Rigorous evaluation of the stool donor for potentially transmissible infections is of the utmost importance. Optimally, this screening should be performed as close to the time of donor stool collection as possible. The FDA recommends that all tests be performed within 4 weeks of FMT and human immunodeficiency virus (HIV) testing within 2 weeks. Donor screening tests outlined in Table 35.2 have been suggested by the FMT Working Group [23]. Additional screening protocols may be modified based on the recipient and the disease being treated. For example, in the case of FMT for IBD, some have suggested donors be screened for cytomegalovirus (CMV), given its potential to cause colitis. It is also likely that screening protocols and FDA guidelines will continue to evolve. The frequency of screening for repeat donors has not been established.

Similar screening for recipients is not done universally but is being performed by some practitioners and investigators, mostly in an effort to document the recipient’s baseline status at the time of transplant in case of disease transmission.

Published methods of donor stool preparation before transplant vary enough that few definite conclusions can be drawn . Historically, fresh donor stool was used, typically within 8 h of passage. More recently, however, the efficacy of FMT with thawed/previously frozen stool has been shown to be equally effective in recurrent CDI in terms of both clinical improvement [30] and engraftment of the donor flora [44]. In most protocols, a standard kitchen blender is used to homogenize donated stool with a dilutant. Bacteriostatic normal saline, water, and even 4 % cow’s milk have been used as dilutants, and although water may give the best results, preservative free saline is most commonly used [20]. Anywhere from 50 to 300 g of stool is blended with 250–500 mL of dilutant to achieve a liquid slurry, which is then filtered to remove particulate matter. Filtration can be performed with simple through gauze or standard coffee filters. Most recommend that, when possible, a fume hood be used during preparation. The optimal dose is unclear in adults but most give at least 250 mL of the final slurry for colonoscopic delivery and at least 50 mL for upper GI tract delivery [45]. Weight- or age-based doses for children have yet to be established. There is limited evidence that supports a trend in higher efficacy and decreased CDI relapse rates when higher doses of donor stool are used and larger volumes of stool slurry are delivered, but this has yet to be adequately studied in a prospective study [20] .

Fecal microbiota transplantation using both upper and lower GI tract delivery has been successful in treating recurrent CDI. Upper GI (UGI) tract delivery methods have included gastric and post-pyloric delivery through a gastroscope or flexible naso-enteric tube and more recently by mouth in encapsulated form, while lower GI (LGI) tract delivery is via retention enema or colonoscope. For children, successful nasogastric tube [32] and colonoscopic [33] delivery have both been successful for recurrent CDI. The largest review of cases to date for FMT in CDI showed higher rates of resolution with delivery via the LGI tract (93.6 %) compared to UGI tract (76.4 %) [20]. A more recent systematic review of CDI cases showed a trend towards better results with LGI tract delivery (91.4 %) compared to UGI tract delivery (82.3 %) although this did not reach statistical significance [21]. A recently completed, small, randomized trial comparing nasogastric and colonoscopic delivery methods in CDI showed no difference in efficacy [46] but larger trials are certainly needed. If UGI tract delivery does prove to be inferior, one reason may be a lack of stability/survival of donor microbiota in the highly acidic gastric environment. Most investigators have countered this potential problem by treating recipients receiving FMT via the stomach with proton pump inhibitors or delivering the solution post-pylorically. There may be theoretical problems with administering LGI tract flora from the donor into a UGI tract location in terms of engraftment although this has not been extensively studied. This has led some to recommend a bowel lavage for all recipients just before FMT, even for those receiving donor material via the UGI tract [45].

Colonoscopic delivery is more invasive and UGI tract delivery via naso-enteric tube, while somewhat less invasive, still has associated risks and may prove unpalatable for some patients. The logical next step is the encapsulation of donor fecal material into a pill form that can be taken orally to reduce these procedural risks.

Beyond CDI, little is known about the optimal delivery method for FMT, but it ultimately may depend on the location and other specifics of the condition being treated. Larger, randomized trials comparing delivery method are needed for both CDI and other diseases that might be treated with this therapy.

There are numerous ethical and regulatory issues surrounding the use of FMT in both the USA and abroad. Given the importance of the ethical, legal, and social issues (ELSIs) related to the microbiome research and technology, the National Institutes of Health (NIH) has specifically solicited research on this topic through the HMP [7]. Unfortunately, research in this area has been slow, and there have only been a few studies addressing the ethical and social issues related to fecal microbiota transplantation [31, 47–49].

The lag in ELSI research on FMT may in part stem from the lack of clarity regarding how FMT is classified. Clearly, it is a biologic substance, but there have been questions about whether or not the microbiome should be classified as an organ or a tissue and whether or not FMT is a drug [50]. In the USA, the FDA has taken an active role in establishing the status of FMT and overseeing it regulation. Although scientists in the field regard the microbiome as an organ [51], the FDA does not recognize stool and the microbiome it contains as an organ or a issue, but as a drug and a biologic product [50].

Most of the existing ELSI literature explores the social issues related to using stool as a drug and patient and physician perceptions of FMT. Early studies focused on whether patients and parents would be willing to consider or undergo FMT. Notwithstanding the obvious “yuck” factor associated with FMT, patient and their families were willing and even eager to consider FMT for both IBD and recurrent CDI [47–49]. More recently, investigators have confirmed that although not all physicians are comfortable performing FMT personally, the great majority are comfortable with FMT as a treatment for CDI and/or the creation of specialized centers where FMT can be performed [52].

Beyond physician and patient acceptance, there are numerous ethical issues related to FMT that have yet to be investigated. These ELSIs are outlined in Table 35.3.

The excitement over FMT and its potential applications has grown exponentially over the past few years. The success of FMT in CDI has spawned investigations into treatment optimization and also into other microbial-based therapeutics, with growing interest from clinicians, scientists, government health agencies, and commercial entities alike. Ongoing trials of FMT in pediatric diseases will provide much needed data about efficacy, safety, durability, and the long-term impact of FMT in young patients.