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Review Article Open Access
Volume 2 | Issue 2 | DOI: https://doi.org/10.33696/pathology.2.020

Faecal Microbiota Transplantation as Primary Treatment for Clostridioidoes difficile Infection-evidence for Change

  • 1The Centre for Digestive Diseases, 229 Great North Road, Five Dock, Sydney, Australia
  • 2Axent Medical Pty Ltd, CSIRO Building 53, 11 Julius Avenue, North Ryde, Sydney, Australia
  • 3Progenabiome, 1845 Knoll Dr, Ventura, CA 93003, USA
+ Affiliations - Affiliations

*Corresponding Author

Sibasish Dolai, Siba.Dolai@cdd.com.au; Thomas J Borody, Thomas.Borody@cdd.com.au

Received Date: May 15, 2021

Accepted Date: May 27, 2021

Abstract

In this mini-review, we summarise the significant body of evidence for the treatment of Clostridioides difficile infection (CDI) with Faecal Microbiota Transplantation (FMT) and propose the transition of FMT from ‘last resort’ treatment to the forefront of CDI management. To address the feasibility of this proposal, we examined the rates of efficacy in FMT treated patients with CDI and also reviewed the safety of FMT across available published studies. A considered view of safety, efficacy, product standardisation, quality control and Good Manufacturing Practices (GMP) allows for a prudent approach in positioning FMT as the primary or initial treatment for CDI.

Keywords

Faecal microbiota transplantation, Clostridioides difficile infection, Recurrent, Treatment, Safety, Efficacy, Donor screening, Colonoscopy, Nasogastric, Review

Introduction

Clostridioides difficile is an anaerobic spore-forming gram positive bacillus that infects the gut microbiota leading to gastrointestinal disease with varied severities ranging from self-limiting diarrhea to life-threatening pseudomembranous colitis, sepsis or death. In the last 20 years, there has been a marked increase in Clostridioides difficile infection (CDI) worldwide with almost 1% of all hospitalizations or 329,460 patients in the United States in 2017, which is due to CDI [1]. In part, this has been due to CDI also becoming more virulent, refractory, and relapsing after standard antibiotic therapy [2]. Current treatment guidelines specify antibiotics as frontline therapy (vancomycin, metronidazole, and fidaxomicin), however, such treatments may deplete bacterial classes and result in non-uniform intestinal microbiota dominated by Proteobacteria [3]. This preliminary antibiotic-induced dysbiosis may further promote resistance leading to relapsed or refractory CDI. Published data shows the relapse rate with vancomycin and metronidazole treatment to be as high as 37% and 50%, respectively [4]. On the other hand, there is now considerable evidence that (FMT) effectively cures CDI and may emerge as an effective initial treatment of CDI even in patients diagnosed with CDI for the first time [5]. There is now evidence to demonstrate a cure rate of up to 98% when more than one FMT infusion is performed [6,7]. Despite this growing new data, the FDA guidelines may be holding physicians back from curing more CDI patients. Current guidelines only approve a single FMT procedure and only in patients with two previous treatment failures with antibiotics [8,9].

Whilst FMT is becoming an increasingly common procedure, a minority of healthcare practitioners still hold reservations regarding its efficacy and safety. Primarily these perspectives have centred around safety, patient tolerability to colonoscopy and fear of infections from donor transplant material [10,11]. Indeed, while FMT has several contraindications [12] particularly for those with immunocompromised conditions, the risks of transmissible infection have been extremely low (as detailed later).

Since 2015 medical professionals have been debating positioning FMT as first-line therapy for CDI [13]. Given FMT involves the transplantation of a highly heterogeneous biological sample (stool) from a healthy donor to the sick patient, regulatory authorities are challenged with providing clear guidance for the regulation of the procedure. Currently, regulatory harmonization is lacking and guidelines continue to conservatively reserve FMT for unresponsive cases only [8]. More recently, FMT has also proved to be an effective treatment for a suite of other gastrointestinal and systemic diseases including Ulcerative Colitis (UC) and Irritable Bowel Syndrome (IBS) which has highlighted the need for further appraisal and guidelines on the standardisation of donor evaluations, production standards, and acceptable clinical indications. In 2019, published consensus statements from an international expert panel proposed a set of best practices in FMT [14], and in late 2020 the identification of possible COVID-19 transmission from FMT further highlighted the need for safety and certainty in donor screening [15].

The treatment of CDI is at a turning point. Given that: 1) FMT is very effective in curing CDI; 2) that using more than one FMT is more efficacious; 3) that antibiotics can compromise the microbiome and increase failure to cure (up to 60%), and 4) that FMT is a simple GI procedure best performed by trans-colonoscopic infusion or enema. Hence, we propose advancing FMT to a front line therapy to eradicate CDI. Furthermore, FMT has been demonstrated to repair the host’s microbiome from damage and replace missing flora simultaneously without delaying the recovery via using antibiotic pre-treatment. In this review, we also briefly update the recent data relating to FMT efficacy, safety and delivery methods in CDI management.

Evidence of Efficacy

Over several decades FMT has been trialled in various formats for CDI with very promising results. In a 2017 systematic review and meta-analysis Quraishi et al. assessed the results of thirty-seven studies including seven randomised controlled trials (RCTs) and 30 case series. FMT was found to be more effective than vancomycin in resolving recurrent and refractory CDI, and clinical resolution across all studies was 92%. Furthermore, administering consecutive courses of FMT following the failure of the first FMT resulted in incrementally improved effects. The review also showed that successful outcomes after FMT were independent of preparation and route of delivery [16]. Moayyedi et al. also released a smaller systematic review of FMT for CDI associated diarrhoea in the same year analysing ten RCTs that evaluated 657 patients. Within this dataset, five RCTs were identified that compared FMT against placebo or vancomycin (total of 284 patients) with FMT demonstrating strong statistical superiority [17]. FMT was also used in a proof-of-concept trial to evaluate its use as a treatment for primary CDI with 78% success compared to 45% in a control metronidazole group, again highlighting FMT as an alternative to antibiotic therapy in primary CDI [18]. The use of FMT as first-line treatment is further supported by a pooled analysis of FMT treatment outcomes between patients receiving vancomycin before treatment versus no pretreatment showing no difference in treatment outcomes [19].

The success of FMT by traditional colonoscopic infusion has also led to novel delivery systems to avoid the disadvantages of bowel prep, anaesthesia, and enteral access. Iqbal et al. performed a systematic review of FMT using donor samples in ingestible capsules. Covering a total of six studies, five case series and one randomized controlled trial, 341 patient data sets were analysed. Efficacy was observed in 285 patients in the first treatment, with no recurrence. An additional 28 patients received a second FMT with resolution and three received resolution on their third FMT. In sum, a resolution rate of 93%. Only one patient did not achieve long-term resolution of symptoms despite of receiving four treatments [20].

The majority of recorded studies have recruited patients diagnosed with recurrent symptoms of diarrhea and serially positive for C. difficile toxin on testing. In many cases, patients had been treated with several courses of Vancomycin with several failures to cure when tapering antibiotics. To investigate the effectiveness of FMT on their first episode of CDI diagnosis Roshan et al. completed a retrospective, single-centre study of 59 patients between 2012 and 2017 treated with FMT on their first episode of CDI [6]. In light of strong evidence that repeated FMT (more than one) leads to increased efficacy rates, all patients were first treated with colonoscopic infusion, followed by an enema the next day. 98% of the 58/59 patients were cleared of C. difficile as verified by culture and toxin testing over the next 4-8 weeks. There were also statistically significant symptomatic reductions in abdominal pain, diarrhoea, and blood in the stool [6].

The efficacy rates in treating CDI with FMT is summarized in (Table 1). Of note are the incremental increases in efficacy on second and third FMT infusions.

Year – Author1 Method of delivery2 Sample No. Efficacy After Single FMT (%)3 Efficacy after additional FMTs (%)3
2020–Roshan et al. [6] Colonoscopy and enema 59 98
2020–Perler et al. [21] Colonscopy, capsule 207 85.5 95.1
2003–Aas et al. [22] Nasogastric 18 83.3
2016–Agrawal et al. [23] Esophagogastroduodenoscopy, push enteroscopy, colonoscopy, flexible sigmoidoscopy, and retention enema 146 82.9 95.9
2014–Allegretti et al. [24] Colonoscopy 13 84.6 92.3
2012–Brandt et al. [25] Colonoscopy 77 91 98
2014–Emanuelsson et al. [26] Rectal catheter 31 74
2015–Ganc et al. [27] Oral push enteroscopy 12 90
2010–Garborg et al. [28] Duodenal, colonoscopy 29 73 83
2012–Hamilton et al. [29] Colonoscopy 43 86 95
2016–Kelly et al. [30] Colonoscopy 46 90.9 93.5
2017–Kao et al. [31] Colonoscopy, capsule 116 96.2
2012–Kassam et al. [32] Enema 27 81 93
2012–Kelly et al. [33] Colonscopy 26 92
2014–Khan et al. [34] Colonoscopy 20 90 100
2014–Lee et al. [35] Retention enema 94 47.9 86
2016–Lee et al. [36] Enema 219 84 93
2009–Macconnachie et al. [37] Nasogastric 15 73 80
2011–Mattila et al. [38] Colonoscopy 36 89 94
2013–Patel et al. [39] Colonoscopy 31 90 100
2013–Pathak et al. [40] Colonoscopy 12 92 100
2014–Ray et al. [41] Colonoscopy 20 100
2010–Rohlke et al. [42] Colonoscopy 19 94 100
2013–Rubin et al. [43] Nasogastric 74 79 90.7
2015–Tauxe et al. [44] Colonscopy and upper GI 31 75 87
2014–Vigvári et al. [45] Nasoduodenal 15 100
2010–Yoon et al. [46] Colonoscopy 12 100
2014–Zainah et al. [47] Nasogastric 14 79
2016–Allegretti et al. [24] Capsules 19 73.5 94
2015–Cammarota et al. [7] Colonoscopy 20 65 90
2015–Kao et al. [48] Colonoscopy, Capsule 29 96
2016–Lee et al. [36] Enema 232 56 91
2013–Van Nood et al. [49] Duodenal infusion 16 81 94
2014–Youngster et al. [50] Capsule 20 70 90
2017–Hota et al. [51] Enema 16 43.8
2017–Jiang et al. [52] Colonoscopy 72 87
2017-Staley et al. [53] Capsule 49 88
2016–Youngster et al. [54] Capsule 180 82 91
2018– Shogbesan et al. [55] Upper GI infusion, capsule in- gestion, colonoscopic infusion, or enema 303 88 93

1Publications and authors are listed in detail in the references section. 2Descriptions of FMT delivery are provided in the latter part of this review. Where several methods are listed a review of several techniques or a comparison study may have been performed. Where applicable only the FMT treated arm was included. 3In some studies, a single primary FMT was performed without a secondary FMT, or vice versa. Where applicable these studies are denoted with (-).

Table 1: An efficacy summary of the literature tabulating treatment success rates after a single FMT procedure and after two or more procedures. Table includes both original studies and systematic analyses.

On comparing 25 of the studies in Table 1 that reported efficacy of single and multiple FMT’s, the mean efficacy of single FMT (80.17) versus >1 FMT (92.78) was a highly significant improvement, (p<0.00001) in achieving CDI cure. Please note some of these reports had overlapping data.

Evidence of Safety

FMT is generally considered safe with a very low risk of infection transmission. The majority of the shortterm safety concerns are attributable to the mode of administration rather than FMT itself. Several studies have been conducted recently to assess the efficacy and safety of FMT for the treatment of CDI. Saha et al. conducted a prospective survey-based study to assess the short term adverse events (n=609) and long term safety (n=447) of FMT for treating recurrent CDI (rCDI) [56]. The majority of the short term adverse events were limited to diarrhoea (>60%) and constipation (19%-33%) and the long term risk of adverse events and infectious complication were low [20]. Although several new diagnoses were observed in their study, none were related to FMT. Similarly, in the largest and longest study on efficacy and safety of FMT treatment of rCDI, Perler et al. reported long term cure with no adverse events related to FMT or downstream disease associated with dysbiosis [21]. Although safety concerns of post-FMT infection transmission was announced by the FDA, regarding 2 cases of drug resistant E. coli infections transmitted by donor stool, a growing number of studies have emphasized the rarity of infection transmission through FMT, even in high risk patient groups [8]. A review by Wang et al. reported remarkably rare infectious complications (2.5% of more than 1000 patients treated) post-FMT [57]. Low risks of FMT related infectious transmission was also observed in high-risk immunocompromised patients [55,58]. More recently, the FMT National registry, designed to assess FMT methods and both safety and effectiveness outcomes, also reported high effectiveness of FMT for CDI with a good safety profile [59]. Although the majority of FMT related adverse events and potential risk of infection transmission are mitigated by stringent selection and screening process of prospective donors, there are still a few reports of distinct adverse reactions.

Brumbaugh et al. performed an analysis in a mediumsized cohort of children where FMT was delivered by nasogastric feeding tube. A total of 47 procedures were performed in 42 children. Vomiting, which was selflimiting, was observed within 24 hours of the FMT occurring in 6 of 47 (13%) procedures [60]. Lai et al. conducted a larger study reviewing 407 articles that referenced FMT and their overall Adverse Events (AEs) [61]. In total 135 studies reported AEs for 4493 patients, with 36 studies experiencing no AEs. The commonest AEs in this group were related to the gastrointestinal system including diarrhoea (13.0%), abdominal distension/flatulence (11.6%), nausea/vomiting (6.1%), abdominal pain (5.5%) and constipation (2.1%). Other common AEs included fever (2.7%), respiratory difficulty (2.4%), headache (1.5%) and fatigue (1.4%). In IBD patients 1.3% experienced IBD flares or IBD-like symptoms. Despite several reviews reporting efficacy outcomes being independent of FMT type (i.e. oral vs colonoscopic), AEs and safety outcomes do appear to be somewhat related. The same review study found AE rates were generally higher in upper GI FMT compared to lower infusions, with exception to IBD cases where IBD flares and fevers were higher but not statistically significant (7.9% vs 1.7%) compared with those who had CDI only.

Soo et al. in 2020 similarly reviewed the short-term safety record of FMT finding very few adverse effects directly attributed to the procedure with most adverse events being self-limiting gastrointestinal symptoms including abdominal cramps, diarrhoea and constipation, which resolved within one week. Of note, the review reported two deaths from aspiration pneumonia related to sedation given at the time of faecal microbiota transplantation and one death from transmission of a multidrug resistant Escherichia coli [62,63]. Nasogastric and nasoduodenal delivery also tended to have higher rates of minor adverse effects relative to other methods despite the seemingly less-invasive procedure [64].

A comprehensive safety study into FMT was conducted by Cicilia Marcella et al. published in 2021. With a stricter set of inclusion criteria, 129 studies were included covering 4241 patients (5688 FMTs). AEs occurred in 19% of FMT procedures compared with <1% reported by Lai et al [61]. The most frequently reported AEs were diarrhoea (10%) and abdominal discomfort/pain/cramping (7%). FMTrelated serious adverse events (SAEs), including infections and deaths occured in 1.4% of patients who underwent FMT (0.99% microbiota-related SAEs). Four of five FMTrelated deaths were reported in patients receiving FMT via the upper gastrointestinal route. Of special note was that all reported FMT-related SAEs were in patients with mucosal barrier injury. The report however concluded that most FMT-related AEs were mild or moderate and self-limiting. Thus although FMT appears to be highly safe, AE’s were related to the method of implantation, thus highlighting the need for improvements to reduce both delivery-related AEs and, microbiota-related AEs [65].

There is a growing increase in the number of FMT indications such as inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease which deserves mention. IBD /UC patients share some overlap with CDI with reported incidences ranging from 1.8%-4.6% [66]. There is some evidence that suggests FMT could worsen symptoms of underlying IBD. Qazi et al. reviewed twentynine studies including 514 IBD patients treated with FMT. The data showed a pooled rate of IBD worsening of 14.9%, with higher rates of IBD worsening using lower GI FMT (16.5%) compared with upper GI delivery (5.6%) [67]. Sood et al. analysed the data of 129 patients with active UC who received extensive multisession FMT via colonoscopy. Minor short-term adverse events included abdominal discomfort, flatulence, abdominal distension, borborygmi, and low-grade fever (30.8%, 15.9%, 9.8%, 7.9%, and 7.6%, respectively). Long-term adverse events included new-onset urticaria (4.3%), arthritis/arthralgia (6.5%), depression (2.2%), partial sensorineural hearing loss (2.2%), and allergic bronchitis (2.2%). Thirteen (12.9%) patients dropped out because of adverse events however it is unclear if these were linked to a single session FMT or the extended length and course of the trial [68]. Due to the prevalence of immunosuppressant medication in the above conditions, FMT studies in the immunosuppressed patient have also been investigated extensively. Shogbesan et al. reviewed forty-four studies covering 303 immunocompromised patients finding equivalent efficacy as high as 93% when multiple treatments were included. Serious AEs included 2 reported deaths, 2 colectomies, 5 treatment-related infections, and 10 subsequent hospitalizations. However, Shogbesan concluded these AE rates in immunocompromised patients were similar to those of immunocompetent patients [55].

In summary, FMT appears to be safe, as the majority of studies demonstrate that FMT doesn’t appear to raise adverse events above the rates seen in the underlying condition. However, in the case of colonoscopy based FMT it is difficult to ascertain whether adverse events (i.e. diarrhea, irregular bowel movements) are related to the FMT procedure or from underlying disease. In the rare reports of death following FMT, the elderly demographic and common presence of multiple co-morbidities makes it difficult to assess whether FMT has any interrelationship. Nevertheless, the nature of the procedure and the risks for donor-recipient infection, or immunological flare from IBD or other co-morbidity remains. Thus, vigilant implementation of standardised quality screening of both patient and recipient remains highly relevant.

Year – Author1 Adverse Event Description2 Cases Reviewed Minor Adverse Event No.2 Serious Adverse Event No.2
2018–Iqbal et al. [20] Serious AE: high grade fever, Ulcerative Colitis 341   3
2021–Saha et al. [56] Mild & Moderate AE: diarrhea (60%), constipation (60%), cramping (50%), IBS (16.9%) Unrelated Serious AE: unrelated deaths (3.8%) 609 365 23
2016-Wang et al. [57] Mild & Moderate AE: all (28.5%) Serious AE: all (9.2%), death (3.5%), infection (2.5%), relapse of IBD (0.6%), CDI (0.9%) 1089 310 100
2021–Kelly et al. [59] Mild & Moderate AE: diarrhea (2%), abdominal pain (2%) Serious AE: hospitalizations (1%), IBS (1%), IBD (1%) 222 9 7
2014–Youngster et al.  [50] Mild & Moderate AE: abdominal cramping and bloating 30 6 0
2016–Youngster et al.  [54] Mild & Moderate AE: fever, diarrhea, vomiting, nausea/ bloating, abdominal pain, fatigue, headache, other com- plaints (270 occurrences) Serious AE: fever, Ulcerative Colitis, hospitalised relapse (9), Unrelated Serious AE: hospitalisation, death (40) 180 112 49
2018–Brumbaugh et al. [60] Mild & Moderate AE: vomiting 42 6 0
2019–Lai et al. [61] Mild & Moderate AE: diarrhoea (13.0%), abdominal distension/flatulence (11.6%), nausea/vomiting (6.1%), abdominal pain (5.5%) and constipation (2.1%), fever (2.7%), respiratory difficulty (2.4%), headache (1.5%) and fatigue (1.4%). 1.3% patients also experienced IBD flares or IBD-like symptoms. Serious AE: aspiration or aspiration pneumonia, sedation complications, bowel perforation, sepsis, hospitalisation, death. 4609   21
2002–Cicilia Marcella et al. [65] Mild & Moderate AE: all (19%), diarrhoea (10%), abdominal discomfort/pain/cramping (7%). Serious AE: infections, death, other (1.4%). 5688 875 59
2018–Shogbesan et al.  [55] Mild & Moderate AE: abdominal pain, irritable bowel syndrome, nausea, fever, diverticulitis. Serious AE: colectomies, bacteremia, hospitalisation,in- flammatory bowel disease, pneumonia, aspiration pneu- monia, death. 303 28 33
2013–Van Nood et al.  [49] Mild & Moderate AE: diarrhea (94%), cramping (31%),belching (19%), constipation (19%). 16 15 0
2016–Lee et al. [69] Mild & Moderate AE: transient diarrhea (70%), abdomi- nal cramps (10%), nausea (<5%), constipation (20%) and excess flatulence (25%) Serious AE: urinary tract infections (<5%), respiratory tract infection 232 162 11
2015-Cammarota et al. [7] Mild & Moderate AE: diarrhoea (94%), bloating and ab- dominal cramping(60%) 20 19 0
2014–Dutta et al. [70] Mild & Moderate AE: low-grade fever (18%), bloating (11%). 27 8 0
2017–Jiang et al. [52] Mild & Moderate AE: nausea, mild diarrhoea and tran- sient abdominal discomfort (86%), fever(2%), fatigue (8%), headache (6%), weight gain (3%) 72 62 0
2016 Baxter et al. [71] Mild & Moderate AE: abdominal distension/bloating/ cramping (2.3%), flatulence (2%), diarrhoea (1.9%), irregular bowel movement (1.2%), IBS Symptoms (1.09%), constipation (1%), other (4%). Serious AE: bacteremia, perforations, death (3) 1190 162 3

1Publications and authors are listed in detail in the references section. 2Adverse events were categorised into mild & moderate and serious. Symptoms such as cramping or diarrhea may include overlap in the single participant. Percentage figures were provided in the description where available from original authors. In some studies, minor events were omitted and denoted with (-).

Table 2: A safety summary of the literature tabulating reported adverse events including both original studies and systematic analyses.

Protocols and Methods

Implementing fundamental safety precautions will limit the spread of pathogenic organisms to the recipient, thus selective and regular screening of donors has been the focus of most institutions performing FMT on a regular basis. Donor screening requirements include general health, absence of gastrointestinal (GI) disease and no antibiotic therapy in the last 90 days. Other exclusions include autoimmune disease, chronic pain syndromes, neurologic disease, certain neuropsychiatric syndromes, metabolic syndrome, obesity, moderate or severe malnutrition, malignancy, ongoing oncologic therapy and being immunocompromised, as well negative serological and stool test results (Table 3).

Serological Stool
Human Immunodeficiency Virus (HIV) Hepatitis C (HBC IgM) Epstein-Barr virus (EBV) Clostridium difficile (EIA)
Treponema pallidum Syphilis Hepatitis B (HBsAg) Clostridium difficile toxin PCR
Cytomegalovirus (CMV) Liver enzyme (Aminotransferases) H.pylori (EIA) Shigatoxin-producing Escherichia coli (STEC)
Hepatitis A (HAV IgM) Human T-Lymphotrophic virus (HTLV 1 & 2) Viral tests (Adenovirus, Norovirus, Rotavirus) Extended-spectrum beta- lactamase (ESBL)–producing Escherichia coli
Epstein-Barr virus (EBV) Hepatitis B (HBV IgM) Enteric pathogen culture (Salmonella, Shigella, Campylobacter) Parasitic tests, (Ovum, Isospora, Cryptosporidium, Giardia)

Table 3: A typical serological and stool screening list for donors [72,73].

As screening can be both time and resource intensive, to limit the delays in recruiting fresh donors, access to universal donors via a biobank allows physicians in the US to obtain stool from biobanks without needing to submit Investigational New Drug applications and more recently to be compliant with COVID safety precautions [74]. There are several notable stool biobanks globally. Terveer et al. compiled a brief list of faeces banks that have been well established and describes the methodologies used at the Netherlands Donor Feces Bank including detailed screening procedures, example questionnaires and personal interviews of the donors concerning risk factors for transmissible diseases [75]. Such risk factors for transmissible disease include body mass index (BMI) > 25 kg/m2; as obesity may also be associated with a specific microbiota composition and other gastrointestinal disorder (e.g., irritable bowel syndrome (IBS), Crohn’s disease, or ulcerative colitis) which are increasingly showing a link to the host’s microbiome. These exclusion criteria, taken altogether, limit the risks of biota-based infection risks to the recipient which has been the main attention of safety concerns. Biobanking also provides the ability to track, measure and validate success rates from specific donor batches which provides added safety precautions, eliminating the risk factors associated from new donors in fresh transplant procedures.

Next, the physician has several options in the choice of transplantation into the GI tract. FMT has been shown to be robust and viably delivered to the lower gut through specialised tools such as colonoscopy, ileocolonoscopy, enema, distal ileum stoma and colostomy. Historically, the most validated procedure has been through retention enema or infusions into the colon aided by colonoscopy [76]. Where patients are deemed unsuitable for a colonic based infusion, methods for upper and mid-gut delivery (stomach, duodenum) have also been well developed; for example, FMT via gastroscope and the nasogastric tube [77]. This method involves insertion of a tube via the nasal cavity, or orally to reach the intestinal tract and the use of smaller more concentrated infusions of 30mL to 60mL with or without x-ray guidance and or the use of a gastroscope [77]. More recently, a few groups have concentrated donor stool into orally ingested capsules which has avoided the need for anesthesia and enteral access altogether, with some reports of equivalent efficacy rates comparable to colonoscopic procedures [31,54,78]. Though this approach appears promising, laboratory facilities to centrifuge and concentrate faecal samples are required, and the ingestion of 30-40 capsules can be challenging in some patients. Nevertheless, further randomised clinical trials are needed to validate this recent approach.

Conclusions

FMT is a proven effective treatment for rCDI. In this review, we highlighted the effectiveness and safety of FMT in CDI and thus demonstrated its readiness as the initial treatment for CDI. While this review only briefly covers issues of efficacy, safety and delivery, we believe that in general cases of CDI there is strong evidence to remove antibiotic treatment which is known to delay cure, promote antimicrobial resistance, dysbiosis and induce CDI recurrence when treatment is tapered. This study was limited by the availability of primary treatment data whereby patients are treated with FMT without antibiotic treatment. Ultimately, larger datasets of primary treatment outcome studies will be the greatest asset in assessing FMT for widespread application. Although the majority of FMT is well tolerated with only minor adverse events and rare infection transmission, there have been some notable adverse events. To advance FMT to the first line of CDI treatment safely, uniform and stringent regulatory guidelines need to be implemented regarding the source, production and processing of the transplantable FMT products. Recently, GMP manufacturing guidelines for FMT products have been established in some countries which have led to improved availability, safety, standardisation, and quality control of FMT products. Indeed, implementing widespread quality control of GMP–FMT products could raise the effectiveness and safety standards for FMT in line with other biological therapies. Whilst there remain questions on the underlying mechanisms of action and cure, or how FMT re-establishes microbial diversity, we propose that FMT should now become the first-line treatment for CDI.

Conflicts of Interest

SD, JN, SH, VD- none.

TJB is the Medical Director of Centre for Digestive Diseases offering FMT, and has filed patents in this field.

Author Contributions Statement

T.B. and S.D. conceived of the presented idea. S.D., J.N, S.H developed the review structure. V.D. encouraged and supervised J.N. to investigate and further research the findings presented in this work.

Funding Statement

None.

References

1. Solanki D, Kichloo A, El-Amir Z, Dahiya DS, Singh J, Wani F, et al. Clostridium difficile Infection Hospitalizations in the United States: Insights From the 2017 National Inpatient Sample. Gastroenterol Res. 2021 Apr 21;14(2):87–95.

2. Song JH, Kim YS. Recurrent Clostridium difficile Infection: Risk Factors, Treatment, and Prevention. Gut Liver. 2019 Jan;13(1):16–24.

3. Binyamin D, Nitzan O, Azrad M, Hamo Z, Koren O, Peretz A. The microbial diversity following antibiotic treatment of Clostridioides difficile infection. BMC Gastroenterol. 2021 Apr 13;21(1):166.

4. Hopkins RJ, Wilson RB. Treatment of recurrent Clostridium difficile colitis: a narrative review. Gastroenterol Rep. 2018 Feb;6(1):21–8.

5. Jaworski A, Borody TJ, Leis S, Gadalla S, Dawson V. Treatment of First-TimeClostridium difficileInfection With Fecal Microbiota Transplantation: 1354. Off J Am Coll Gastroenterol ACG. 2015 Oct;110:S587.

6. Roshan N, Clancy AK, Borody TJ. Faecal Microbiota Transplantation is Effective for the Initial Treatment of Clostridium difficile Infection: A Retrospective Clinical Review. Infect Dis Ther. 2020 Dec 1;9(4):935–42.

7. Cammarota G, Masucci L, Ianiro G, Bibbò S, Dinoi G, Costamagna G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015 May;41(9):835– 43.

8. Research C for BE and. Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies [Internet]. U.S. Food and Drug Administration. FDA; 2020 [cited 2021 May 13]. Available from: https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/ enforcement-policy-regarding-investigational-new-drugrequirements- use-fecal-microbiota-0

9. Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC, Franzos MA, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2011 Dec;9(12):1044–9.

10. Al-Bakri AG, Akour AA, Al-Delaimy WK. Knowledge, attitudes, ethical and social perspectives towards fecal microbiota transplantation (FMT) among Jordanian healthcare providers. BMC Med Ethics. 2021 Feb 27;22(1):19.

11. Madar PC, Petre O, Baban A, Dumitrascu DL. Medical students’ perception on fecal microbiota transplantation. BMC Med Educ. 2019 Oct 11;19(1):368.

12. Mullish BH, Marchesi JR, Thursz MR, Williams HRT. Microbiome manipulation with faecal microbiome transplantation as a therapeutic strategy in Clostridium difficile infection. QJM Int J Med. 2015 May 1;108(5):355– 9.

13. Experts debate fecal transplants as first-line therapy for CDI [Internet]. [cited 2021 May 13]. Available from: https://www.mdedge.com/gihepnews/article/103881/ infectious-diseases/experts-debate-fecal-transplantsfirst- line-therapy-cdi

14. Cammarota G, Ianiro G, Kelly CR, Mullish BH, Allegretti JR, Kassam Z, et al. International consensus conference on stool banking for faecal microbiota transplantation in clinical practice. Gut. 2019 Dec;68(12):2111–21.

15. Ianiro G, Mullish BH, Kelly CR, Sokol H, Kassam Z, Ng SC, et al. Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel. Lancet Gastroenterol Hepatol. 2020 May;5(5):430–2.

16. Quraishi MN, Widlak M, Bhala N, Moore D, Price M, Sharma N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther. 2017 Sep;46(5):479– 93.

17. Moayyedi P, Yuan Y, Baharith H, Ford AC. Faecal microbiota transplantation for Clostridium difficileassociated diarrhoea: a systematic review of randomised controlled trials. Med J Aust. 2017 Aug 21;207(4):166–72.

18. Juul FE, Garborg K, Bretthauer M, Skudal H, Øines MN, Wiig H, et al. Fecal Microbiota Transplantation for Primary Clostridium difficile Infection. N Engl J Med. 2018 Jun 28;378(26):2535–6.

19. Sofi AA, Silverman AL, Khuder S, Garborg K, Westerink JMA, Nawras A. Relationship of symptom duration and fecal bacteriotherapy in Clostridium difficile infection-pooled data analysis and a systematic review. Scand J Gastroenterol. 2013 Mar;48(3):266–73.

20. Iqbal U, Anwar H, Karim MA. Safety and efficacy of encapsulated fecal microbiota transplantation for recurrent Clostridium difficile infection: a systematic review. Eur J Gastroenterol Hepatol. 2018 Jul;30(7):730–4.

21. Perler BK, Chen B, Phelps E, Allegretti JR, Fischer M, Ganapini V, et al. Long-Term Efficacy and Safety of Fecal Microbiota Transplantation for Treatment of Recurrent Clostridioides difficile Infection. J Clin Gastroenterol. 2020 Sep;54(8):701–6.

22. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis Off Publ Infect Dis Soc Am. 2003 Mar 1;36(5):580–5.

23. Agrawal M, Aroniadis OC, Brandt LJ, Kelly C, Freeman S, Surawicz C, et al. The Long-term Efficacy and Safety of Fecal Microbiota Transplant for Recurrent, Severe, and Complicated Clostridium difficile Infection in 146 Elderly Individuals. J Clin Gastroenterol. 2016 Jun;50(5):403–7.

24. Allegretti JR, Korzenik JR, Hamilton MJ. Fecal microbiota transplantation via colonoscopy for recurrent C. difficile Infection. J Vis Exp JoVE. 2014 Dec 8;(94).

25. Brandt LJ, Aroniadis OC, Mellow M, Kanatzar A, Kelly C, Park T, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012 Jul;107(7):1079–87.

26. Emanuelsson F, Claesson BEB, Ljungström L, Tvede M, Ung K-A. Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients. Scand J Infect Dis. 2014 Feb;46(2):89–97.

27. Ganc AJ, Ganc RL, Reimão SM, Frisoli Junior A, Pasternak J. Fecal microbiota transplant by push enteroscopy to treat diarrhea caused by Clostridium difficile. Einstein Sao Paulo Braz. 2015 Jun;13(2):338–9.

28. Garborg K, Waagsbø B, Stallemo A, Matre J, Sundøy A. Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhoea. Scand J Infect Dis. 2010 Dec;42(11–12):857–61.

29. Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012 May;107(5):761–7.

30. Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med. 2016 Nov 1;165(9):609–16.

31. Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2017 Nov 28;318(20):1985–93.

32. Kassam Z. Fecal Transplant via Retention Enema for Refractory or Recurrent Clostridium difficile Infection. Arch Intern Med. 2012 Jan 23;172(2):191.

33. Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol. 2012 Feb;46(2):145–9.

34. Khan MA, Sofi AA, Ahmad U, Alaradi O, Khan AR, Hammad T, et al. Efficacy and safety of, and patient satisfaction with, colonoscopic-administered fecal microbiota transplantation in relapsing and refractory community- and hospital-acquired Clostridium difficile infection. Can J Gastroenterol Hepatol. 2014 Sep;28(8):434–8.

35. Lee CH, Belanger JE, Kassam Z, Smieja M, Higgins D, Broukhanski G, et al. The outcome and long-term follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2014 Aug;33(8):1425–8.

36. Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, et al. Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2016 Jan 12;315(2):142.

37. MacConnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal transplant for recurrent Clostridium difficileassociated diarrhoea: a UK case series. QJM Mon J Assoc Physicians. 2009 Nov;102(11):781–4.

38. Mattila E, Uusitalo-Seppälä R, Wuorela M, Lehtola L, Nurmi H, Ristikankare M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology. 2012 Mar;142(3):490–6.

39. Patel NC, Griesbach CL, DiBaise JK, Orenstein R. Fecal microbiota transplant for recurrent Clostridium difficile infection: Mayo Clinic in Arizona experience. Mayo Clin Proc. 2013 Aug;88(8):799–805.

40. Pathak R, Enuh HA, Patel A, Wickremesinghe P. Treatment of relapsing Clostridium difficile infection using fecal microbiota transplantation. Clin Exp Gastroenterol. 2013 Dec 27;7:1–6.

41. Ray A, Smith R, Breaux J. Fecal Microbiota Transplantation for Clostridium difficile Infection: The Ochsner Experience. Ochsner J. 2014;14(4):538–44.

42. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol. 2010 Sep;44(8):567–70.

43. Rubin TA, Gessert CE, Aas J, Bakken JS. Fecal microbiome transplantation for recurrent Clostridium difficile infection: report on a case series. Anaerobe. 2013 Feb;19:22–6.

44. Tauxe WM, Haydek JP, Rebolledo PA, Neish E, Newman KL, Ward A, et al. Fecal microbiota transplant for Clostridium difficile infection in older adults. Ther Adv Gastroenterol. 2016 May;9(3):273–81.

45. Vigvári S, Nemes Z, Vincze A, Solt J, Sipos D, Feiszt Z, et al. [Experience with fecal transplantation in the treatment of Clostridium difficile infection]. Orv Hetil. 2014 Nov 2;155(44):1758–62.

46. Yoon SS, Brandt LJ. Treatment of refractory/ recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol. 2010 Sep;44(8):562–6.

47. Zainah H, Hassan M, Shiekh-Sroujieh L, Hassan S, Alangaden G, Ramesh M. Intestinal microbiota transplantation, a simple and effective treatment for severe and refractory Clostridium difficile infection. Dig Dis Sci. 2015 Jan;60(1):181–5.

48. Kao D, Roach B, Beck P, Hotte N, Madsen K, Louie T. A Dual Center, Randomized Trial Comparing Colonoscopy and Oral Capsule Delivered Fecal Microbiota Transplantation in the Treatment of RecurrentClostridium difficileInfection: Preliminary Results Presidential Poster: 1258. Off J Am Coll Gastroenterol ACG. 2015 Oct;110:S553.

49. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407–15.

50. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014 Nov 5;312(17):1772–8.

51. Hota SS, Sales V, Tomlinson G, Salpeter MJ, McGeer A, Coburn B, et al. Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial. Clin Infect Dis Off Publ Infect Dis Soc Am. 2017 Feb 1;64(3):265–71.

52. Jiang ZD, Ajami NJ, Petrosino JF, Jun G, Hanis CL, Shah M, et al. Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridum difficile infection - fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Aliment Pharmacol Ther. 2017 Apr;45(7):899–908.

53. Staley C, Hamilton MJ, Vaughn BP, Graiziger CT, Newman KM, Kabage AJ, et al. Successful Resolution of Recurrent Clostridium difficile Infection using Freeze- Dried, Encapsulated Fecal Microbiota; Pragmatic Cohort Study. Am J Gastroenterol. 2017 Jun;112(6):940–7.

54. Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H, Levin J, et al. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Med. 2016 Sep 9;14(1):134.

55. Shogbesan O, Poudel DR, Victor S, Jehangir A, Fadahunsi O, Shogbesan G, et al. A Systematic Review of the Efficacy and Safety of Fecal Microbiota Transplant for Clostridium difficile Infection in Immunocompromised Patients. Can J Gastroenterol Hepatol. 2018;2018:1394379.

56. Saha S, Mara K, Pardi DS, Khanna S. Long-term Safety of Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection. Gastroenterology. 2021 May;160(6):1961-1969.e3.

57. Wang S, Xu M, Wang W, Cao X, Piao M, Khan S, et al. Systematic Review: Adverse Events of Fecal Microbiota Transplantation. PloS One. 2016;11(8):e0161174.

58. Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014 Jul;109(7):1065–71.

59. Kelly CR, Yen EF, Grinspan AM, Kahn SA, Atreja A, Lewis JD, et al. Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results From the FMT National Registry. Gastroenterology. 2021 Jan 1;160(1):183-192.e3.

60. Brumbaugh DE, Zoeten EFD, Pyo-Twist A, Fidanza S, Hughes S, Dolan SA, et al. An Intragastric Fecal Microbiota Transplantation Program for Treatment of Recurrent Clostridium difficile in Children is Efficacious, Safe, and Inexpensive. J Pediatr. 2018 Mar 1;194:123-127.e1.

61. Lai CY, Sung J, Cheng F, Tang W, Wong SH, Chan PKS, et al. Systematic review with meta-analysis: review of donor features, procedures and outcomes in 168 clinical studies of faecal microbiota transplantation. Aliment Pharmacol Ther. 2019 Feb;49(4):354–63.

62. Baxter M, Ahmad T, Colville A, Sheridan R. Fatal Aspiration Pneumonia as a Complication of Fecal Microbiota Transplant. Clin Infect Dis. 2015 Jul 1;61(1):136–7.

63. DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, et al. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. N Engl J Med. 2019 Nov 21;381(21):2043–50.

64. Soo WT, Bryant RV, Costello SP. Faecal microbiota transplantation: indications, evidence and safety. Aust Prescr. 2020 Apr;43(2):36–8.

65. Marcella C, Cui B, Kelly CR, Ianiro G, Cammarota G, Zhang F. Systematic review: the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment Pharmacol Ther. 2021 Jan;53(1):33–42.

66. Issa M, Vijayapal A, Graham MB, Beaulieu DB, Otterson MF, Lundeen S, et al. Impact of Clostridium difficile on inflammatory bowel disease. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2007 Mar;5(3):345–51.

67. Qazi T, Amaratunga T, Barnes EL, Fischer M, Kassam Z, Allegretti JR. The risk of inflammatory bowel disease flares after fecal microbiota transplantation: Systematic review and meta-analysis. Gut Microbes. 2017 Nov 2;8(6):574–88.

68. Sood A, Singh A, Mahajan R, Midha V, Mehta V, Gupta YK, et al. Acceptability, tolerability, and safety of fecal microbiota transplantation in patients with active ulcerative colitis (AT&S Study). J Gastroenterol Hepatol. 2020 Mar;35(3):418–24.

69. Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, et al. Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2016 Jan 12;315(2):142– 9.

70. Dutta SK, Girotra M, Garg S, Dutta A, von Rosenvinge EC, Maddox C, et al. Efficacy of combined jejunal and colonic fecal microbiota transplantation for recurrent Clostridium difficile Infection. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2014 Sep;12(9):1572–6.

71. Baxter M, Colville A. Adverse events in faecal microbiota transplant: a review of the literature. J Hosp Infect. 2016 Feb;92(2):117–27.

72. Baxter M, Colville A. Adverse events in faecal microbiota transplant: a review of the literature. J Hosp Infect. 2016 Feb;92(2):117–27.

73. Woodworth MH, Neish EM, Miller NS, Dhere T, Burd EM, Carpentieri C, et al. Laboratory Testing of Donors and Stool Samples for Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. J Clin Microbiol. 2017 Apr;55(4):1002–10.

74. Krajicek E, Fischer M, Allegretti JR, Kelly CR. Nuts and Bolts of Fecal Microbiota Transplantation. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2019 Jan;17(2):345–52.

75. Terveer EM, van Beurden YH, Goorhuis A, Seegers JFML, Bauer MP, van Nood E, et al. How to: Establish and run a stool bank. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2017 Dec;23(12):924–30.

76. Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Ther Adv Gastroenterol. 2012 Nov;5(6):403–20.

77. Kronman MP, Nielson HJ, Adler AL, Giefer MJ, Wahbeh G, Singh N, et al. Fecal microbiota transplantation via nasogastric tube for recurrent clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr. 2015 Jan;60(1):23–6.

78. Hecker MT, Obrenovich ME, Cadnum JL, Jencson AL, Jain AK, Ho E, et al. Fecal Microbiota Transplantation by Freeze-Dried Oral Capsules for Recurrent Clostridium difficile Infection. Open Forum Infect Dis. 2016 Apr;3(2):ofw091.

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