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Faecal microbiota transplantation: a review of FMT as an alternative treatment for Clostridium difficile infection

Faecal microbiota transplantation: a review of FMT as an alternative treatment for Clostridium... Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 BioscienceHorizons Volume 9 2016 10.1093/biohorizons/hzw007 .............................................. .................................................. .................................................. ............... Review article Faecal microbiota transplantation: a review of FMT as an alternative treatment for Clostridium difficile infection Chris Dowle Department of Biosciences, Swansea University, Singleton Park, Swansea SA2 8PP, UK *Corresponding author: Church House, Oxenhall, Newent, Gloucestershire GL18 1RN, UK. Email: chris.dowle@live.co.uk Supervisor: Dr Luca Börger, Department of Biosciences, Swansea University, Swansea, UK. .............................................. .................................................. .................................................. ............... Clostridium difficile infection (CDI) is the most common aetiology of hospital acquired infections, the leading cause of nosoco- mial diarrhoea and a significant clinical and economic burden. Recommended treatment for CDI is prescription of broad- spectrum antibiotics. Antibiotic treatment disrupts natural gut microbiota allowing C. difficile to colonize. Clostridium difficile is also resistant to antibiotics and may persist in the gastrointestinal tract for months causing recurrent disease. There is a pressing need for alternate therapies. Faecal microbiota transplantation (FMT) is a promising treatment option whereby healthy donor faecal samples are infused into a patient thus, theoretically, restoring normal bowel conditions. Until recently there has been a paucity of randomized controlled trials and reports of FMT efficacy have been limited to case studies and series. Here, a meta-analysis of 684 patients treated with FMT across 23 independent studies was conducted, reporting a mean resolution rate of 90.4%. Three RCTs are included that, although methodologically limited, appear to verify reports of high efficacy in case reports with minimal adverse effects. FMT appears to be a safe, highly efficacious and affordable treat- ment option. Future research should focus on potential long-term safety concerns and optimizing protocols for donor screening, patient selection and FMT administration. Key words: Clostridium difficile, diarrhoea, FMT, hospital-acquired infection, cross infection, microbiota Submitted on 20 July 2016; accepted on 20 July 2016 .............................................. .................................................. .................................................. ............... The clinical burden of CDI in Europe is also significant, high- Introduction lighted by a recent study of 34 European countries where the Clostridium difficile infection (CDI) is the most common aeti- reported mean rate of CDI was 4.1 per 10 000 patient-days ology of hospital acquired infections superseding methicillin- per hospital (Bauer et al., 2011). The Gram-positive bacter- resistant Staphylococcus aureus (MRSA) (Miller et al., 2011). ium exists in both a vegetative and spore form. In spore form, CDI, the leading cause of nosocomial diarrhoea, is respon- C. difficile is resistant to high temperatures, chemical treat- sible for significant morbidity and mortality. A United States ment, UV light and antibiotics (Heinlen and Ballard, 2010). Centers for Disease Control and Prevention (CDC) study esti- Spore resistance to antibiotics means that C. difficile can per- mated that during 2011, in the US alone, there were ~453 000 sist in the gastrointestinal (GI) tract after treatment potentially cases of CDI resulting in ~29 000 deaths (Lessa et al., 2015). contributing to recurrence of the infection (Johnson et al., The economic burden of CDI in the US is ~$4.8 billion per 1989). Presently, the FDA-approved drug of choice for mid- annum (Vonberg et al., 2008; Dubberke and Olsen, 2012). mild episodes of CDI is metronidazole, a nitroimidazole that ............................................................................................... .................................................................. © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. works against anaerobic bacteria (Cohen et al., 2010). The transmission of diseases such as norovirus (Schwartz et al., favoured drug for first case moderate-severe episodes or 2013). Despite this, there is still great variation within where previous metronidazole treatments have failed is a gly- screening protocols (Moayyedi et al., 2014), even after copeptide, vancomycin (Cohen et al., 2010). Between 2004 appeals for standardization (Bakken et al., 2011; Allen- and 2007, treatment failures of metronidazole increased by Vercoe et al., 2012). The main gap within the literature, until 16–38%, vancomycin failures remained between 1% and 6% recently, was randomized controlled trials (RCTs), needed (Zar et al., 2007). to confirm the efficacy, safety and optimal protocols of FMT. The first RCT was conducted by van Nood et al. Intestinal microflora defends itself from harmful microor- (2013) and more recently RCTs have been conducted by ganisms by a mechanism known as colonization resistance Youngster et al. (2014) and Cammarota et al. (2015). (Wilson, 2005). For example, Bacteroides thuringiensis DPC Despite growing excitement surrounding FMT, there is little 6431—a bacterial strain isolated from human faeces— literature addressing concerns of potential long-term safety produces a bacteriocin (Thuricin CD) that directly targets such as the onset of obesity (Alang and Kelly, 2015), or our C. difficile and consequently prevents C. difficile from infect- relative lack of knowledge about human microbiome inter- ing the host (Rea et al., 2010). Antimicrobial treatments dis- actions despite recent advances (Kamada et al., 2013). rupt colonization resistance thus creating favourable conditions for the successful colonization of C. difficile (Olson et al., 1994; Owens et al., 2008). Transmission rates Synthesis are likely to increase as carrier patients contaminate their environment, in turn increasing the risk of successful C. diffi- FMT delivery procedure cile colonization in susceptible patients such as the immuno- compromised (Owens et al., 2008). CDI is now a recognized Due to the relative lack of RCTs, there is presently no agree- risk associated with any antimicrobial treatments (e.g. ment on the most effective transplantation route. Resolution Clindamycin (Pear et al., 1994; Johnson et al., 1999; Gerding, of CDI has been achieved using colonoscopy (Borody et al., 2004); Cephalosporins (Johnson et al., 1999; Gerding, 2004); 2003; Keller et al., 2009; Arkkila et al., 2010; Garborg et al., Fluoroquinolones (McCusker et al., 2003; Gaynes et al., 2010; Rohlke et al., 2010; Yoon and Brandt, 2010; Wilcox, 2004; Loo et al., 2005)). Global antibiotic consumption 2011; Brandt et al., 2012; Hamilton et al., 2012; Kelly et al., increased by 36% from 2000 to 2010 with significant 2012; Matilla et al., 2012; Kelly et al., 2014; Cammarota increases in Brazil, China, India, South Africa and Russia et al., 2015), rectal enemas (Paterson et al., 1994; Borody (Van Boeckel et al., 2014). In the US, prescription rates of et al., 2003; Silverman et al., 2010; Kassam et al., 2012), broad spectrum antibiotics increased two-fold during the nasogastric tubes (Aas et al., 2003; Macconnachie et al., same time frame (Lee et al., 2014). With widespread reports 2009; Rubin et al., 2013), nasojejunal tubes (Borody et al., of antimicrobial resistance, increasing burdens on healthcare 2003; Keller et al., 2009), nasoduodenal tubes (van Nood systems and rapidly evolving strains of C. difficile associated et al., 2013), orally administered frozen capsules (Youngster with increased virulence and epidemic infection rates (Loo et al., 2014) and gastroscopy (Garborg et al., 2010) (Table 1). et al., 2005), there is a pressing need for alternative therapies. Postigo and Kim (2012) found no significant difference The aim of faecal microbiota transplantation (FMT) is in efficacy between colonoscopy and nasogastric deliveries. simple; to counteract the susceptibility to infection of micro- However, there may have been sample selection bias in the bial flora in the gut caused by antibiotics, which allows the data collected for this meta-analysis. Since FMT is not the pathogenesis of CDI, by reinstating natural microbial col- standard treatment for recurrent CDI, the small homogen- onies in the patient by faecal transplantation from a healthy ous population of patients receiving FMT may have intro- donor. Faeces from a healthy donor is introduced thus, the- duced an unavoidable sample selection bias into the original oretically, restoring normal bowel conditions (i.e. reso- papers used in this analysis. Furthermore, by limiting their lution, indicated by (i) C. difficile negative stool assays and/ searches to English-language publications the results cannot or (ii) relief of diarrhoea). Using orally administered stool be generalized to the wider population of reported CDI for diarrhoea treatment can be traced back to fourth century cases treated with FMT. The meta-analysis was also fairly China (Zhang et al., 2012). The first example of FMT via small and only included 12 studies with a total of 182 enema for treatment of pseudomembranous colitis was patients, 148 of whom received colonoscopy treatment. describedin1958(Eiseman et al., 1958). FMT was first used There are also pathophysiological differences between stool for CDI treatment in 1983 where the patient presented infusion via nasogastric tubes and colonoscopy or enema immediate resolution and was asymptomatic at the 9-month (Kassam et al., 2013). Nasogastric delivery has potential for follow-up (Schwan et al., 1984). With reports of resolution bacterial overgrowth in achlorhydric individuals (Yoon and rates of ~90%, FMT has recently surged in popularity both Brandt, 2010) but the impacts of this on the GI tract are not within the literature and the public eye (Gough et al., 2011; well documented (Guo et al., 2012). Alternatively, rectal Kassam et al., 2013; Sha et al., 2014). Screening processes enemas are both safe and cheap but it is not known if prox- for donors are rigorous in order to prevent the transmission imal colonization can be achieved by rectal repopulation of of communicable diseases but concerns remain about the the microflora (Kassam et al.,2013). The reduced tone of ............................................................................................... .................................................................. 2 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. Table 1. Summary of FMT in CDI treatment across 22 studies Reference Sample Age FMT route Resolution Adverse effects? size (range) rate (%) Aas et al., 2003 18 73 (51–88) Nasogastric 94 None Arkkila et al., 2010 37 69 (24–90) Colonoscopy 92 None Borody et al., 2003 24 (19–59) Colonoscopy/rectal enema/ 83 Some transient nasojejunal tube Brandt et al., 2012 77 65 (22–87) Colonoscopy 91 One unresponsive patient was not further treated and died of an unclear cause 4 1 Cammarota et al., 2015 20 71 (29–89) Colonoscopy 90 None Faust et al., 2002 653 (37–74) Unknown 100 None Garborg et al., 2010 40 75 (53–94) Gastroscopy (38) or 83 None colonoscopy (2) Hamilton et al., 2012 43 65 Colonoscopy 86 Some patients reported irregular bowel movements and flatulence lasting ~2 weeks Jorup-Ronstrom et al., 22 75 (27–94) Colonoscopy and enema 69 None Kassam et al., 2012 27 69 (26–87) Enema 93 None Keller et al., 2009 11 NR Colonoscopy/ nasojejunal 100 None tube Kelly et al., 2012 26 59 (19–86) Colonoscopy 92 None Kelly et al., 2014 80 NR NR 89 Few Macconnachie et al., 2009 15 82 (68–95) Nasogastric 73 None Matilla et al., 2012 70 73 (22–90) Colonoscopy 94 None Paterson et al., 1994 656 (30–80) Enema 100 None Rohlke et al., 2010 19 49 (32–82) Colonoscopy 100 None Rubin et al., 2013 74 63 (6–94) Nasogastric 80 None Silverman et al., 2010 765 (30–88) Self-administered enema 100 None 6 1 van Nood et al., 2013 17 73 Nasoduodenal tube 81 Some transient Wilcox, 2011 13 69 (27–93) Colonoscopy 100 None Yoon and Brandt, 2010 12 66 (30–86) Colonoscopy 100 None 4 2 Youngster et al., 2014 20 65 (11–89) Orally administered frozen 90 None FMT capsules Average resolution 90.42 rate (%) Donor relation, follow-up periods and additional comments provided in Table A1 (Appendix). NR = not reported. Mean age. Median age. Seven patients in this study had associated irritable bowel syndrome (IBS). RCT. All patients in this study were immunocompromised. This is the first RCT of FMT. ............................................................................................... .................................................................. 3 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. rectal sphincters in elderly patients may also reduce the abdominal pain) all of which resolved after 2–3 weeks chances of faecal infusion retention and hence reduce treat- (Hamilton et al. 2012; Kelly et al., 2014). Brandt et al. (2012) ment efficacy (Kassam et al., 2012). Colonoscopy is an reported that one patient who was unresponsive to the treat- attractive option, not least because it is able to deliver large ment was not further treated and died in a care home of an volume FMT along the entire colon. Nevertheless, the pro- unclear cause. Kelly et al. (2014) used FMT to treat CDI in cedure is less safe than rectal enemas with an increased risk immunocompromised patients. Of the 80 patients treated, 12 of perforation (Kassam et al., 2013)oraspiration(Kelly presented with serious adverse effects (death or hospitaliza- et al.,2014). Colonoscopy is also more expensive and time tion) ≤12 weeks post FMT. Ten were hospitalized. Two consuming. Procedure costs and safety of any FMT treat- deaths occurred, one as a result of aspiration during the col- ment should be carefully considered. onoscopy and one unrelated death. No patients suffered infec- tions directly related to FMT. Three patients reported mild bowel discomfort and five irritable bowel disease (IBD) Patient selection patients experienced disease flare post-FMT. Although this study did not report any adverse effects in relation to the There are no official guidelines for criteria that patients must infusion of faecal material there was a complication with the meet to be deemed eligible for FMT, but guidelines for clinical colonoscopy in one patient. Aside from the surgical complica- testing have been put forward by the Faecal Microbiota tion, this study showed promise for the treatment of immuno- Transplantation Workgroup (Bakken et al., 2011). These compromised patients with FMT. The sample size of 80 was guidelines propose selection criteria for both patients and the largest of the studies reviewed here. To confirm their donors. Patients must display recurrent or relapsing CDI with results there is a need for a well-designed RCT that includes (i) at least three episodes of mild-to-moderate CDI and treat- immunocompromised patients. A review by Kassam et al. ment failure of a minimum 6-week course of vancomycin, or (ii) (2013) postulated that there may be a relationship between a minimum of two severe (requiring hospitalization) episodes of FMT via nasogastric or nasojejunal tube and increased risk of CDI; be unresponsive to standard therapy for ≥1 week during complications such as upper GI bleeding, enteritis and peri- moderate CDI, or a severe infection with no response to stand- tonitis. There are also case reports concerning the transmis- ard treatment after 48 h (Bakken et al., 2011). sion of norovirus following FMT (Schwartz, Gluck, Koon, 2013). Although transmission was found not to be related to Donor screening FMT, the study highlighted concerns about screening protocols. A major risk associated with FMT is the potential transmis- sion of infectious diseases. Accordingly, screening processes Limitations of case reports of potential donors are rigorous (Bakken et al., 2011). Serology tests of blood samples from potential donors screen Literature detailing clinical use and results of FMT is, at pre- for HIV types 1 and 2, syphilis and hepatitis A, B and C sent, almost exclusively limited to case studies and reports. In viruses. Stool is screened for C. difficile toxins, parasites and this review, 20/23 (87%) articles reviewed are case series or other enteric pathogens (e.g. Giardia, Cryptosporidium, reports. Case reports cannot be used to generate information Isospora and Rotavirus), and Helicobacter pylori (Bakken on rates or ratios of treatment success due to the lack of et al., 2011). Donor selection is then a process of elimination cause-and-effect relationships and representative population based around specific exclusion criteria (Table 2). A recent samples. However, case series can be used to further study by Hamilton et al. (2012) described a standardised strengthen arguments for cause-and-effect relationships and method for the preparation and use of frozen stool samples. indeed generate hypotheses. A major publication bias in FMT Of particular interest was the fact that samples appeared to treatment trials may exist, with only the case reports and ser- retain their efficacy against CDI despite being cryopreserved. ies reporting positive results reaching publication (Albrecht The implications of this include use of universal donors who et al., 2005). Another limitation of case reports/series is that will reduce costs associated with screening process for mul- they are written retrospectively. This can lead to an absence tiple patients (Borody and Khoruts, 2012). Frozen samples of relevant medical data which was not recorded at the time. have since been used in an RCT comparing the efficacy of col- Furthermore, the experiments have no repeatability, it is onoscopy and nasogastric tubes for FMT (Youngster et al., impossible to recreate duplicate situations. Experiments or 2014). observations under similar settings and circumstances can be amalgamated to form a case series. The inherent selection bias Safety introduced in case studies/reports can be minimized by con- ducting RCTs. Adverse effects of FMT are low (Table 1), indicating that FMT is a safe procedure. However, no studies have sought Randomized controlled trials adverse effects (Moayyedi et al., 2014). Within the studies reviewed, 18 (78%) reported no adverse effects at all. Of the The first RCT conducted by van Nood et al. (2013) repre- five studies that reported adverse effects, three were mild tran- sented an important step towards determining the efficacy of sient effects (e.g. flatulence, irregular bowel movements and FMT. Patients were randomly assigned to have treatment for ............................................................................................... .................................................................. 4 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. Table 2. Exclusion criteria guidelines for stool donors Exclusion criteria Reference Positive test results for: HIV type 1 or 2, syphilis or hepatitis A, B or C Bakken et al., 2011 Stool assays positive for: C. difficile toxins, enteric bacterial pathogens or parasites Positive results for any communicable disease History of chronic diarrhoea, constipation, IBD, IBS, colorectal polyps or cancer, morbid obesity, atopy, metabolic syndrome, CFS Immunocompromised patients Historical intravenous drug abuse, high-risk sexual activity, tattoo or incarceration, within the past 6 months History of malignancy (excluding non-melanoma skin cancer) Antibiotic use within 3 months Atopic diseases including eczema, asthma or eosinophilic disorders of the GI tract Major GI surgery Matilla et al., 2012 Systemic auto-immune diseases Bakken et al., 2011 IBD, irritable bowel disease; IBS, irritable bowel syndrome; CFS, chronic fatigue syndrome. CDI by infusion of faeces via a duodenal tube (17 patients), 2015). Firstly, if the drug in question is not prescribed for vancomycin (13), or vancomycin and bowel lavage (13). They administration via a feeding tube then administration of the demonstrated a resolution rate of 81% in the FMT group drug via this route falls outside of the product licence. This compared to a resolution rate of 31% for those receiving just means that the manufacturers are no longer accountable for vancomycin. There was no significant difference between the any adverse effects of the drug and the administering phys- vancomycin with bowel lavage and the vancomycin-only ician assumes liability. Other concerns arise when considering treatment groups suggesting that bowel lavage alone does not the risk of drug errors linked with feeding tube administration play a significant role in the resolution of CDI. The study was of drugs via intravenous syringes; unsuitable drug formula- cut short by interim analysis based on the overwhelming dif- tions causing blockages of feeding tubes; shared use of tablet ference between treatments and the success of FMT. There crushing tools increasing risk of cross-contamination; and are several limitations associated with the study. Firstly, the inappropriate handling of drug powders leading to occupa- study was non-blinded. Although RCTs remove the selection tional exposure (White and Bradnam, 2015). In order to pro- bias of case studies if they are non-blinded they do not prevent ceed with this suggested study format, careful consideration differing treatment of study groups such as biased assessment would have to be given to the potential consequences, both and differential co-interventions (Karanicolas et al., 2010). legal and professional, of administering vancomycin via the Furthermore, treatment of patients by clinicians may differ feeding tube. This would include consultation with pharma- between blinded and non-blinded trials (Schulz and Grimes, cists, drug manufacturers, patients, relatives and other health- 2002). Bias may also factor into data collection, outcome care professionals. Protocols of how to administer adjudicators and statistical analyses (Karanicolas et al., vancomycin via this route are provided in the Handbook of 2010). Drug Administration via Enteral Feeding Tubes (White and Bradnam, 2015). The small sample size of 17 patients receiv- One way to potentially overcome the issue of blinding in ing the study treatment is another major limitation. this study may be to administer the vancomycin via the naso- duodenal tube. Administering the treatments in the same way Youngster et al. (2014) inoculated patients with faecal could blind the study physicians as to which patients were material that had been previously frozen. This was the first receiving FMT and which were receiving vancomycin. In RCT to compare treatment routes (nasogastric tube versus col- order to prevent vancomycin treatment being identified in the onoscopy) and to use frozen inoculate. They found that both third treatment arm by the administration of bowel lavage, it treatment routes were equally effective. Like van Nood et al. may be prudent to introduce a fourth treatment arm in which (2013), this was a non-blinded trial with a small sample size patients receiving faecal infusions also receive bowel lavage. (20) thus suffering the same limitations. However, this was However, this alternative methodology brings new limitations another important step in the literature which showed that as the administration of medication via enteral feeding tubes cryopreserved faecal samples retain their efficacy. This may is complicated by a number of issues (White and Bradnam, have far-reaching implications for collection, storage and use of ............................................................................................... .................................................................. 5 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. donor stool samples. Cammarota et al. (2015) followed a simi- (range 6–80). Of the 23 articles reviewed, three were RCTs lar study design to van Nood et al. (2013). They randomized (van Nood et al., 2013; Youngster et al., 2014; Cammarota treatment arms of FMT or vancomycin between 39 patients, 20 et al., 2015). These studies are significant as they are the first and 19, respectively. The FMT treatment arm had a resolution representation of the potential efficacy of FMT as a treatment rate of 90% compared with 26% in the vancomycin treatment option for CDI. Many previous reviews have previously high- group. This study was also non-blinded and shares the asso- lighted the absence or paucity of RCTs in the literature ciated limitations of this with the two other RCTs. (Brandt et al., 2012; Kassam et al., 2013; Moayyedi et al., 2014; Sha et al., 2014). The most common procedure used, Small sample sizes within the current RCTs limit general- colonoscopy (14), was used exclusively in 10 studies. Enemas ization of results to wider populations. Equally, non-blinded were used in five studies, exclusively in three, of which self- study designs pose significant limitations; however, recurrent administered enemas were used in one (Silverman et al., CDI presents a clinical challenge for which blinded studies 2010). Nasogastric tubes were used exclusively in three stud- may not be practicable even if they are desirable (Cammarota ies. Nasojejunal tubes (2), nasoduodenal tubes (1), orally et al., 2015). Despite this, the results of these studies can pro- administered tablets (1) and gastroscopy (1) were also used. vide cautious optimism for the future of FMT. All three stud- Faust et al. (2002) did not report an FMT route. Follow-up ies showed FMT to have high efficacy across varying periods ranged from 60 days to 5 years and were not reported treatment routes and, importantly, superior efficacy to the in four studies. currently ubiquitous antibiotic treatments. Furthermore, there is promising signs for the use of cryopreserved faecal samples In the 23 studies reviewed, there were numerous combina- (Youngster et al., 2014) and solid foundations for further tions of stool donors (Table A1, Appendix). Family and rela- studies to build on these results and test their reliability. tives were used as donors in 16 studies. Spouses/intimate partners were the donors in six studies. Unrelated healthy donors provided stool in eight studies. One donor was a mem- Long-term concerns ber of the clinic staff (Aas et al., 2003). Close friends (4), and One danger with the shortage of well-designed RCTs is the ten- household members (2) also provided stool. Donor relation to dency for people to draw conclusions too rapidly. While the the patient was not reported in two studies (Keller et al., average resolution rate appears to be around 90% (Kassam 2009; Kelly et al., 2014 (abstract only)). et al.,2013; Sha et al.,2014) there are currently no RCTs that have monitored long-term effects of FMT. Obesity and meta- Conclusions bolic syndrome are two examples of conditions in which the microbiome plays a part (Tsai and Coyle, 2009; Nicholson FMT for the treatment of CDI appears to be highly efficacious et al.,2012). A recent case study documented a 32-year-old (90.42%) regardless of the infusion route. This is consistent woman who developed new-onset obesity following successful with the findings of other reviews (Kassam et al.,2013; Sha FMT treatment for CDI (Alang and Kelly, 2015). This was et al.,2014). In most of the studies reviewed (14/23) clini- noteworthy as she had no history of obesity and the donor also cians appear to favour colonoscopy, although a recent RCT experienced notable weight gain, leading the authors to showed that colonoscopy and nasogastric infusion were hypothesize that obesity onset was related to FMT, something equally effective (Youngster et al., 2014). Clear guidelines which is supported by animal models (Ridaura et al.,2013). for practitioners to follow in terms of donor selection are No comparable data from microbiome sequencing of the required. At present too much variation within the selection patient and donor exists. This is an important limitation to this procedures may lead to the omission of certain screening case study as cause and effect cannot be proven. Other theoret- tests and the potentially life-threatening transmission of ical long-term problems associated with FMT need to be inves- infectious diseases, such as norovirus (Schwartz et al., tigated. Some specialists already err on the side of caution 2013). This is of particular concern in the treatment of rejecting donors with high body mass indexes or a history of immunocompromised patients. Hamilton et al. (2012) colon cancer (Leading, 2014). described a standardized method for the preparation and use of frozen samples for FMT while retaining the efficacy of the treatment. These findings were supported in an RCT Meta-analysis (Youngster et al., 2014). Benefits of using frozen samples Twenty-five articles were identified for review. Of these, 23 include: reduced screening costs through use of universal articles were included in the analysis composed of journal donors, and improved storage, ease of access and transpor- articles (78%) and abstracts (22%). Two articles were tation of samples between hospitals. inaccessible online and the authors were unavailable when Although there are numerous case studies highlighting the contacted. Only studies with a minimum of 5 patients receiv- short-term success of FMT, long-term safety concerns still need ing FMT were included. In total, 684 patients were treated to be addressed. Our knowledge of human microbiome interac- with FMT for CDI across 23 studies with a mean resolution tions is still in its infancy (Kamada et al., 2013); there may rate of 90.42% (Fig. 1; Table 1). These results are in line with be unexpected long-term complications following FMT, such other reviews (Kassam et al., 2013 (89.7%); Sha et al., 2014 as obesity (Alang and Kelly, 2015), whichneedtobefurther (90.7%)). The mean sample size for included studies was 30 ............................................................................................... .................................................................. 6 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. Figure 1. Percentage resolution of CDI following FMT in 23 studies. Dotted line = mean resolution rate (90.42%). studied. These potential complications should be carefully con- made to make these trials blinded, although this may be imprac- sidered before use of FMT to treat children and young adults. tical. FMT remains a highly promising treatment option that Despite the multitude of reports demonstrating the high efficacy appears to be efficacious, safe in the short-term and affordable. of FMT, it is yet to become a treatment option available to many patients. Clinicians are rightly cautious to offer FMT as an Author biography option due to the shortage of RCTs. However, this has led to reports of well-meaning relatives offering stool samples for Chris graduated from Swansea University in 2015 with a First uncontrolled, self-administered enemas after seeking advice Class Honours BSc in Biology and a departmental award for online (Brandt, 2013; Youngster et al., 2014). This is dangerous his final year research project. This literature review was sub- in many regards, not least that the stool samples are unscreened. mitted as part of Chris’s final year as an undergraduate. Patients treating themselves in this manner are likely to lack Having always had a strong interest in the practical applica- understanding of the potential adverse effects and risks asso- tions of science for patient care, Chris is hoping to pursue a ciated with FMT (Brandt, 2013). There is a paucity of literature career in medicine by gaining acceptance to a graduate entry directly comparing multiple routes of FMT and their efficacy; medicine course and is currently working as a healthcare more RCTs are required in order to find the optimal procedure. assistant in a neurological centre. There is some evidence that treatment routes do not differ signifi- cantly (Postigo and Kim, 2012; Youngster et al., 2014), but FMT route should be based on individual patient situations Acknowledgements (Owens et al., 2013). Future research should continue to focus on long-term effects of FMT and designing robust RCTs with I would like to thank Dr Luca Börger for his help and feed- larger sample sizes to test the efficacy of FMT. Efforts should be back on this paper. ............................................................................................... .................................................................. 7 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. and Hospital Epidemiology: the Official Journal of the Society of References Hospital Epidemiologists of America, 31, 431–455. Aas, J., Gessert, C. E. and Bakken, J. S. (2003) Recurrent Clostridium diffi- Dubberke, E. R. and Olsen, M. A. 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(2012) Fecal trans- case series, Anaerobe, 19, 22–26. plantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile Infection, Gastroenterology, 142, 490–496. Schulz, K. F. and Grimes, D. A. (2002) Blinding in randomised trials: hid- ing who got what, Lancet, 359, 696–700. McCusker, M. E., Harris, A. D., Perencevich, E. et al. (2003) Fluoroquinolone use and Clostridium difficile-associated diarrhea, Schwan, A., Sjolin, S., Trottestam, U. et al. (1984) Relapsing Clostridium Emerging Infectious Diseases, 9, 730–733. difficile enterocolitis cured by rectal infusion of normal faeces, Scandinavian Journal of Infectious Diseases, 16, 211–215. Miller, B. A., Chen, L. F., Sexton, D. J. et al. (2011) Comparison of the bur- dens of hospital-onset, healthcare facility-associated Clostridium dif- Schwartz, M., Gluck, M. and Koon, S. (2013) Norovirus gastroenteritis ficile infection and of healthcare-associated infection due to after fecal microbiota transplantation for treatment of methicillin-resistant Staphylococcus aureus in community hospitals, Clostridiumdifficile Infection despite asymptomatic donors and Infection Control and Hospital Epidemiology: the Official Journal of lack of sick contacts, The American Journal of Gastroenterology, the Society of Hospital Epidemiologists of America, 32, 387–390. 108, 1367–1367. ............................................................................................... .................................................................. 9 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. Sha, S., Liang, J., Chen, M. et al. (2014) Systematic review: faecal micro- Wilcox, G. M. (2011) Early experience with a fecal bateriotherapy biota transplantation therapy for digestive and nondigestive (FB) program for recurrent and C. difficile infection (CDI), disorders in adults and children, Alimentary Pharmacology & Gastroenterology, 140 (Suppl), S361. Therapeutics, 39, 1003–1032. Wilson, M. (2005) Microbial Inhabitants of Humans: their Ecology Silverman, M. S., Davis, I. and Pillai, D. R. (2010) Success of self- and Role in Health and Disease, Cambridge University Press, administered home fecal transplantation for chronic Clostridium dif- Cambridge. ficile Infection, Clinical Gastroenterology and Hepatology: the Official Yoon, S. S. and Brandt, L. J. (2010) Treatment of refractory/recurrent C. Clinical Practice Journal of the American Gastroenterological difficile-associated disease by donated stool transplanted via colon- Association, 8, 471–473. oscopy: a case series of 12 patients, Journal of Clinical Tsai, F. and Coyle, W. J. (2009) The microbiome and obesity: Is obesity Gastroenterology, 44, 562–566. linked to our gut flora? Current Gastroenterology Reports, 11, 307–313. Youngster, I., Sauk, J., Pindar, C. et al. (2014) Fecal Microbiota Van Boeckel, T. P., Gandra, S., Ashok, A. et al. (2014) Global Transplant for relapsing Clostridium difficile infection using a frozen antibiotic consumption 2000 to 2010: an analysis of national inoculum from unrelated donors: a randomized, open-label, con- pharmaceutical sales data, The Lancet Infectious Diseases, 14, trolled pilot study, Clinical Infectious Diseases : an Official Publication 742–750. of the Infectious Diseases Society of America, 58, 1515–1522. van Nood, E., Vrieze, A., Nieuwdorp, M. et al. (2013) Duodenal infusion Zar, F. A., Bakkanagari, S. R., Moorthi, K. M. L. S. T. et al. (2007) A com- of donor feces for recurrent Clostridium difficile, The New England parison of vancomycin and metronidazole for the treatment of Journal Medicine, 368, 407–415. Clostridium difficile-associated diarrhea, stratified by disease sever- ity, Clinical Infectious Diseases: an Official Publication of the Infectious Vonberg, R. P., Reichardt, C., Behnke, M. et al. (2008) Costs of nosoco- Diseases Society of America, 45, 302–307. mial Clostridium difficile-associated diarrhoea, The Journal of Hospital Infection, 70, 15–20. Zhang, D., Luo, W., Shi, Y. et al. (2012) Should we standardize the 1,700- year-old fecal microbiota transplantation? The American Journal of White, R. and Bradnam, V. (2015) Handbook of Drug Administration via Gastroenterology, 107, 1755–1755. Enteral Feeding Tubes, 3rd edn, Pharmaceutical Press, London. ............................................................................................... .................................................................. 10 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. ............................................................................................... .................................................................. Appendix Table A1. Summary table of studies included in the review Reference Sample Mean or FMT route Donor relation Resolution Follow-up Adverse effects? Comments size median rate (%) period age (range) Youngster 20 65 (11–89) Orally Unrelated 90 6 months None et al., 2014 administered volunteer frozen FMT donors capsules Aas et al., 2003 18 73 (51–88) Nasogastric Family members 94 90 days None Two patients died before and clinic staff post-treatment stool sample could be collected. One patient suffered clinical relapse with resolution after a single course of vancomycin Arkkila et al., 2010 37 69 (24–90) Colonoscopy Relatives (30/37), 92 5–12 months None Two patients relapsed after unrelated receiving new antibiotic donors (7/37) treatments, repeated the transplantation and had full resolution. One non- cured patient died one month after FMT of toxic megacolon—unrelated to FMT Borody et al., 2003 24 (7/ (19–59) Colonoscopy/ Family members 83 4–69 weeks Some transient 2/24 reported no change in 24 rectal enema/ and unrelated symptoms, one of which had nasojejunal donors from had a recurrent infection. IBS) tube PTRC Donor 4/7 patients with IBS bank were all Cd negative and experienced at least minimal improvements in symptoms Brandt et al., 2012 77 65 (22–87) Colonoscopy Family members 91 90 days One unresponsive Secondary cure rate was (65), friends (9), patient was not 98% relatives (2), further treated unknown donor and died of an (1) unclear cause Continued Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. ............................................................................................... .................................................................. Table A1. Continued Reference Sample Mean or FMT route Donor relation Resolution Follow-up Adverse effects? Comments size median rate (%) period age (range) Cammarota 20 71 (29–89) Colonoscopy Relatives and 90 12 months None et al., 2015 partners Faust et al., 2002 6 53 (37–74) Unknown Direct family 100 9 and 50 None members months Garborg 40 75 (53–94) Gastroscopy (38) Close relatives 83 80 days None 6/11 patients who did not et al., 2010 or respond to first treatment colonoscopy repeated the procedure. (2) 4/6 had resolution. 5/7 unresponsive to treatment were seriously ill from long lasting diarrhoeal disease and co-morbidity and died <80 days after procedure. Two were believed to have IBD Hamilton 43 65 (NR) Colonoscopy Spouses, direct 86 2 months Some patients Secondary cure rate was et al., 2012 relatives, and reported 95% friends irregular bowel movements and flatulence for a couple of weeks which resolved. Jorup-Ronstrom 22 75 (27–94) Colonoscopy and One unrelated 69 1–68 mo None 6/32 patients failed to et al., 2012 enema donor Median 26 respond to treatment. months This was the first study where a culture of faecal microbes has been re- cultivated for years (10) and retained the possibility to cure patients with CDI Kassam et al., 2012 27 69 (26–87) Enema Two unrelated 93 427 days None donors (average) Keller et al., 2009 11 NR Colonoscopy/ NR 100 NR None nasojejunal tube Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. ............................................................................................... .................................................................. Kelly et al., 2012 26 59 (19–86) Colonoscopy Family member or 92 2–30 months None One patient became partner reinfected 11 months post-FMT after a course of cephalexin. Another had diarrhoea 2 months post-FMT and had 1 week of vancomycin with no relapse (did not have stool tested for Cd before this). Kelly et al., 2014 80 NR NR 89 12 weeks Few All patients were immunocompromised. 12/80 had serious adverse effects <12 post FMT. Ten were hospitalized. Two deaths occurred, one as a result of aspiration during the colonoscopy and one unrelated death. No patients suffered infections directly related to FMT. Three patients reported mild bowel discomfort and five IMD patients experienced disease flare post FMT Macconnachie 15 82 (68–95) Nasogastric Relatives 73 8 and 24 None 4/15 relapsed. Two et al., 2009 months responded to a 10 -day course of metronidazole (previous ab courses had failed). One patient relapsed due to receiving insufficient donor stool, procedure was repeated and they were symptom free after 12 days. One patient relapsed after receiving broad spectrum antibiotics Continued Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. ............................................................................................... .................................................................. Table A1. Continued Reference Sample Mean or FMT route Donor relation Resolution Follow-up Adverse effects? Comments size median rate (%) period age (range) Matilla et al., 2012 70 73 (22–90) Colonoscopy Family, home 94 12 months None 4/70 patients had initial sharers, resolution then relapsed unknown after antibiotic causes for donors unrelated illnesses. Of these, two were successfully treated with FMT and the other two successfully treated with antibiotics. Ten patients died of unrelated illnesses during follow-up period Paterson 6 56 (30–80) Enema Spouse 100 NR None et al., 1994 Rohlke et al., 2010 19 49 (32–82) Colonoscopy Relatives, partners, 100 6 months–5 None Three patients were close friends years reinfected after a new antibiotic treatment between 6 months and 4 years after treatment Rubin et al., 2013 74 63 (6–94) Nasogastric Home sharers, 80 60 days None 16/75 patients relapsed. Of family these, nine cases were resolved after a single treatment of vancomycin Silverman 7 65 (30–88) Self- Relatives 100 14 months None et al., 2010 administered enema van Nood 16 73 Nasodeodunal Unrelated 81 10 weeks None et al., 2013 tube Wilcox, 2011 13 69 (27–93) Colonoscopy Family members 100 2–14 months None and close friends Yoon and Brandt, 12 66 (30–86) Colonoscopy Family members 100 NR None 2010 or partners Donor relation refers to the relationship between donor and recipient. NR = not reported, ‘Unknown’ is used where information was not available in data provided in the abstract. PTRC = Probiotic Therapy Research Centre, Australia. Additional comments are provided where deemed prudent. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BioScience Horizons Oxford University Press

Faecal microbiota transplantation: a review of FMT as an alternative treatment for Clostridium difficile infection

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Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 BioscienceHorizons Volume 9 2016 10.1093/biohorizons/hzw007 .............................................. .................................................. .................................................. ............... Review article Faecal microbiota transplantation: a review of FMT as an alternative treatment for Clostridium difficile infection Chris Dowle Department of Biosciences, Swansea University, Singleton Park, Swansea SA2 8PP, UK *Corresponding author: Church House, Oxenhall, Newent, Gloucestershire GL18 1RN, UK. Email: chris.dowle@live.co.uk Supervisor: Dr Luca Börger, Department of Biosciences, Swansea University, Swansea, UK. .............................................. .................................................. .................................................. ............... Clostridium difficile infection (CDI) is the most common aetiology of hospital acquired infections, the leading cause of nosoco- mial diarrhoea and a significant clinical and economic burden. Recommended treatment for CDI is prescription of broad- spectrum antibiotics. Antibiotic treatment disrupts natural gut microbiota allowing C. difficile to colonize. Clostridium difficile is also resistant to antibiotics and may persist in the gastrointestinal tract for months causing recurrent disease. There is a pressing need for alternate therapies. Faecal microbiota transplantation (FMT) is a promising treatment option whereby healthy donor faecal samples are infused into a patient thus, theoretically, restoring normal bowel conditions. Until recently there has been a paucity of randomized controlled trials and reports of FMT efficacy have been limited to case studies and series. Here, a meta-analysis of 684 patients treated with FMT across 23 independent studies was conducted, reporting a mean resolution rate of 90.4%. Three RCTs are included that, although methodologically limited, appear to verify reports of high efficacy in case reports with minimal adverse effects. FMT appears to be a safe, highly efficacious and affordable treat- ment option. Future research should focus on potential long-term safety concerns and optimizing protocols for donor screening, patient selection and FMT administration. Key words: Clostridium difficile, diarrhoea, FMT, hospital-acquired infection, cross infection, microbiota Submitted on 20 July 2016; accepted on 20 July 2016 .............................................. .................................................. .................................................. ............... The clinical burden of CDI in Europe is also significant, high- Introduction lighted by a recent study of 34 European countries where the Clostridium difficile infection (CDI) is the most common aeti- reported mean rate of CDI was 4.1 per 10 000 patient-days ology of hospital acquired infections superseding methicillin- per hospital (Bauer et al., 2011). The Gram-positive bacter- resistant Staphylococcus aureus (MRSA) (Miller et al., 2011). ium exists in both a vegetative and spore form. In spore form, CDI, the leading cause of nosocomial diarrhoea, is respon- C. difficile is resistant to high temperatures, chemical treat- sible for significant morbidity and mortality. A United States ment, UV light and antibiotics (Heinlen and Ballard, 2010). Centers for Disease Control and Prevention (CDC) study esti- Spore resistance to antibiotics means that C. difficile can per- mated that during 2011, in the US alone, there were ~453 000 sist in the gastrointestinal (GI) tract after treatment potentially cases of CDI resulting in ~29 000 deaths (Lessa et al., 2015). contributing to recurrence of the infection (Johnson et al., The economic burden of CDI in the US is ~$4.8 billion per 1989). Presently, the FDA-approved drug of choice for mid- annum (Vonberg et al., 2008; Dubberke and Olsen, 2012). mild episodes of CDI is metronidazole, a nitroimidazole that ............................................................................................... .................................................................. © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. works against anaerobic bacteria (Cohen et al., 2010). The transmission of diseases such as norovirus (Schwartz et al., favoured drug for first case moderate-severe episodes or 2013). Despite this, there is still great variation within where previous metronidazole treatments have failed is a gly- screening protocols (Moayyedi et al., 2014), even after copeptide, vancomycin (Cohen et al., 2010). Between 2004 appeals for standardization (Bakken et al., 2011; Allen- and 2007, treatment failures of metronidazole increased by Vercoe et al., 2012). The main gap within the literature, until 16–38%, vancomycin failures remained between 1% and 6% recently, was randomized controlled trials (RCTs), needed (Zar et al., 2007). to confirm the efficacy, safety and optimal protocols of FMT. The first RCT was conducted by van Nood et al. Intestinal microflora defends itself from harmful microor- (2013) and more recently RCTs have been conducted by ganisms by a mechanism known as colonization resistance Youngster et al. (2014) and Cammarota et al. (2015). (Wilson, 2005). For example, Bacteroides thuringiensis DPC Despite growing excitement surrounding FMT, there is little 6431—a bacterial strain isolated from human faeces— literature addressing concerns of potential long-term safety produces a bacteriocin (Thuricin CD) that directly targets such as the onset of obesity (Alang and Kelly, 2015), or our C. difficile and consequently prevents C. difficile from infect- relative lack of knowledge about human microbiome inter- ing the host (Rea et al., 2010). Antimicrobial treatments dis- actions despite recent advances (Kamada et al., 2013). rupt colonization resistance thus creating favourable conditions for the successful colonization of C. difficile (Olson et al., 1994; Owens et al., 2008). Transmission rates Synthesis are likely to increase as carrier patients contaminate their environment, in turn increasing the risk of successful C. diffi- FMT delivery procedure cile colonization in susceptible patients such as the immuno- compromised (Owens et al., 2008). CDI is now a recognized Due to the relative lack of RCTs, there is presently no agree- risk associated with any antimicrobial treatments (e.g. ment on the most effective transplantation route. Resolution Clindamycin (Pear et al., 1994; Johnson et al., 1999; Gerding, of CDI has been achieved using colonoscopy (Borody et al., 2004); Cephalosporins (Johnson et al., 1999; Gerding, 2004); 2003; Keller et al., 2009; Arkkila et al., 2010; Garborg et al., Fluoroquinolones (McCusker et al., 2003; Gaynes et al., 2010; Rohlke et al., 2010; Yoon and Brandt, 2010; Wilcox, 2004; Loo et al., 2005)). Global antibiotic consumption 2011; Brandt et al., 2012; Hamilton et al., 2012; Kelly et al., increased by 36% from 2000 to 2010 with significant 2012; Matilla et al., 2012; Kelly et al., 2014; Cammarota increases in Brazil, China, India, South Africa and Russia et al., 2015), rectal enemas (Paterson et al., 1994; Borody (Van Boeckel et al., 2014). In the US, prescription rates of et al., 2003; Silverman et al., 2010; Kassam et al., 2012), broad spectrum antibiotics increased two-fold during the nasogastric tubes (Aas et al., 2003; Macconnachie et al., same time frame (Lee et al., 2014). With widespread reports 2009; Rubin et al., 2013), nasojejunal tubes (Borody et al., of antimicrobial resistance, increasing burdens on healthcare 2003; Keller et al., 2009), nasoduodenal tubes (van Nood systems and rapidly evolving strains of C. difficile associated et al., 2013), orally administered frozen capsules (Youngster with increased virulence and epidemic infection rates (Loo et al., 2014) and gastroscopy (Garborg et al., 2010) (Table 1). et al., 2005), there is a pressing need for alternative therapies. Postigo and Kim (2012) found no significant difference The aim of faecal microbiota transplantation (FMT) is in efficacy between colonoscopy and nasogastric deliveries. simple; to counteract the susceptibility to infection of micro- However, there may have been sample selection bias in the bial flora in the gut caused by antibiotics, which allows the data collected for this meta-analysis. Since FMT is not the pathogenesis of CDI, by reinstating natural microbial col- standard treatment for recurrent CDI, the small homogen- onies in the patient by faecal transplantation from a healthy ous population of patients receiving FMT may have intro- donor. Faeces from a healthy donor is introduced thus, the- duced an unavoidable sample selection bias into the original oretically, restoring normal bowel conditions (i.e. reso- papers used in this analysis. Furthermore, by limiting their lution, indicated by (i) C. difficile negative stool assays and/ searches to English-language publications the results cannot or (ii) relief of diarrhoea). Using orally administered stool be generalized to the wider population of reported CDI for diarrhoea treatment can be traced back to fourth century cases treated with FMT. The meta-analysis was also fairly China (Zhang et al., 2012). The first example of FMT via small and only included 12 studies with a total of 182 enema for treatment of pseudomembranous colitis was patients, 148 of whom received colonoscopy treatment. describedin1958(Eiseman et al., 1958). FMT was first used There are also pathophysiological differences between stool for CDI treatment in 1983 where the patient presented infusion via nasogastric tubes and colonoscopy or enema immediate resolution and was asymptomatic at the 9-month (Kassam et al., 2013). Nasogastric delivery has potential for follow-up (Schwan et al., 1984). With reports of resolution bacterial overgrowth in achlorhydric individuals (Yoon and rates of ~90%, FMT has recently surged in popularity both Brandt, 2010) but the impacts of this on the GI tract are not within the literature and the public eye (Gough et al., 2011; well documented (Guo et al., 2012). Alternatively, rectal Kassam et al., 2013; Sha et al., 2014). Screening processes enemas are both safe and cheap but it is not known if prox- for donors are rigorous in order to prevent the transmission imal colonization can be achieved by rectal repopulation of of communicable diseases but concerns remain about the the microflora (Kassam et al.,2013). The reduced tone of ............................................................................................... .................................................................. 2 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. Table 1. Summary of FMT in CDI treatment across 22 studies Reference Sample Age FMT route Resolution Adverse effects? size (range) rate (%) Aas et al., 2003 18 73 (51–88) Nasogastric 94 None Arkkila et al., 2010 37 69 (24–90) Colonoscopy 92 None Borody et al., 2003 24 (19–59) Colonoscopy/rectal enema/ 83 Some transient nasojejunal tube Brandt et al., 2012 77 65 (22–87) Colonoscopy 91 One unresponsive patient was not further treated and died of an unclear cause 4 1 Cammarota et al., 2015 20 71 (29–89) Colonoscopy 90 None Faust et al., 2002 653 (37–74) Unknown 100 None Garborg et al., 2010 40 75 (53–94) Gastroscopy (38) or 83 None colonoscopy (2) Hamilton et al., 2012 43 65 Colonoscopy 86 Some patients reported irregular bowel movements and flatulence lasting ~2 weeks Jorup-Ronstrom et al., 22 75 (27–94) Colonoscopy and enema 69 None Kassam et al., 2012 27 69 (26–87) Enema 93 None Keller et al., 2009 11 NR Colonoscopy/ nasojejunal 100 None tube Kelly et al., 2012 26 59 (19–86) Colonoscopy 92 None Kelly et al., 2014 80 NR NR 89 Few Macconnachie et al., 2009 15 82 (68–95) Nasogastric 73 None Matilla et al., 2012 70 73 (22–90) Colonoscopy 94 None Paterson et al., 1994 656 (30–80) Enema 100 None Rohlke et al., 2010 19 49 (32–82) Colonoscopy 100 None Rubin et al., 2013 74 63 (6–94) Nasogastric 80 None Silverman et al., 2010 765 (30–88) Self-administered enema 100 None 6 1 van Nood et al., 2013 17 73 Nasoduodenal tube 81 Some transient Wilcox, 2011 13 69 (27–93) Colonoscopy 100 None Yoon and Brandt, 2010 12 66 (30–86) Colonoscopy 100 None 4 2 Youngster et al., 2014 20 65 (11–89) Orally administered frozen 90 None FMT capsules Average resolution 90.42 rate (%) Donor relation, follow-up periods and additional comments provided in Table A1 (Appendix). NR = not reported. Mean age. Median age. Seven patients in this study had associated irritable bowel syndrome (IBS). RCT. All patients in this study were immunocompromised. This is the first RCT of FMT. ............................................................................................... .................................................................. 3 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. rectal sphincters in elderly patients may also reduce the abdominal pain) all of which resolved after 2–3 weeks chances of faecal infusion retention and hence reduce treat- (Hamilton et al. 2012; Kelly et al., 2014). Brandt et al. (2012) ment efficacy (Kassam et al., 2012). Colonoscopy is an reported that one patient who was unresponsive to the treat- attractive option, not least because it is able to deliver large ment was not further treated and died in a care home of an volume FMT along the entire colon. Nevertheless, the pro- unclear cause. Kelly et al. (2014) used FMT to treat CDI in cedure is less safe than rectal enemas with an increased risk immunocompromised patients. Of the 80 patients treated, 12 of perforation (Kassam et al., 2013)oraspiration(Kelly presented with serious adverse effects (death or hospitaliza- et al.,2014). Colonoscopy is also more expensive and time tion) ≤12 weeks post FMT. Ten were hospitalized. Two consuming. Procedure costs and safety of any FMT treat- deaths occurred, one as a result of aspiration during the col- ment should be carefully considered. onoscopy and one unrelated death. No patients suffered infec- tions directly related to FMT. Three patients reported mild bowel discomfort and five irritable bowel disease (IBD) Patient selection patients experienced disease flare post-FMT. Although this study did not report any adverse effects in relation to the There are no official guidelines for criteria that patients must infusion of faecal material there was a complication with the meet to be deemed eligible for FMT, but guidelines for clinical colonoscopy in one patient. Aside from the surgical complica- testing have been put forward by the Faecal Microbiota tion, this study showed promise for the treatment of immuno- Transplantation Workgroup (Bakken et al., 2011). These compromised patients with FMT. The sample size of 80 was guidelines propose selection criteria for both patients and the largest of the studies reviewed here. To confirm their donors. Patients must display recurrent or relapsing CDI with results there is a need for a well-designed RCT that includes (i) at least three episodes of mild-to-moderate CDI and treat- immunocompromised patients. A review by Kassam et al. ment failure of a minimum 6-week course of vancomycin, or (ii) (2013) postulated that there may be a relationship between a minimum of two severe (requiring hospitalization) episodes of FMT via nasogastric or nasojejunal tube and increased risk of CDI; be unresponsive to standard therapy for ≥1 week during complications such as upper GI bleeding, enteritis and peri- moderate CDI, or a severe infection with no response to stand- tonitis. There are also case reports concerning the transmis- ard treatment after 48 h (Bakken et al., 2011). sion of norovirus following FMT (Schwartz, Gluck, Koon, 2013). Although transmission was found not to be related to Donor screening FMT, the study highlighted concerns about screening protocols. A major risk associated with FMT is the potential transmis- sion of infectious diseases. Accordingly, screening processes Limitations of case reports of potential donors are rigorous (Bakken et al., 2011). Serology tests of blood samples from potential donors screen Literature detailing clinical use and results of FMT is, at pre- for HIV types 1 and 2, syphilis and hepatitis A, B and C sent, almost exclusively limited to case studies and reports. In viruses. Stool is screened for C. difficile toxins, parasites and this review, 20/23 (87%) articles reviewed are case series or other enteric pathogens (e.g. Giardia, Cryptosporidium, reports. Case reports cannot be used to generate information Isospora and Rotavirus), and Helicobacter pylori (Bakken on rates or ratios of treatment success due to the lack of et al., 2011). Donor selection is then a process of elimination cause-and-effect relationships and representative population based around specific exclusion criteria (Table 2). A recent samples. However, case series can be used to further study by Hamilton et al. (2012) described a standardised strengthen arguments for cause-and-effect relationships and method for the preparation and use of frozen stool samples. indeed generate hypotheses. A major publication bias in FMT Of particular interest was the fact that samples appeared to treatment trials may exist, with only the case reports and ser- retain their efficacy against CDI despite being cryopreserved. ies reporting positive results reaching publication (Albrecht The implications of this include use of universal donors who et al., 2005). Another limitation of case reports/series is that will reduce costs associated with screening process for mul- they are written retrospectively. This can lead to an absence tiple patients (Borody and Khoruts, 2012). Frozen samples of relevant medical data which was not recorded at the time. have since been used in an RCT comparing the efficacy of col- Furthermore, the experiments have no repeatability, it is onoscopy and nasogastric tubes for FMT (Youngster et al., impossible to recreate duplicate situations. Experiments or 2014). observations under similar settings and circumstances can be amalgamated to form a case series. The inherent selection bias Safety introduced in case studies/reports can be minimized by con- ducting RCTs. Adverse effects of FMT are low (Table 1), indicating that FMT is a safe procedure. However, no studies have sought Randomized controlled trials adverse effects (Moayyedi et al., 2014). Within the studies reviewed, 18 (78%) reported no adverse effects at all. Of the The first RCT conducted by van Nood et al. (2013) repre- five studies that reported adverse effects, three were mild tran- sented an important step towards determining the efficacy of sient effects (e.g. flatulence, irregular bowel movements and FMT. Patients were randomly assigned to have treatment for ............................................................................................... .................................................................. 4 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. Table 2. Exclusion criteria guidelines for stool donors Exclusion criteria Reference Positive test results for: HIV type 1 or 2, syphilis or hepatitis A, B or C Bakken et al., 2011 Stool assays positive for: C. difficile toxins, enteric bacterial pathogens or parasites Positive results for any communicable disease History of chronic diarrhoea, constipation, IBD, IBS, colorectal polyps or cancer, morbid obesity, atopy, metabolic syndrome, CFS Immunocompromised patients Historical intravenous drug abuse, high-risk sexual activity, tattoo or incarceration, within the past 6 months History of malignancy (excluding non-melanoma skin cancer) Antibiotic use within 3 months Atopic diseases including eczema, asthma or eosinophilic disorders of the GI tract Major GI surgery Matilla et al., 2012 Systemic auto-immune diseases Bakken et al., 2011 IBD, irritable bowel disease; IBS, irritable bowel syndrome; CFS, chronic fatigue syndrome. CDI by infusion of faeces via a duodenal tube (17 patients), 2015). Firstly, if the drug in question is not prescribed for vancomycin (13), or vancomycin and bowel lavage (13). They administration via a feeding tube then administration of the demonstrated a resolution rate of 81% in the FMT group drug via this route falls outside of the product licence. This compared to a resolution rate of 31% for those receiving just means that the manufacturers are no longer accountable for vancomycin. There was no significant difference between the any adverse effects of the drug and the administering phys- vancomycin with bowel lavage and the vancomycin-only ician assumes liability. Other concerns arise when considering treatment groups suggesting that bowel lavage alone does not the risk of drug errors linked with feeding tube administration play a significant role in the resolution of CDI. The study was of drugs via intravenous syringes; unsuitable drug formula- cut short by interim analysis based on the overwhelming dif- tions causing blockages of feeding tubes; shared use of tablet ference between treatments and the success of FMT. There crushing tools increasing risk of cross-contamination; and are several limitations associated with the study. Firstly, the inappropriate handling of drug powders leading to occupa- study was non-blinded. Although RCTs remove the selection tional exposure (White and Bradnam, 2015). In order to pro- bias of case studies if they are non-blinded they do not prevent ceed with this suggested study format, careful consideration differing treatment of study groups such as biased assessment would have to be given to the potential consequences, both and differential co-interventions (Karanicolas et al., 2010). legal and professional, of administering vancomycin via the Furthermore, treatment of patients by clinicians may differ feeding tube. This would include consultation with pharma- between blinded and non-blinded trials (Schulz and Grimes, cists, drug manufacturers, patients, relatives and other health- 2002). Bias may also factor into data collection, outcome care professionals. Protocols of how to administer adjudicators and statistical analyses (Karanicolas et al., vancomycin via this route are provided in the Handbook of 2010). Drug Administration via Enteral Feeding Tubes (White and Bradnam, 2015). The small sample size of 17 patients receiv- One way to potentially overcome the issue of blinding in ing the study treatment is another major limitation. this study may be to administer the vancomycin via the naso- duodenal tube. Administering the treatments in the same way Youngster et al. (2014) inoculated patients with faecal could blind the study physicians as to which patients were material that had been previously frozen. This was the first receiving FMT and which were receiving vancomycin. In RCT to compare treatment routes (nasogastric tube versus col- order to prevent vancomycin treatment being identified in the onoscopy) and to use frozen inoculate. They found that both third treatment arm by the administration of bowel lavage, it treatment routes were equally effective. Like van Nood et al. may be prudent to introduce a fourth treatment arm in which (2013), this was a non-blinded trial with a small sample size patients receiving faecal infusions also receive bowel lavage. (20) thus suffering the same limitations. However, this was However, this alternative methodology brings new limitations another important step in the literature which showed that as the administration of medication via enteral feeding tubes cryopreserved faecal samples retain their efficacy. This may is complicated by a number of issues (White and Bradnam, have far-reaching implications for collection, storage and use of ............................................................................................... .................................................................. 5 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. donor stool samples. Cammarota et al. (2015) followed a simi- (range 6–80). Of the 23 articles reviewed, three were RCTs lar study design to van Nood et al. (2013). They randomized (van Nood et al., 2013; Youngster et al., 2014; Cammarota treatment arms of FMT or vancomycin between 39 patients, 20 et al., 2015). These studies are significant as they are the first and 19, respectively. The FMT treatment arm had a resolution representation of the potential efficacy of FMT as a treatment rate of 90% compared with 26% in the vancomycin treatment option for CDI. Many previous reviews have previously high- group. This study was also non-blinded and shares the asso- lighted the absence or paucity of RCTs in the literature ciated limitations of this with the two other RCTs. (Brandt et al., 2012; Kassam et al., 2013; Moayyedi et al., 2014; Sha et al., 2014). The most common procedure used, Small sample sizes within the current RCTs limit general- colonoscopy (14), was used exclusively in 10 studies. Enemas ization of results to wider populations. Equally, non-blinded were used in five studies, exclusively in three, of which self- study designs pose significant limitations; however, recurrent administered enemas were used in one (Silverman et al., CDI presents a clinical challenge for which blinded studies 2010). Nasogastric tubes were used exclusively in three stud- may not be practicable even if they are desirable (Cammarota ies. Nasojejunal tubes (2), nasoduodenal tubes (1), orally et al., 2015). Despite this, the results of these studies can pro- administered tablets (1) and gastroscopy (1) were also used. vide cautious optimism for the future of FMT. All three stud- Faust et al. (2002) did not report an FMT route. Follow-up ies showed FMT to have high efficacy across varying periods ranged from 60 days to 5 years and were not reported treatment routes and, importantly, superior efficacy to the in four studies. currently ubiquitous antibiotic treatments. Furthermore, there is promising signs for the use of cryopreserved faecal samples In the 23 studies reviewed, there were numerous combina- (Youngster et al., 2014) and solid foundations for further tions of stool donors (Table A1, Appendix). Family and rela- studies to build on these results and test their reliability. tives were used as donors in 16 studies. Spouses/intimate partners were the donors in six studies. Unrelated healthy donors provided stool in eight studies. One donor was a mem- Long-term concerns ber of the clinic staff (Aas et al., 2003). Close friends (4), and One danger with the shortage of well-designed RCTs is the ten- household members (2) also provided stool. Donor relation to dency for people to draw conclusions too rapidly. While the the patient was not reported in two studies (Keller et al., average resolution rate appears to be around 90% (Kassam 2009; Kelly et al., 2014 (abstract only)). et al.,2013; Sha et al.,2014) there are currently no RCTs that have monitored long-term effects of FMT. Obesity and meta- Conclusions bolic syndrome are two examples of conditions in which the microbiome plays a part (Tsai and Coyle, 2009; Nicholson FMT for the treatment of CDI appears to be highly efficacious et al.,2012). A recent case study documented a 32-year-old (90.42%) regardless of the infusion route. This is consistent woman who developed new-onset obesity following successful with the findings of other reviews (Kassam et al.,2013; Sha FMT treatment for CDI (Alang and Kelly, 2015). This was et al.,2014). In most of the studies reviewed (14/23) clini- noteworthy as she had no history of obesity and the donor also cians appear to favour colonoscopy, although a recent RCT experienced notable weight gain, leading the authors to showed that colonoscopy and nasogastric infusion were hypothesize that obesity onset was related to FMT, something equally effective (Youngster et al., 2014). Clear guidelines which is supported by animal models (Ridaura et al.,2013). for practitioners to follow in terms of donor selection are No comparable data from microbiome sequencing of the required. At present too much variation within the selection patient and donor exists. This is an important limitation to this procedures may lead to the omission of certain screening case study as cause and effect cannot be proven. Other theoret- tests and the potentially life-threatening transmission of ical long-term problems associated with FMT need to be inves- infectious diseases, such as norovirus (Schwartz et al., tigated. Some specialists already err on the side of caution 2013). This is of particular concern in the treatment of rejecting donors with high body mass indexes or a history of immunocompromised patients. Hamilton et al. (2012) colon cancer (Leading, 2014). described a standardized method for the preparation and use of frozen samples for FMT while retaining the efficacy of the treatment. These findings were supported in an RCT Meta-analysis (Youngster et al., 2014). Benefits of using frozen samples Twenty-five articles were identified for review. Of these, 23 include: reduced screening costs through use of universal articles were included in the analysis composed of journal donors, and improved storage, ease of access and transpor- articles (78%) and abstracts (22%). Two articles were tation of samples between hospitals. inaccessible online and the authors were unavailable when Although there are numerous case studies highlighting the contacted. Only studies with a minimum of 5 patients receiv- short-term success of FMT, long-term safety concerns still need ing FMT were included. In total, 684 patients were treated to be addressed. Our knowledge of human microbiome interac- with FMT for CDI across 23 studies with a mean resolution tions is still in its infancy (Kamada et al., 2013); there may rate of 90.42% (Fig. 1; Table 1). These results are in line with be unexpected long-term complications following FMT, such other reviews (Kassam et al., 2013 (89.7%); Sha et al., 2014 as obesity (Alang and Kelly, 2015), whichneedtobefurther (90.7%)). The mean sample size for included studies was 30 ............................................................................................... .................................................................. 6 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. Figure 1. Percentage resolution of CDI following FMT in 23 studies. Dotted line = mean resolution rate (90.42%). studied. These potential complications should be carefully con- made to make these trials blinded, although this may be imprac- sidered before use of FMT to treat children and young adults. tical. FMT remains a highly promising treatment option that Despite the multitude of reports demonstrating the high efficacy appears to be efficacious, safe in the short-term and affordable. of FMT, it is yet to become a treatment option available to many patients. Clinicians are rightly cautious to offer FMT as an Author biography option due to the shortage of RCTs. However, this has led to reports of well-meaning relatives offering stool samples for Chris graduated from Swansea University in 2015 with a First uncontrolled, self-administered enemas after seeking advice Class Honours BSc in Biology and a departmental award for online (Brandt, 2013; Youngster et al., 2014). This is dangerous his final year research project. This literature review was sub- in many regards, not least that the stool samples are unscreened. mitted as part of Chris’s final year as an undergraduate. Patients treating themselves in this manner are likely to lack Having always had a strong interest in the practical applica- understanding of the potential adverse effects and risks asso- tions of science for patient care, Chris is hoping to pursue a ciated with FMT (Brandt, 2013). There is a paucity of literature career in medicine by gaining acceptance to a graduate entry directly comparing multiple routes of FMT and their efficacy; medicine course and is currently working as a healthcare more RCTs are required in order to find the optimal procedure. assistant in a neurological centre. There is some evidence that treatment routes do not differ signifi- cantly (Postigo and Kim, 2012; Youngster et al., 2014), but FMT route should be based on individual patient situations Acknowledgements (Owens et al., 2013). Future research should continue to focus on long-term effects of FMT and designing robust RCTs with I would like to thank Dr Luca Börger for his help and feed- larger sample sizes to test the efficacy of FMT. Efforts should be back on this paper. ............................................................................................... .................................................................. 7 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. and Hospital Epidemiology: the Official Journal of the Society of References Hospital Epidemiologists of America, 31, 431–455. Aas, J., Gessert, C. E. and Bakken, J. S. (2003) Recurrent Clostridium diffi- Dubberke, E. R. and Olsen, M. A. 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Enteral Feeding Tubes, 3rd edn, Pharmaceutical Press, London. ............................................................................................... .................................................................. 10 Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. ............................................................................................... .................................................................. Appendix Table A1. Summary table of studies included in the review Reference Sample Mean or FMT route Donor relation Resolution Follow-up Adverse effects? Comments size median rate (%) period age (range) Youngster 20 65 (11–89) Orally Unrelated 90 6 months None et al., 2014 administered volunteer frozen FMT donors capsules Aas et al., 2003 18 73 (51–88) Nasogastric Family members 94 90 days None Two patients died before and clinic staff post-treatment stool sample could be collected. One patient suffered clinical relapse with resolution after a single course of vancomycin Arkkila et al., 2010 37 69 (24–90) Colonoscopy Relatives (30/37), 92 5–12 months None Two patients relapsed after unrelated receiving new antibiotic donors (7/37) treatments, repeated the transplantation and had full resolution. One non- cured patient died one month after FMT of toxic megacolon—unrelated to FMT Borody et al., 2003 24 (7/ (19–59) Colonoscopy/ Family members 83 4–69 weeks Some transient 2/24 reported no change in 24 rectal enema/ and unrelated symptoms, one of which had nasojejunal donors from had a recurrent infection. IBS) tube PTRC Donor 4/7 patients with IBS bank were all Cd negative and experienced at least minimal improvements in symptoms Brandt et al., 2012 77 65 (22–87) Colonoscopy Family members 91 90 days One unresponsive Secondary cure rate was (65), friends (9), patient was not 98% relatives (2), further treated unknown donor and died of an (1) unclear cause Continued Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. ............................................................................................... .................................................................. Table A1. Continued Reference Sample Mean or FMT route Donor relation Resolution Follow-up Adverse effects? Comments size median rate (%) period age (range) Cammarota 20 71 (29–89) Colonoscopy Relatives and 90 12 months None et al., 2015 partners Faust et al., 2002 6 53 (37–74) Unknown Direct family 100 9 and 50 None members months Garborg 40 75 (53–94) Gastroscopy (38) Close relatives 83 80 days None 6/11 patients who did not et al., 2010 or respond to first treatment colonoscopy repeated the procedure. (2) 4/6 had resolution. 5/7 unresponsive to treatment were seriously ill from long lasting diarrhoeal disease and co-morbidity and died <80 days after procedure. Two were believed to have IBD Hamilton 43 65 (NR) Colonoscopy Spouses, direct 86 2 months Some patients Secondary cure rate was et al., 2012 relatives, and reported 95% friends irregular bowel movements and flatulence for a couple of weeks which resolved. Jorup-Ronstrom 22 75 (27–94) Colonoscopy and One unrelated 69 1–68 mo None 6/32 patients failed to et al., 2012 enema donor Median 26 respond to treatment. months This was the first study where a culture of faecal microbes has been re- cultivated for years (10) and retained the possibility to cure patients with CDI Kassam et al., 2012 27 69 (26–87) Enema Two unrelated 93 427 days None donors (average) Keller et al., 2009 11 NR Colonoscopy/ NR 100 NR None nasojejunal tube Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Bioscience Horizons � Volume 9 2016 Review article ............................................................................................... .................................................................. ............................................................................................... .................................................................. Kelly et al., 2012 26 59 (19–86) Colonoscopy Family member or 92 2–30 months None One patient became partner reinfected 11 months post-FMT after a course of cephalexin. Another had diarrhoea 2 months post-FMT and had 1 week of vancomycin with no relapse (did not have stool tested for Cd before this). Kelly et al., 2014 80 NR NR 89 12 weeks Few All patients were immunocompromised. 12/80 had serious adverse effects <12 post FMT. Ten were hospitalized. Two deaths occurred, one as a result of aspiration during the colonoscopy and one unrelated death. No patients suffered infections directly related to FMT. Three patients reported mild bowel discomfort and five IMD patients experienced disease flare post FMT Macconnachie 15 82 (68–95) Nasogastric Relatives 73 8 and 24 None 4/15 relapsed. Two et al., 2009 months responded to a 10 -day course of metronidazole (previous ab courses had failed). One patient relapsed due to receiving insufficient donor stool, procedure was repeated and they were symptom free after 12 days. One patient relapsed after receiving broad spectrum antibiotics Continued Downloaded from https://academic.oup.com/biohorizons/article/doi/10.1093/biohorizons/hzw007/2526818 by DeepDyve user on 13 July 2022 Review article Bioscience Horizons � Volume 9 2016 ............................................................................................... .................................................................. ............................................................................................... .................................................................. Table A1. Continued Reference Sample Mean or FMT route Donor relation Resolution Follow-up Adverse effects? Comments size median rate (%) period age (range) Matilla et al., 2012 70 73 (22–90) Colonoscopy Family, home 94 12 months None 4/70 patients had initial sharers, resolution then relapsed unknown after antibiotic causes for donors unrelated illnesses. Of these, two were successfully treated with FMT and the other two successfully treated with antibiotics. Ten patients died of unrelated illnesses during follow-up period Paterson 6 56 (30–80) Enema Spouse 100 NR None et al., 1994 Rohlke et al., 2010 19 49 (32–82) Colonoscopy Relatives, partners, 100 6 months–5 None Three patients were close friends years reinfected after a new antibiotic treatment between 6 months and 4 years after treatment Rubin et al., 2013 74 63 (6–94) Nasogastric Home sharers, 80 60 days None 16/75 patients relapsed. Of family these, nine cases were resolved after a single treatment of vancomycin Silverman 7 65 (30–88) Self- Relatives 100 14 months None et al., 2010 administered enema van Nood 16 73 Nasodeodunal Unrelated 81 10 weeks None et al., 2013 tube Wilcox, 2011 13 69 (27–93) Colonoscopy Family members 100 2–14 months None and close friends Yoon and Brandt, 12 66 (30–86) Colonoscopy Family members 100 NR None 2010 or partners Donor relation refers to the relationship between donor and recipient. NR = not reported, ‘Unknown’ is used where information was not available in data provided in the abstract. PTRC = Probiotic Therapy Research Centre, Australia. Additional comments are provided where deemed prudent.

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