on the prevention of CDI recurrence and the effectiveness of FMT treatment by analyzing the Clinicaltrials.gov dataset.

Disruption of the intestinal microbiome contributes to many human conditions and symptoms (Weiss and Hennet, 2017). Recurrence of CDI is a serious condition caused by disruption of the intestinal microbiome because of the use of antibiotics (Seekatz et al., 2022). Hospitalized patients who have been prescribed antibiotics for a long period have a high risk of C. difficile infection, and C. difficile toxins cause abdominal pain and diarrhea (Goldberg et al., 2015). Antibiotics prescribed as standard treatments for both acute and recurring illnesses do not treat abdominal syndromes such as dysbiosis; in fact, they frequently make them worse (Seekatz et al., 2022). Monoclonal antibodies, such as bezlotoxumab, can reduce the risk of recurrences, but they do not treat the underlying dysbiosis (Wilcox et al., 2017; Seekatz et al., 2022). They are recommended to be used in conjunction with standard-of-care antibiotics for preventing recurrent CDI in patients at high risk of recurrence. FMT is a developing therapeutic approach in which the gut microbiome of a recipient is restored by introducing bacteria from a healthy donor's stool into the recipient's gut. There are several FMT preparation methods and routes of administration. The effectiveness of FMT is considered to vary between different routes (Gough et al., 2011). The oldest technique followed for FMT is the direct infusion of donor stool through colonoscopy, and it is considered to be simple, safe, and 92% effective in the treatment of recurrent CDI (Kelly et al., 2012). Other FMT administration methods include nasogastric or nasoenteric tube and enema (Brandt and Aroniadis, 2013). Several barriers to the use of FMT have emerged, such as determining the features of a healthy microbiome, assuring the receiver's safety in terms of long-term consequences, sufficiently monitoring the recipient of the fecal material, and attaining high-quality control (Kim and Gluck, 2019). Therefore, the preferred administration method and the route of FMT depend on overcoming these barriers to ensure treatment efficacy.

FMT delivered via intestinal suspensions is reported to provide a high rate of symptom resolution, reaching 92% in some studies (Gough et al., 2011). Most of the clinical trials included in this review were performed using fecal suspensions delivered via enema and colonoscopy. RBX2660 is one of the FMT preparations used in the clinical trials described in this review (Table 2), and it was approved by the FDA under the name Rebyota (Kim et al., 2023). The potential of this preparation to restore the microbiome can alleviate CDI recurrence, and it was more effective than the placebo in terms of restoring the microbiome (Blount et al., 2019). The standardization of the material for FMT preparation from the donor can significantly simplify the clinical use of FMT for recurrent CDI (Hamilton et al., 2012). The transplant material is prepared from a donor stool from two sources: current patients and universal donors from a stool bank (Edelstein et al., 2016). The major drawback in the use of FMT for recurrent CDI is the lack of standardization regarding the preparation process and administration techniques (Berry and Khanna, 2023). In addition, patients who have completed antibiotic therapy for recurrent CDI and who are 18 years and older can receive Rebyota as a prophylactic biotherapeutic treatment (Berry and Khanna, 2023). It should be taken rectally and needs to be administered only once (Kim et al., 2023).

FMT can also be performed using prepared capsules. FMT capsule formulations combine the ease of administration of an antibiotic with the efficacy of FMT for treating recurrent CDI (Varga et al., 2021). One study in this review (Table 2) examined FMT performed using prepared capsules, and two studies delivered a full-spectrum microbiota using an oral formulation (CP101). One study was terminated in phase III, and the primary outcomes were not analyzed because no patients completed treatment (Table 1). Another study using oral CP101 was completed, with the primary outcome being achieved in 80.3% of patients (Table 3). The third study using CP101 presented some results assessing its efficacy (primary outcome) and safety (secondary outcome) in subjects with recurrent CDI (Table 2). Based on the percentage of participants with adverse events after oral FMT, safety was not achieved in comparison with the placebo, and many adverse events from recurrent CDI were observed. The Penn microbiome therapy for recurrent CDI was examined in a terminated clinical trial that administered three preparations (the Penn microbiome therapy 001 [enema product], the Penn microbiome therapy 002 [suspension product], and the Penn microbiome therapy 003 [capsule product]), as detailed in Tables 1, 2. This study observed a low rate of clinical resolution with one or two doses. However, the mortality rate was 0% (Table 3). From these results, the achievement of the primary and secondary outcomes was inconsistent for oral FMT preparations, and further clinical trials are needed.

Regarding the cost-effectiveness of preventing CDI recurrence, FMT performed via colonoscopy was identified as the most cost-effective approach in one clinical trial included in this review (Konijeti et al., 2014). The study recorded cure rates exceeding 88.4% and CDI recurrence rates lower than 14.9% with colonoscopy-based FMT compared with antibiotics (Konijeti et al., 2014). This finding was also suggested in a study published nearly 10 years before this review. The recently approved orally administered FMT named Vowst was examined in a clinical trial (SER-109) and then received FDA approval on 26 April 2023 (Jain et al., 2023). This product is non-invasive and more patient-friendly, and it minimizes the risk of iatrogenic consequences (Jain et al., 2023). Regardless of the number of past CDIs by age or antibiotic type (vancomycin or fidaxomicin), a remarkable clinical response was observed at week 8 in 91.3% of patients receiving Vowst, and the rate increased to 94.6% at week 24 (Khanna et al., 2022). Moreover, 87.6% of patients in the Vowst group were free from recurring CDI at the end of 8 weeks in comparison to 60.2% of participants in the placebo group, indicating that Vowst decreased CDI recurrence. Along with having a better safety profile, Vowst also caused comparatively mild-to-moderate transient side effects. The rigorous inclusion criteria used in the clinical trials (phase 1) raise some uncertainties about the specific efficacy of Vowst in patients with CDI outside those who participated in the trials (McGovern et al., 2021). For instance, patients with cancer, those requiring additional antibacterial medication (surgical prophylaxis and urinary tract infections), and those with a history of inflammatory bowel disease were excluded, as were female participants who were pregnant, nursing, or lactating (Jain et al., 2023). Regarding the safety profile, mild-to-moderate adverse effects were noted in a phase III trial (McGovern et al., 2021). We can conclude that the better safety profile along with a low number of FMT courses (either coloscopy or oral) can be considered more cost-effective than expensive antibiotics. However, economic analyses need to be conducted to explore the benefit and effectiveness of oral capsule formulations for FMT (Jain et al., 2023), as the cost-effectiveness of Rebyota and Vowst was not examined in their clinical trials.

This review had several limitations. Because the variables linked to the FMT technique were inconsistently classified across trials, operational definitions were established beforehand to facilitate data abstraction. Limited clinical trials progressed to completion, and from these publications, data on the techniques of FMT and cost-effectiveness were not sufficiently recorded. In addition, three trials were terminated without generating data because no patients could be analyzed.

Based on the records of FMT treatment for recurrent CDI from ClinicalTrials.gov, the completed clinical trials recorded high clinical resolution rates of CDI symptoms with mild-to-moderate SAEs but extremely low mortality rates. However, resolution rates can be affected by variations in the FMT process. Colonoscopy in the earliest studies achieved a high success rate, and even higher success rates were achieved in later trials using oral formulations for full-spectrum FMT. Furthermore, the data indicate that, in cases in which conventional therapies have failed, FMT using FDA-approved products could be an extremely safe and effective treatment for recurrent CDI. These methods proved to be differentially effective, suggesting that personalized approaches to FMT may enhance its success rate. Moreover, several studies highlighted the potential cost-effectiveness of FMT, which is a significant consideration given the economic burden of CDI. The analysis encompassed a diverse range of interventional studies, which demonstrated a notable variance in success rates, reflecting the heterogeneity of FMT applications and patient demographics. Despite these variations, the collective data highlight a trend toward positive outcomes with the use of FMT in the management of CDI.

In conclusion, the analyzed database substantiates that FMT is a safe and effective treatment for recurrent CDI. It highlights the potential for FMT to be incorporated more prominently into clinical practice as a therapeutic strategy against CDI. Future research should focus on standardizing FMT procedures, optimizing delivery methods, and monitoring for long term to fully exploit its therapeutic benefits and ensure the consistent safety and effectiveness of FMT.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

NO: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review & editing.