Paul Feuerstadt, MD, FACG, AGAF and Neil Stollman, MD, FACP, FACG, AGAF
There are several approaches to performing a fecal microbiota transplantation (FMT), and it can be confusing to decide which approach is optimal for you and your patient. The options include administration into the upper gastrointestinal (GI) tract (eg, via upper endoscopy, nasoenteric tube, orally administered capsules) or the lower GI tract (eg, via enema, flexible sigmoidoscopy, colonoscopy; Table 8-1). Also, providers who perform FMT vary according to training, with gastroenterologists and surgeons being able to perform upper endoscopy, flexible sigmoidoscopy, and colonoscopy, and those trained in infectious disease or primary care being limited to the less invasive methods, such as enema, oral capsule, and nasoenteric administration.
How does one choose a modality? There is a lot to consider, and this chapter will succinctly outline the methodologies and key data supporting them to assist you in optimizing selection of the most appropriate FMT delivery modality.
Preparation Prior to Fecal Microbiota Transplantation
The ideal preparation prior to FMT is currently unknown and requires further investigation. Factors to consider include whether patients should remain on antibiotics until FMT, the timing of stoppage of antibiotics prior to FMT, and the utility of purging the bowel prior to the procedure.
Standard-of-care (SOC) antibiotics are used to treat Clostridioides difficile infection (CDI); however, when an FMT is indicated following SOC antibiotics, the course of antibiotics is often extended up until the time of FMT to prevent a subsequent recurrence prior to FMT (Practical Pearl 8-1). However, this is not a data-supported method. The ideal antibiotic choice and optimal length of therapy preceding FMT remain unknown. In practice, most clinicians performing FMT continue to administer SOC antibiotics until the FMT procedure can be set up logistically. At high-volume FMT centers, this can often be organized in a few days, but at lower-volume centers, this might take a week if ondemand shipping from a stool bank is the source of the material, or it may be even longer if the clinicians are using a patient-selected model. Given the recurrent nature of CDI and the risks off antibiotics, the most ethical, and practical, intervention seems to be to continue suppressive therapy until FMT can be performed.
Practical Pearl 8-1
How Do You Prepare Your Patient for a Fecal Microbiota Transplantation?
- Prior to the day of the FMT, patients should be advised to hold their SOC antibiotic (eg, vancomycin). Typically, it is held from 1 to 3 days prior to FMT.
- Clinical tip: If administering via colonoscopy, have patients take their last doses the day before the bowel lavage. The preparation will help to wash out any residual vancomycin.
- Standard bowel lavage is performed the day before FMT by colonoscopy. This is to assist with luminal visualization and also potentially remove any residual antibiotics and possibly spores.
- Bowel preparation is generally not given before upper GI tract delivery, including capsules.
The time to stop SOC antibiotics prior to FMT is a matter of debate as well. Most practitioners will stop these therapies 1 to 3 days prior to the procedure. This is believed to be a reasonable window allowing sufficient time to clear the majority of the antimicrobial from the patient’s system while still limiting the rapid reproliferation of C. difficile off treatment. Further investigation is needed to clarify this issue.
Another area of debate with limited data involves whether a bowel lavage enhances the efficacy of FMT. A bowel preparation theoretically purges the majority of the original deficient microbiota from the patient prior to the FMT, allowing the newly introduced microbiota a more favorable environment for engraftment. In most practices, purging enemas are given prior to FMT via flexible sigmoidoscopy, and full bowel purge is only performed prior to colonoscopic FMT. Most providers do not give a bowel lavage prior to nasoenteric infusions or capsule or enema administration.
Upper Gastrointestinal Tract Administration
There are 2 main methods for FMT delivery via the upper GI tract: nasoenteric infusion and orally administered capsules. A nasoenteric infusion is a procedure where a nasogastric, nasoduodenal, or nasojejunal tube is passed into the patient and FMT material is infused. The first prospective randomized clinical trial of patients with recurrent CDI (rCDI) reporting superiority of FMT to a standard antibiotic course with vancomycin, used FMT via nasoduodenal tube infusion.1 This prospective study was important because it showed that, in addition to significantly higher rates of clinical cure of CDI, the recipient’s microbiota diversity was restored following FMT.1 De spite this method’s efficacy and its visibility in such an important trial, it has significant drawbacks given the discomforts of passage of a nasoenteric tube, the patient visualizing FMT material being passed into their digestive tract, and risks of aspiration of the material. On the other hand, this modality can be performed by most practitioners, so this remains a viable option in some centers.
It is worth noting that there are different risk profiles to nasogastric (the most logistically feasible) vs nasoduodenal or nasojejunal tubes. Due to the administration of the FMT material in the pre-pyloric location, the risk of aspiration is higher using a nasogastric tube than nasoduodenal or nasojejunal tubes, which are both post-pyloric. Newer nasoduodenal/nasojejunal systems may permit visualization, and these are more commonly used in Europe. That said, from a patient perspective, perception studies suggest that patients would prefer not to undergo an FMT via nasoenteric tube administration.2
An easier and more palatable method of FMT is via orally administered capsules, which can be provided by all practitioners. With this method, FMT material is directly enclosed in a coated capsule, which is swallowed by the patient, either in one sitting or over the course of several days. Depending on the capsule formulation, prior to taking the capsules some patients are advised to take acid suppressive medications, such as proton-pump inhibitors. This is done to theoretically minimize capsule breakdown in the acidic environment of the stomach, thereby minimizing degradation of the FMT material in the proximal digestive tract. There is no high-quality data to support or refute this approach; however, the need may be related of the specific capsule coating. Youngster et al3 published data from an open-label pilot study (N = 20) using orally administered capsules (15 capsules on 2 consecutive days) showing that with 1 or 2 courses, patients with rCDI had an overall clinical cure rate of 90%, without any serious related adverse events. Other studies have also shown reasonable efficacy and safety profiles with capsule FMT, and given the ease of administration and patient preference, we suspect it will be the most commonly used modality in the future.
In outlining FMT administration techniques of the upper GI tract, we have presented data for CDI, in which the goal is to reconstitute the depleted colonic microbiota. The upper administrative techniques will commonly distribute FMT material into the small bowel in addition to the large bowel. It has been speculated that this may be associated with greater rates of post-procedure small intestinal bacterial overgrowth and gas/bloat symptoms; however, Allegretti et al4,5 conducted a large cohort study that suggests this may not be a concern. In one study comparing capsules designed to release in the colon with others starting release in the stomach, clinical cure rates for CDI were similar between both groups, but colonic engraftment of the donor stool was higher in the capsules with colonic release.6 Although underpowered, this study suggests there may be utility in precision targeting of FMT material.
There are still many unanswered questions regarding FMT by upper GI tract, including the ideal dose/dose regimen (eg, the number of capsules, volume of stool infused via nasoenteric tube, and concentration of microbial species administered); whether lyophilized, frozen, or fresh capsule formulations are optimal; whether single- or multi-day administration is preferable; and the role, if any, of adjunctive acid suppression.
Lower Gastrointestinal Tract Administration
There are 3 main methods of lower GI tract administration, including enema, flexible sigmoidoscopy, and colonoscopy. Enema administration can be performed in the office setting, where a patient is placed in left lateral decubitus position and a flexible catheter is inserted into the rectum, through which the FMT material is then infused. This method was first shown to be safe and effective in patients with CDI by Kassam et al7,8 using a retention enema. In a follow-up study of retention enema FMT for CDI, Lee et al9 compared frozen and thawed stool with freshly donated FMT material and reported that frozen was noninferior to fresh. The similar efficacy supports the efficient process of stool banks freezing and shipping samples to centers, sparing them the expensive and onerous screening process. However, it should be noted that the efficacy after a single FMT via enema in both groups was low (62.7% frozen vs 62.1% fresh). For CDI, FMT via enema remains an option, but this also requires more investigation to clarify the volume of donor material required, the minimum duration that the enema should be retained, and whether a single enema is sufficient. Enemas also seem safe with a theoretical risk for perforation, but this has yet to be reported, and this method allows for direct administration of the microbiota to the colon.
Colonoscopy and flexible sigmoidoscopy are procedures where a flexible tube with a fiber-optic camera at the tip is passed into the colon. This technique is most commonly used to inspect the lining of the colon and assess for pathology. When it is being used for FMT, the scope is either passed about one-third of the length of the colon (eg, flexible sigmoidoscopy) or the entire length of the large bowel (eg, colonoscopy). Prior to flexible sigmoidoscopy, a saline enema is usually administered to cleanse the distal colon that will be inspected. Before a colonoscopy, a large-volume purge of the colonic contents is required. For FMT, at the time when the endoscope has reached its most proximal point in the bowel, FMT material is passed through the endoscope directly into the bowel lumen. This is commonly given either as a single administration in the most proximal area of bowel reached (ie, terminal ileum or cecum) or in segments, including the cecum and ascending and transverse colon. In the segmental approach, it is less commonly distributed in the left colon given that the material from the proximal large bowel will traverse this region, distributing the transplanted material.
There are multiple studies supporting the safety and efficacy for FMT by colonoscopy in those with rCDI and administration of fresh stool is similar to frozen and thawed.10,11 Some providers administer loperamide 2 to 4 mg either just prior to or following the FMT by colonoscopy, in an effort to increase the duration of retention of the transplanted material and enhance the likelihood of engraftment. There are insufficient data to support or refute this intervention. As with all methods of FMT, there are limitations to using colonoscopy/flexible sigmoidoscopy, including the invasive nature of the procedures and that colonoscopy most commonly requires monitored anesthesia care for sedation. There are also risks associated with endoscopic interventions, including risks of anesthesia and standard endoscopic risks, such as bleeding, infection, and perforation. In the setting of FMT, the benefits of the therapy frequently outweigh the risks, but the clinician needs to consider these factors when choosing a modality.
Unanswered questions include the optimal dose/dose regimen, the ideal locations within the colon the material should be administered, whether loperamide usage is beneficial, and whether there is a threshold of time following the FMT, prior to passage of stool from the patient, that optimizes efficacy.
Efficacies of the Various Modalities
In the first meta-analysis performed considering the efficacy of FMT in patients with rCDI, Kassam et al10 assessed 11 case series including 273 patients and reported that FMT was 89% effective at preventing CDI recurrence. In addition, overall, lower administration was more effective than upper modalities.10 Quraishi et al11 performed a more recent meta-analysis that considered 37 studies, including numerous case series and 7 randomized clinical trials (N = 1973). This meta-analysis once again showed that lower administration (92% to 97%) was more efficacious than upper modalities (82% to 94%; P = .02).11 Given the colonic involvement of CDI, the superior efficacy of lower administration techniques is logical and reinforced by these data.
Some studies have compared modalities head-to-head in patients with CDI. Kao et al12 conducted a randomized clinical trial (N = 116) that compared FMT via frozen oral capsules vs frozen FMT material delivered via colonoscopy. In this study, capsule administration (96.2%) was noninferior to colonoscopy (96.2%), with no related serious adverse events.12 In another study that compared lyophilized FMT capsules vs FMT enema with frozen FMT material, capsules (84%) yielded similar efficacy to the enema treatment (88%; P = .76).13
We have many options to deliver FMT to patients, but quite a bit of research is still needed to identify the specifics of delivery. The choice of the most appropriate should be driven in part by the options available to the provider and, of course, the preferences of the well-informed patient. Meta-analyses support lower GI administration techniques being modestly more efficacious than upper, but head-to-head trials show similar efficacies between FMT by capsule and colonoscopy. Less invasive methods clinically seem to be best from a patient care prospective and universal ability of providers to administer the FMT. Given this, capsules may end up being the most widely adopted. As a clinician, it is probably best to follow this axiom to choose which FMT modality is best for your patient population (Practical Pearl 8-2).
Practical Pearl 8-2
How Do You Select the Right Delivery Modality for Your Patient?
There are many considerations when deciding on the appropriate delivery modality for your patients. Here are a few practical points to keep in mind:
- Dysphagia or significant GI motility disorders: If a patient has ongoing dysphagia or any difficulty swallowing pills, FMT by capsule should be avoided to minimize aspiration risk. Additionally, a patient with a significant GI motility disorder, such as gastroparesis, should also avoid FMT capsules.
- Major comorbidities: If a patient has significant comorbidities that would make sedation unsafe (eg, significant cardiorespiratory disease), consider FMT by capsule (or possibly enema) as opposed to colonoscopy.
- Colostomy: In a patient with a colostomy, endoscopic administration can be performed via the stoma.
- Potential GI pathology: If there is concern about underlying luminal pathology, colonoscopy is preferred for mucosal assessment and biopsy.
- Patient-centric: The selection of a delivery modality should always involve a conversation with the patient regarding his or her preferences if no contraindications are present.