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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 4  |  Issue : 2  |  Page : 142-152

Fecal microbiota transplantation: Safe, simple, and effective


1 Department of Surgery, Section of Gastroenterology, Bethlehem, Pennsylvania, USA
2 Department of Medicine, Section of Gastroenterology, Bethlehem, Pennsylvania, USA
3 Department of Family Medicine, St. Luke's Hospital – Warren, Phillipsburg, New Jersey, USA
4 Department of Surgery, Western Michigan University Stryker School of Medicine, Kalamazoo, Michigan, USA
5 Department of Research and Innovation, St. Luke's University Health Network, Bethlehem, Pennsylvania, USA

Date of Submission22-Jul-2018
Date of Acceptance01-Aug-2018
Date of Web Publication30-Aug-2018

Correspondence Address:
Dr. Stanislaw P Stawicki
Department of Research and Innovation, St. Luke's University Health Network, Bethlehem, Pennsylvania 18015
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJAM.IJAM_33_18

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  Abstract 


Fecal microbiota transplantation (FMT) re-emerged over the last decade, primarily in response to the escalating problem of health-care-associated Clostridium difficile (CD) infection (CDI). Increasing virulence and antibiotic resistance of CD prompted intensified efforts to broaden therapeutic options for this emerging health threat. It is well established that homeostasis of intestinal flora (or microbiota) is critical to human well-being. Introduction and misuse of various health-care related interventions, including antibiotics and gastric acid-reducing agents, contributed to the current state of crisis. Common therapeutic options for CDI include antibiotics, probiotics, and surgery. More recently, there has been as shift toward the utilization of FMT as a second-line option for severe/complicated CDI. The aim of this review is to provide health-care professionals with a concise summary of management options for CDI, with special focus on FMT and its indications, contraindications, and implementation experiences.
The following core competencies are addressed in this article: Medical knowledge, Patient care and procedural skills, Systems-based practice.

Keywords: Clostridium difficile colitis, Clostridium difficile infection, fecal microbiota transplantation, management options, pseudomembranous colitis, review


How to cite this article:
Smith EA, Duarte-Chavez R, Samia H, Knight P, Tolentino JC, Wojda TR, Cornejo K, Siciliano M, Geme B, Stawicki SP. Fecal microbiota transplantation: Safe, simple, and effective. Int J Acad Med 2018;4:142-52

How to cite this URL:
Smith EA, Duarte-Chavez R, Samia H, Knight P, Tolentino JC, Wojda TR, Cornejo K, Siciliano M, Geme B, Stawicki SP. Fecal microbiota transplantation: Safe, simple, and effective. Int J Acad Med [serial online] 2018 [cited 2018 Dec 11];4:142-52. Available from: http://www.ijam-web.org/text.asp?2018/4/2/142/240135




  Introduction Top


The human gastrointestinal (GI) tract houses a complex and highly diverse microbial population, estimated to consist of as many as 1000–1200 species of bacteria, most of which are present in the large intestine.[1] Among predominant colonic microbes are Bacteroides and Firmicutes species.[2],[3] Microbiota plays three key roles in the gut, including: (a) broad range of metabolic functions such as synthesis of vitamins, breakdown of dietary carbohydrates, and bile processing;[4],[5] (b) protective exclusion of certain pathogens from growing through competition for nutrients and production of antimicrobial factors;[6] and (c) the maintenance of mucosal immunity through complex interactions involving the gut epithelium.[7],[8] It has been noted that across different individuals, microbiota can vary substantially, with certain antibiotics and disease processes believed to contribute to loss of homeostatic balance.[9]

Clostridium difficile (CD) was first implicated as the cause of antibiotic-associated pseudomembranous colitis (PMC or CD infection [CDI]) in 1978.[1],[2],[3],[9],[10] The colonic microbial balance can be significantly disrupted by medications, notably antibiotics and gastric acid-reducing agents, which may lead to direct and/or indirect microbiota alterations.[10] This results in “competitive proliferation” of certain pathogens, including CD, as well as potentially harmful disruption of epithelial immunity.[11],[12],[13] In the context of PMC/CDI, resultant pathologic manifestations range from self-limiting diarrhea to life-threatening colitis with multisystem organ failure. In the recent past, both the incidence of PMC/CDI and antibiotic resistance patterns of CD dramatically increased due to liberal antibiotic use and the appearance of the virulent NAP1 strain.[14],[15],[16] This resulted in a 2-fold increase in CD-related hospitalizations between 2000 and 2010, including an estimated 453,000 cases and 29,300 deaths during 2011 in the United States alone.[15] The importance of well-informed clinical decisions is especially critical in the setting of severe CD colitis (CDC) or fulminant CDC (fCDC). Currently, there is no universally recognized severity classification system for CDC, with the most comprehensive system being the Hines VA CDI Severity Score (HVCSS).[17] It is generally accepted that fCDC is characterized by the presence of systemic toxicity or shock.[18],[19],[20],[21] Although only 2%–10% of cases evolve into fCDC, the mortality rate in this patient subset is substantial (13%–80%, average ~30%).[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] This high mortality, coupled with the resource-intensive nature and the complexity of both medical and surgical management, mandates that providers clearly understand the current state of clinical research, diagnostics, therapeutics, and guidelines relating to the management of the entire spectrum of CD-related illness, from minimally symptomatic PMC to fCDC [Figure 1].
Figure 1: Spectrum of clinical severity and associated manifestations seen among patients with Clostridium difficile infection. Note that recurrent Clostridium difficile infection most often occurs at the “mild-to-moderate” end of this spectrum, while complicated or fulminant Clostridium difficile infection occurs toward the “right-sided end” of disease severity manifestations. Fecal microbiota transplantation is most commonly used for either multiply recurrent disease or for severe disease unresponsive to traditional, nonsurgical management

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Although traditional management approaches are generally effective against CDI, recurrence rates have increased, posing a substantial challenge.[17] Recurrent CDI (rCDI) is strongly associated with a decrease in fecal microbial diversity and loss of microbial homeostasis.[9],[32],[33] Fecal microbiota transplant (FMT) is a procedure in which fecal matter from a healthy donor is mixed with saline solution and placed into a recipient with recurrent, severe, or complicated CDI.[17],[34],[35] The primary purpose of FMT is to re-establish a healthy microbiota balance that facilitates the resistance to growth of pathogenic bacteria, thus reducing the chance of recurrent or worsening infection.[17],[35],[36] This review will highlight key considerations surrounding the clinical management of CDI, beginning with an overview of nonsurgical and operative approaches and then focusing on FMT as the emerging treatment option for growing number of cases.


  Overview of Medical Management Top


Because asymptomatic colonization of the gut can be detected in as many as 14% of patients admitted to hospital, it is critically important to promptly and accurately determine if CDI/PMC is indeed present.[37] Once this determination is made, various clinical tools can be employed to help quantify the severity of CDI, including the previously mentioned HVCSS[17] and the Infectious Diseases Society of America (IDSA) clinical severity prediction tool.[23],[37],[38] Regardless of which particular guideline is followed, it is important to approach each case in a systematic, standardized, and evidence-based fashion.

Diagnostic testing for CDI continues to evolve. Multiple modalities for CDI testing exist, although no single method can be considered as “the best diagnostic test”. The IDSA and the Society of Healthcare Epidemiology of America (SHEA) recommend testing patients with new onset of diarrhea, defined as at least three unformed stools in 24 hours, or worsened diarrhea that cannot be attributed to other causes.[38],[39],[40],[41]

The two tests used as reference methods in comparisons with other modalities are the toxigenic culture (TC) and the cell cytotoxicity neutralization assay (CCNA). TC utilizes incubation and growth of the organism in a stool sample followed by a toxin test. A significant disadvantage associated with TC is the long turn around required for a result, as well as the labor and resources required to perform the test.[42] The CCNA involves detection of C. difficile toxin-induced cytopathic effect in a stool filtrate when applied to a cell line. CCNA has a moderate sensitivity compared to TC, and has variable results dependent on degradation of the specimen and laboratory factors, including which cell line is used.[42] Toxin A and B enzyme immunoassays (EIA) use monoclonal or polyclonal antibioties directed against C. difficile toxins, and tend to have a poor sensitivities and varying specificities for detecting CDI depending on the assays used.[42] Glutamate dehydrogenase immunoassays (GDH) detect the glutamate dehydrogenase enzyme produced by all C. difficile strains. Such testing can be done rapidly; however, confirmatory validation must be done, as the antigen detected is present in both toxigenic and nontoxigenic strains.[42] Finally, nucleic acid amplification tests (NAAT) utilize PCR to detect C. difficile genes and typically have a high sensitivity. Finally, although biomarkers such as fecal lactoferrin have been studied in detecting clinically significant CDI, their role in diagnostics remains controversial.[38] Important considerations when choosing diagnostic modality include how rapidly the test can be performed and the the associated cost. The advantages and disadvantages of each test are listed in [Table 1].[42]
Table 1: Summary of diagnostic tests for CDI with advantages and disadvantages

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The IDSA and SHEA currently recommend using a multistep algorithm including a stool toxin test plus GDH, NAAT, or GDH arbitrated by NAAT for testing of CDI in patients at increased risk for clinically significant CDI, primarily because using these tests in combination results in optimized positive and negative predictive value. Additionally, in patients with clinical symptoms of CDI, it is recommended to use either NAAT alone or a multistep algorithm with toxin or GDH plus toxin.[38]

The traditional management approach to PMC consists of an attempt to eradicate CD using vancomycin and/or metronidazole for a predefined time course, depending on disease severity and initial versus recurrent episode status.[43],[44] For mild-to-moderate, first-time occurrence of CDI in adults, it is recommended that the first-line management consists of oral vancomycin (125 mg four times daily [QID] for 10–14 days), with alternative agents to consider being oral fidaxomicin (200 mg twice daily [BID] for 10 days) or oral metronidazole (500 mg thrice daily [TID] for 10–14 days).[37] For severe, uncomplicated CDI, first-line management should consist of oral vancomycin (125 mg QID for 10–14 days) or oral fidaxomicin (200 mg BID for 10 days).[37]

For more severe, complicated or fulminant cases involving hypotension, ileus, or megacolon, enteral vancomycin (125–500 mg QID for 10–14 days through nasogastric tube) in conjunction with intravenous metronidazole (500 mg Q 8 h) should be given.[37] Alternatively, enteral fidaxomicin (200 mg BID for 10 days) with intravenous metronidazole (500 mg Q 8 h) can be substituted.[37] In cases involving concurrent paralytic ileus, rectal administration of vancomycin (500 mg in ~100 mL of saline, Q 6 h as retention enema) can be substituted for oral administration.[37]

For recurrent episodes, oral vancomycin (125 mg QID for 14 days) should be used, especially if the initial episode was treated with oral metronidazole. Alternatively, a prolonged taper and pulsed vancomycin regimen (125 mg QID for 10-14 days, then BID for 1 week, QD for 1 week, and finally every other day for 2-8 weeks) can be used if metronidazole was used during the initial episode.[37] Oral fidaxomicin (200 mg BID for 10 days) should be used to treat a first recurrence if vancomycin was used for the initial episode.[37] For severe, uncomplicated first recurrence, oral vancomycin (125 mg QID for 14 days) or oral fidaxomicin (200 mg BID for 10 days) can be utilized.[37] For second or subsequent recurrences, oral vancomycin can be used as a prolonged taper and/or pulsed regimen, as outlined above. Alternative approaches include vancomycin 125 mg QID for 10 days) followed by rifaximin (400 mg TID for 20 days) or fidaxomicin alone (200 mg BID for 10 days).[37] However, this is also one of the settings where FMT may be indicated following a recurrence despite prolonged vancomycin taper.[37] Additionally, there is some evidence to support the use of probiotics to help prevent CDI in both children and adults receiving antibiotics, with potential role in CDI treatment.[45] However, in a large meta-analysis, there was insufficient evidence to support the use of probiotics for the prevention and or treatment of CDI.[46]

Lastly, monoclonal antibodies have been advocated as adjunctive therapy. A multi-center randomized trial in the US and Canada found that while monoclonal antibodies did not alter the severity of C. difficile-associated disease, they may reduce disease recurrence; therefore the authors recommend administration of this therapy to patients at high risk for recurrent infection.[47]

Although the concept of antibiotic stewardship is generally well understood, it should be emphasized that the use of antibiotics in patients with suspected CDI should be stopped immediately, with only rare exceptions permitted. If antibiotics are necessary, then their spectrum should be narrowed as much as feasible. For complex cases, Infectious Disease expert consultation is highly recommended. Finally, hand washing with soap and water, both before and after examining a patient, is superior to alcohol based solutions due to better spore removal properties.


  Overview of Surgical Management Top


The decision to abandon medical management in favor of surgical treatment is perhaps the most difficult aspect of caring for patients with fulminant CDI (fCDI), requiring careful consideration of potential risks, benefits, and alternatives. Given the morbidity and mortality associated with a potentially avoidable procedure on the one hand and the mortality associated with the patient's condition in the other hand, objective assessment criteria incorporating the best available clinical evidence become a necessity.[38],[48]

Adding to the complexity of this clinical scenario is the lack of accurate prognostic tools aimed at predicting which patients with CDI will progress to fCDI. Although various studies describe different risk factors for the development of fCDI (e.g., age >70 years; white blood cell [WBC] count >16,000–18,000; and abdominal pain), practitioners do not universally utilize objectivized bedside assessment tools.[18],[20],[29],[49],[50] In one study, van der Wilden et al.[18] sought to develop a reliable scoring tool to stratify patients with CDI into low- and high-risk categories. In their prospective analysis of 746 patients, of whom 48 (6.4%) went on to develop fCDI, four factors were significantly associated with fCDI (age >70 years [2 points]; WBC >20,000 or <2,000 [1 point]; cardiorespiratory failure [e.g., mechanical ventilation or vasopressors, 7 points]; and diffuse abdominal tenderness [6 points]). In that study, a score of ≥6 points equated with “high-risk” designation; however, some have pointed out the small sample size and single-center nature of this report.[18] Another criticism of this scoring tool is that patients without cardiorespiratory failure or diffuse abdominal pain are designated as “low risk” by default. Because cardiorespiratory failure is a predictor of increased mortality in patients with CDI, a scoring tool that identifies at-risk patients during earlier stages of the disease process would hypothetically provide a mortality benefit.[21],[27],[51],[52]

Contemporary literature highlights the importance of early surgical management of patients with fCDI, as opposed to a prolonged trial of antibiotic therapy alone.[22],[26],[27],[52],[53],[54],[55] Although most studies do not describe an optimum window of time within which patients would most benefit from an operation, few reports point to lower mortality among individuals with a shorter time between diagnosis and the surgical procedure.[21],[22],[25] Halabi et al.[25] retrospectively reviewed the Nationwide Inpatient Sample from 2001 to 2010 to identify risk factors for colectomy and postcolectomy mortality. Of importance, surgical therapy performed >3 days following admission correlated with greater mortality.[25] At this juncture, we will discuss major surgical options utilized in the setting of fCDI.


  Total Abdominal Colectomy Top


Total abdominal colectomy is the primary surgical approach for patients with fCDI.[22],[23],[28],[29],[30],[31],[52],[53],[54],[56],[57],[58] In parallel with the increasing incidence of CDI, Halabi et al. reported that the rate of colectomies in this group increased by 32% from 2001 to 2010.[25] Although total colectomy is associated with significant morbidity and mortality, it results in improved survival when compared to medical management alone.[21],[22],[25] Of importance, total colectomy has been found to be superior to subtotal colectomy in terms of mortality (11%–56% vs. 14%–100%, respectively) and percentage of patients that needed subsequent surgery.[29],[58],[59] Patients and their families must be properly informed regarding not only the risks associated with the procedure but also the substantial postoperative morbidity. In two studies looking at long-term follow-up among postcolectomy patients, long-term survival was found to be low (5-year survival of 11%–38%) and associated morbidity relatively high.[57],[60] Between 14% and 20% of patients were able to undergo successful ostomy takedown and restoration of GI continuity.[57],[60]


  Diverting Loop Ostomy and Colonic Lavage Top


Among relatively recent developments, Neal et al.,[20] evaluated minimally invasive, colon-sparing surgical approach to treating fCDI. Their study involved 42 patients with “severe, complicated CD-associated disease” plus predefined indications for surgical management (e.g., peritonitis, sepsis, mental status change, vasopressor requirement, and ventilatory failure). The primary treatment strategy consisted of surgical creation of a loop ileostomy, followed by the intraoperative impregnation of the colon with 8 L of polyethylene glycol (PEG) 3350/electrolyte solution through the newly created ostomy. The lavage solution was drained using a rectal tube, and a 24Fr Malecot catheter was secured into the distal lumen of the ileostomy. During the postoperative period, the Malecot catheter was used to infuse 500 mg of vancomycin in 500 mL of lactated ringers every 8 h for 10 days. In addition, each patient received 500 mg of intravenous metronidazole every 8 h for 10 days.[20] Of the 42 patients included in the study, only three required additional surgery. Within the latter group, one patient underwent an immediate total colectomy due to unremitting abdominal compartment syndrome, one received a subtotal colectomy for recurring vasopressor dependence on postoperative day 10, and one required a subtotal colectomy 12 h after the initial procedure due to abdominal compartment syndrome. Colonic preservation was accomplished in 39 of 42 (93%) cases, and only one patient developed a recurrent episode of CDC.[20] At the time of publication, 15 of 19 patients with a minimum follow-up of 6 months had undergone successful ileostomy reversal. When compared with 42 patients that had undergone total colectomy for “severe, complicated CD-associated disease,” it was noted that patients undergoing loop ileostomy with colonic lavage had lower 30-day mortality (19% vs. 50% in the colectomy group).[20] Although this study reported promising results, it is limited by relatively small sample size and the fact that it was performed at a single institution.[20],[21] That being said, the potential benefit of this technique over total colectomy warrants further investigation. There is currently a multi-institutional randomized controlled trial underway that will hopefully shed more light on the efficacy of loop ileostomy with colonic lavage for fCDC.[24],[59] Until then, expert societies recommend that total colectomy is the preferred surgical approach, with some suggesting reserving loop ileostomy with colonic lavage for select patients unable to tolerate a total colectomy.[23],[24],[28],[58],[59]


  Fecal Microbiota Transplantation Top


Historical perspective

Fecal microbiota transplantation (FMT) is not an entirely new concept. In fact, some of the earliest historical applications of FMT have been described as early as the 4th century in China.[61] Although exact indications or etiologies of illness are not known, it has been reported that human fecal suspensions were administered orally to those affected with severe diarrhea or food poisoning.[61],[62] The utility of FMT has also been mentioned in veterinary medicine around the 17th century by the Italian anatomist Girolamo Fabrizi d'Acquapendente.[62],[63] The first modern application of FMT in the U.S. was reported in 1958 by Eiseman et al., who used fecal enemas to treat fCDI.[62],[64] These early clinical implementations resulted in rapid recovery of patients with fCDI.[65] Since 1958, various institutions worldwide have offered FMT as a therapeutic option for patients with CDI, with reportedly excellent clinical results.[36] Moreover, the role of FMT is currently being evaluated for a variety of medical conditions, from ulcerative colitis to diabetes and Parkinson's disease.[66]

Pathophysiologic considerations

The human GI tract houses a very diverse and equally complex microbial population of approximately 1000–1200 species of bacteria, most of which are present in the large intestine.[1] This rich microbiome is critical to the human nutrient metabolism, immune system development, protection against opportunistic pathogens, and various endocrine-like functions.[67],[68],[69] Commonly, adult humans are colonized with approximately 9 different divisions of bacteria and one of archaea (Methanobrevibacter smithii).[67] The predominant types of bacteria seen in the adult GI tract include Firmicutes (Gram positive), Actinobacteria (Gram positive), and Bacteroides (Gram negative).[67] Each section of the GI tract has a particular density of bacteria based upon certain environmental factors (i.e., pH, oxygen content, and nutrient density).[67] Gut microbes contribute to a broad range of metabolic functions including vitamin synthesis, bile metabolism, and breakdown of carbohydrates. At the same time, gut bacteria play a protective role by “crowding out” certain pathogens through competition for nutrients and antimicrobial factor production.[6] Finally, gut flora contributes to “mucosal immunity” through complex interactions with epithelial surfaces.[7],[8]

The specific composition of microbiota can be modulated by medications – most notably antibiotics and antiacid agents – which can lead to a disruption in homeostasis.[36],[70] This then enables certain pathogens, such as CD, to competitively “overgrow” normal bacterial species, disrupt epithelial immunity, and result in a range of illness from self-limiting diarrhea to life-threatening colitis.[11],[12],[13] Recurrent infections involving pathogens not normally found in the colon are often associated with a decrease in fecal microbial diversity and inability to maintain homeostasis.[33],[71],[72] Fecal microbiota transplant (FMT) is a procedure in which fecal matter from a healthy donor is mixed with saline solution and placed into the GI tract (usually the colon) of a recipient with a disrupted microbial homeostasis (e.g., CDI), with the primary intent of re-establishing the composition of a healthy microbiota and thus restoring the innate resistance toward growth of disease-causing pathogens.[17]

Clinical assessment and indications

To appropriately assess whether an indication for FMT exists, the treating provider must consider both the function and composition of the GI microbiota in the context of pathologic findings. Microbiota dysbiosis is defined as the imbalance of bacteria within the gut.[73] In addition to CDI, microbiota dysbiosis can also contribute to inflammatory bowel disease, irritable bowel syndrome, impaired bile and lipid metabolism, cardiovascular disease, glucose homeostasis, metabolic syndrome and obesity, as well as various immunologic, rheumatologic, and other systemic manifestations.[67],[68],[69],[73],[74],[75],[76],[77],[78],[79] In the setting of CDI, specific indications have been established for FMT, with primary consideration given to safety and efficacy of FMT when compared to other available therapeutic options. These considerations change along the clinical spectrum of CDI manifestations, from uncomplicated disease treated with simple antibiotic regimen to multiply recurrent or complicated CDI warranting the application of FMT.[17],[36]

Evidence supports the use of FMT as safe and effective in both adult and pediatric patients with recurrent/refractory CDI.[77] In the setting of rCDI, high-quality clinical data demonstrate that significant majority (75%–95%) of patients who underwent FMT with antibiotic treatment experienced resolution of symptoms within 3 months.[17],[36],[80] Clinical studies show that patients receiving FMT experience restoration of normal fecal microbiota balance.[69] Early data were sufficiently compelling to prompt the American College of Gastroenterology to modify their guidelines for relapsing CDI and formally recommend FMT.[67],[69],[77],[78]

Various treatment guidelines exist to assist clinicians in deciding when to utilize FMT as a therapeutic option. Kelley et al.[81] summarized the recent recommendations by the FMT workgroup, established in 2010, as well as the American College of Gastroenterology. While FMT is most commonly used for rCDI, other uses have been investigated. Most recently, in March 2016, the United States Food and Drug Administration released a clarifying draft guidance for industry titled, “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat  Clostridium difficile Scientific Name Search ection Not Responsive to Standard Therapies.”[82],[83] These new guidelines specify that while an investigational new drug (IND) permit is not required to treat rCDI, it is strongly encouraged.[17] The use of fecal microbiota transplant to treat any other condition, or when performed for research purposes, does require an IND permit.[82],[83] [Table 2] outlines the most recent indications for FMT, including applicable/corresponding literature source(s).
Table 2: Summary of recommendations for fecal microbiota transplantation use in the setting of Clostridium difficile infection

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Contraindications

While no absolute contraindications currently exist for potential recipients, there are multiple comorbid conditions that should be considered before performing FMT.[17],[88],[89] Special caution is needed when approaching patients receiving immunosuppressive agents or suffering from any disease process resulting in severe immunodeficiency. Immunosuppressive agents include high-dose corticosteroids, posttransplant immunosuppression such as calcineurin inhibitors, mammalian target of rapamycin inhibitors, and chemotherapeutic and antineoplastic agents such as tumor necrosis factor inhibitors.[89] Additional disease processes associated with immunodeficiency that should be considered as potential (or relative) contraindications include decompensated liver cirrhosis, advanced HIV/AIDS, and recent bone marrow transplantation.[84]

Donor selection and preparation

Donor selection for FMT has been variable throughout the evolution and maturation of this therapeutic modality.[90],[91],[92],[93] Most frequently, immediate family members, significant others, or individuals known to the clinician performing FMT are selected as stool donors.[93],[94] This is believed to be advantageous because such donors tend to have similar infectious risk profiles and may be less likely to transmit unforeseen infection(s).[88] Furthermore, donors and recipients that are similar in age may harbor a similar microbiota, resulting in a better overall match and more compatible posttransplant GI microbial milieu. An important consideration when attempting to find FMT donors is the overall perception of bias due to lack of random allocation, which contributed to the rise of anonymous donor banks. The intent of such institutions is to standardize the FMT donation and end-user delivery process.[17],[95]

Infectious disease testing is commonly performed for both the donor and the corresponding stool sample before specimen banking and subsequent use in FMT. Situations, however, do exist in which donor screening and testing may not be required (e.g., the donor is a sexually intimate partner).[84] Although specific regulations and protocols may vary based on institutions and geographic locations, it is recommended that donors undergo blood testing, stool sampling for culture, antigen testing, serology and polymerase chain reaction, as well as a screening questionnaire.[61],[84],[93] [Table 3] outlines the specific tests recommended for stool donors.[93] Once a suitable donor has been selected, the use of a standardized predonation protocol is recommended. Such approach calls for the donor's bowel preparation with a mild laxative (e.g., 60 mL of milk of magnesia) the night before the donation.[93],[96],[97] Participants should also avoid any foods to which they may be allergic for 5 days before the procedure, and must notify supervising providers of any signs or symptoms of infection that may occur before donation.[84]
Table 3: High-level summary of diagnostic testing recommended during the fecal microbiota transplantation donation process

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Recipient preparation

Recipients of FMT should, if clinically possible, complete all recommended aspects of pretransplant preparation. These steps standardize the overall process and increase the likelihood of procedural success. Before transplant, all recipients should stop taking antibiotics for at least 24–48 h.[98],[99] The rationale behind this particular step is that antibiotics disrupt the natural colonic flora that inherently protects the microbiome homeostasis.[100] Bowel lavage, though not universally recommended in every protocol, is encouraged when patients are clinically able to tolerate it. The basis of lavage is to flush out residual feces, antibiotics, and CD-related materials (bacteria, toxins, and spores) before FMT.[98] PEG-electrolyte lavage has become the standard preparation for colonoscopy, and it is recommended the night before FMT.[98],[99] Utilization of bowel lavage has also been recommended in FMT administration through upper GI route.[34]

Procedural techniques and delivery

Once a donor has been selected, the stool sample collected, and the recipient appropriately prepared, the FMT delivery procedure can begin. Different techniques of delivery have been used in FMT.[17] They can be broadly classified into upper and lower GI routes. Of importance, it is recommended that the FMT process be completed within 6 h of donation.[101] Once the stool has been obtained, it is recommended that approximately 50 g of the sample should be combined with 200–800 mL of normal saline.[101] This solution should then be homogenized either by manual shaking or with the assistance of a blending device, with all large particles removed through straining.[101] The resultant solution should then be drawn up into large 60 mL syringes in preparation for administration.

Upper gastrointestinal route

Fecal microbiota transplant has been described using nasogastric and nasojejunal administration in multiple studies.[34],[84],[100] Upper endoscopy has also been utilized successfully.[102],[103] The nasogastric or nasojejunal approach utilizes the same method to prepare the FMT solution as described in the previous section of this review. However, compared to lower GI routes, the technique utilizes a smaller amount of solution administered (e.g., approximately 30 mL).[100],[104],[105],[106] Retrospective case series describing the efficacy of FMT in treating rCDI through upper GI administration showed favorable clinical results. In one case series of 74 patients undergoing FMT via upper endoscopy, stool samples consisted of 25 mL of stool and saline instilled into the stomach using a nasogastric tube (64 cases), PEG tube (4 cases), or endoscope (7 cases).[105] Following the FMT, patients were followed for a minimum of 60 days, with clinical recovery in 79% cases.[105]

Patients who opt for upper GI administration should complete the same preparation as outlined. In addition, patients should take a proton pump inhibitor (e.g., omeprazole or pantoprazole) the night before the FMT procedure.[100],[104],[105],[106] The nasogastric or nasojejunal tube should be placed carefully and subsequently confirmed with radiography to avoid inadvertent instillation into the tracheobronchial tree.[107] A syringe should then be used to flush the solution through the tube, with the patient remaining upright for the procedure. The tube should then be flushed with normal saline before removal.[100] The patient can then be discharged from the clinic or endoscopy suite and return to normal dietary function.

Lower gastrointestinal route

Administration of FMT directly into the colon (through enema or colonoscopy) is considered by many as the standard delivery method.[17],[36] Although different studies describe technical variations in lower GI administration of FMT, the fundamental concept is similar throughout all reports.[102],[108],[109] Administration through colonoscopy involves advancing the colonoscope to the cecum and administering a fecal transplant solution through the working port.[17] While the exact amount of transplanted material has not been determined, the average reported range for lower GI administration is 200–300 mL.[99] Administration through enema tends to involve slightly smaller amounts of solution.[101] Lower GI route for FMT is typically well tolerated by patients and has been reported to have high cure rates of approximately 85%–95% and relapse rates of only 5%–10%.[17],[110]

Postprocedural and follow-up considerations

Regardless of the route of administration, it is important for patients to follow a predetermined postprocedural protocol. Counterintuitive from CDI perspective, patients should receive a one-time dose of an over-the-counter antidiarrheal (e.g., loperamide) to help slow down the transit of the FMT material through the GI tract.[111] In addition, it is recommended that patients avoid excretion of FMT for >4 h.[101] Although it has been noted that postprocedurally patients may have irregular bowel habits and even temporary worsening of diarrhea, these symptoms are likely to resolve within a few weeks.[17],[112] As with all procedures, recipients should be advised to notify physicians of any signs of clinical worsening, suspected infection, or return of pre-FMT symptoms of CDI.


  Conclusion Top


All clinicians should be well versed with fundamental diagnostic and management aspects of CDI, including the expanding clinical uses for FMT. Knowledge of the indications, basic techniques, and potential complications will enable clinicians to make informed decisions and guide patients regarding benefits (as well as risks) associated with both medical and procedural management of CDI. Given excellent outcomes reported by increasing number of studies, indications for FMT are likely to expand further, with high probability of FMT displacing some of the more invasive options (e.g., ileostomy-based irrigation or total colectomy) due to better disease control at the “lower end” of the CDI acuity spectrum.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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