Journal of Hospital Infection 100 (2018) S1eS31

Available online at www.sciencedirect.com

Journal of Hospital Infection

journal homepage: www.elsevier.com/locate/jhin

Guidelines The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelinesq,qq Benjamin H. Mullish a,b,y, Mohammed Nabil Quraishi c,y, Jonathan P. Segal a,d,y, Victoria L. McCune e,f, Melissa Baxter g, Gemma L. Marsden h, David Moore i, Alaric Colville g, Neeraj Bhala c,i,j, Tariq H. Iqbal c,j, Christopher Settle k, Graziella Kontkowski l, Ailsa L. Hart a,d, Peter M. Hawkey f, ￮ ￮ Horace RT Williams a,b, , Simon D. Goldenberg m,n,*, a Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK b Departments of Gastroenterology and Hepatology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, Paddington, London, UK c Department of Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK d Inflammatory Bowel Disease Unit, St Mark’s Hospital, Harrow, London, UK e Public Health England, Public Health Laboratory Birmingham, Birmingham, UK f Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK g Department of Microbiology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK h Healthcare Infection Society, London, UK i Institute of Applied Health Research, University of Birmingham, Birmingham, UK j Institute of Translational Medicine, University of Birmingham, Edgbaston, Birmingham, UK k Department of Microbiology, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UK l C diff Support, UK m Centre for Clinical Infection and Diagnostics Research, King’s College London, London, UK n Department of Microbiology, Guy’s and St Thomas’ NHS Foundation Trust, London UK

q “NICE has accredited the process used by the Healthcare Infection Society to produce ‘The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines’. The NICE accreditation of HIS methodology is valid for 5 years from March 2015. More information on accreditation can be viewed at http://www.nice.org.uk/about/what-we-do/accreditation”. qq Versions of this Guideline are published simultaneously in The Journal of Hospital Infection and Gut. https://doi.org/10.1136/gutjnl-2018- 316818. The Editors of the Journals have agreed that joint publication of the article is justified to ensure dissemination of the guidance to all relevant healthcare professionals. * Corresponding author. Address: Department of Microbiology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London, SE1 7EH, United Kingdom. E-mail address: [email protected] (S.D. Goldenberg). y Joint first authors. ￮ Joint senior authors. https://doi.org/10.1016/j.jhin.2018.07.037 0195-6701/ª 2018 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved. S2 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31

ARTICLE INFO about 25% of patients, and some may suffer multiple recurrences. Article history: This guideline reviews the evidence for FMT as a treatment Received 2 July 2018 for Clostridium difficile infection (CDI) and other conditions. Accepted 23 July 2018 Recommendations are made for: which patients are most likely to benefit, how donors should be selected and screened, how FMT should be prepared and administered, how patients Keywords: should be followed up, and how FMT services should be microbiota configured. faecal transplant Clostridium difficile inflammatory bowel disease Introduction The aim of the British Society of Gastroenterology (BSG)/ Healthcare Infection Society (HIS) faecal microbiota transplant (FMT) working group was to establish a guideline that defined best practice in all aspects of a FMT service, by providing evidence-based recommendations wherever possible, and consensus multi-disciplinary expert opinion where specific published evidence is currently lacking. This included the evaluation of the use of FMT in the treatment of Clostridium difficile infection (CDI; also referred to as Clostridioides Executive summary difficile [1]), and also in potential non-CDI indications. Rele- vant guidance published to date includes the interventional Interest in the therapeutic potential of faecal microbiota procedure guidance from the National Institute for Health and transplant (FMT) has been increasing globally in recent years, Care Excellence (NICE) [2], UK, European and US microbiolog- particularly as a result of randomised studies in which it has ical guidelines on the treatment of CDI [3e5], and recent been used as an intervention. The main focus of these studies expert consensus documents on FMT in clinical practice [6,7]. has been the treatment of recurrent or refractory Clostridium Furthermore, there have also been national recommendations difficile infection (CDI), but there is also an emerging evi- regarding FMT produced by working groups in several different dence base regarding potential applications in non-CDI set- countries [8e10]. Principally as a result of randomised studies tings. The key clinical stakeholders for the provision and that have been published in recent years [11e18], FMT has governance of FMT services in the United Kingdom (UK) have become an accepted treatment for recurrent/refractory CDI. tended to be in two major specialty areas: gastroenterology The unique remit and objectives of this guideline when and microbiology/infectious diseases. While the National commissioned by the BSG and HIS were: Institute for Health and Care Excellence (NICE) guidance (2014) for use of FMT for recurrent or refractory CDI has i. To review the rapidly-growing body of randomised trial become accepted in the UK, clear evidence-based UK guide- evidence for the efficacy of FMT in the treatment of lines for FMT have been lacking. This resulted in discussions adults (18 years), both in CDI and in other clinical con- between the British Society of Gastroenterology (BSG) and ditions, much of which has been published after the Healthcare Infection Society (HIS), and a joint BSG/HIS FMT publication of current CDI treatment algorithms [3,4]. working group was established. This guideline document is the ii. To provide specific guidance about best practice for an culmination of that joint dialogue. FMT service within the context of the regulatory frame- work for the intervention as it currently exists in the UK Lay summary [19,20].

Faecal microbiota transplant (FMT) involves the transfer The elucidation of the mechanisms underlying the efficacy of a sample of faeces from a healthy donor to a recipient. of FMT in treating CDI remains an active area of global There are several different ways to administer the trans- research, with the aim of rationalising FMT from its current plant, including via endoscopy, rectally as an enema, via crude form to a more targeted, refined therapeutic modality nasogastric/nasoenteral tube (tube passed through the nose [21]. Previous research has demonstrated that commensal into the stomach/upper part of the small intestine), or via bacteria cultured from the stool of healthy donors [22], oral ingestion of capsules that contain faecal material. The sterile faecal filtrate [23], and/or spores of Firmicutes transplant may either be administered fresh (i.e. immedi- derived from ethanol-treated stool from healthy donors [24] ately after preparation), or may be prepared in advance, may have similar efficacy to conventional FMT in treating stored in a freezer and thawed when required. FMT is an CDI, although results of the latter approach produced disap- accepted and effective treatment for recurrent infection by pointing outcome data when extended to a Phase II clinical Clostridium difficile, a bacterium which can cause severe trial [25]. For the purposes of this guideline, the BSG/HIS illness with diarrhoea, most commonly in frail elderly pop- working group considered only studies that used the admin- ulations as a complication of antibiotic use. Despite istration of manipulated whole stool (including encapsulated adequate treatment, Clostridium difficile infection recurs in faeces). They deemed studies using cultured microorganisms B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S3 (or their proteins, metabolites or other components), or Working Party Report microbiota suspensions, to be in the pre-clinical research stage, without firm evidence. What is the Working Party Report? FMT has been shown to be very acceptable to patients, both in the setting of CDI [11,26] and in non-CDI settings, e.g. ul- The report is a set of recommendations covering key aspects cerative colitis [27]. However, the absence of appropriate of safe and efficacious delivery of a FMT service for recurrent/ protocols [28e31] specifically taking into account UK clinical refractory CDI. The guidelines also review the evidence for the practice and regulation of FMT has been perceived as a barrier use of FMT for non-CDI indications. to the use of FMT in the UK and Ireland: these guidelines seek to The diagnosis and management of Clostridium difficile rectify this problem. infection in general are outside of the remit of these guidelines. Guideline development team The working group recommendations have been developed systematically through multi-disciplinary discussions based on Acknowledgements published evidence. They should be used in the development of local protocols for all relevant healthcare settings. The authors would like to acknowledge the support of the Gut Microbiota for Health Expert Panel of the British Society of Why do we need a Working Party Report for this topic? Gastroenterology, along with that of the Healthcare Infection Society. They would also like to thank Ian Rees from the MHRA There is widespread and growing interest in the use of FMT for contributions regarding the legal aspects and clinical as a treatment for recurrent CDI. The previous absence of governance of FMT within the UK and beyond. randomised trials and lack of evidence-based guidelines describing best practice related to its use has led to uncer- tainty as to how to establish an FMT service. Existing services Source of funding may be providing suboptimal clinical care. There is now a developing portfolio of randomised study evidence (including There was no external funding for this work. BHM is the randomised controlled trial data) regarding the use of FMT in recipient of a Medical Research Council (MRC) Clinical Research CDI and non-CDI indications, providing the opportunity to Training Fellowship (grant reference: MR/R000875/1). BHM and develop an evidence-based guideline for its use. There have HRTW receive support from the National Institute for Health also been recent changes to the UK regulatory framework for Research (NIHR) Imperial Biomedical Research Centre (BRC) FMT (see Section Basic requirements for implementing a FMT based at Imperial College Healthcare NHS Trust and Imperial service), which are not well-understood by clinicians. College London. What is the purpose of the Working Party Report’s Disclosure of potential conflict of interest recommendations? THI: Acted as consultant, advisor or speaker for Pharma- The main purpose is to inform clinicians about the use of cosmos and Shield Therapeutics. FMT (and about the establishment of an FMT service) for the ALH: Acted as consultant, advisory board member or treatment of recurrent and refractory CDI, and other possible speaker for AbbVie, Atlantic, Bristol-Myers Squibb, future indications. The recommendations provide an evidence- Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceu- based approach to a high quality clinical service, with appro- ticals, Pfizer, Pharmacosmos, Shire and Takeda. ALH also priate governance structures. This document also serves to serves on the Global Steering Committee for Genentech. illustrate areas in which there are current gaps in knowledge, SDG: Received consultancy fees, speaker fees and which will help to direct future areas of research. research grant support from Astellas between 2015-2017; received consultancy fees and speaker fees from MSD What is the scope of the guidelines? between 2015-2017; and received consultancy fees in 2017 from Pfizer. The main scope of the guidelines is to provide guidance for All other authors declared no conflict of interest. the optimal provision of an effective and safe FMT service, principally for recurrent or refractory CDI, but non-CDI in- dications are also considered. These guidelines only apply to Relationship of authors with sponsor adult patients (18 years); the working party did not consider the role of FMT in the treatment of either CDI or non-CDI in- BSG and HIS commissioned the authors to undertake the dications in children or young people. The guidelines were Working Party Report. The authors represent the membership written with a focus on UK practice, but also with consideration of both societies. of more global practice as it applied.

Responsibility for guidelines What is the evidence for these guidelines?

The views expressed in this publication are those of the Questions for review were derived from the Working Party authors, and have been endorsed by BSG and HIS following Group, which included patient representatives in accordance consultation. with the PICO process [32]. To prepare these S4 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 recommendations, the working group collectively reviewed Refractory Clostridium difficile infection. relevant peer-reviewed research. Methods are described fully Recommendation: below; they were in accordance with SIGN 50 [33] and the FMT should be considered in cases of refractory CDI Cochrane Collaboration [34]. (conditional).

FMT as initial therapy for Clostridium difficile infection. Who developed these guidelines? Recommendation: FMT should not be administered as initial treatment for CDI The working group included gastroenterologists, infectious (strong). diseases/microbiology clinicians, a clinical scientist, a sys- tematic reviewer, and patient representatives. Antimicrobial/antitoxin therapy prior to considering FMT for patients with CDI. Who are these guidelines for? Recommendations:

Any healthcare practitioner may use these guidelines and i. FMT for recurrent CDI should only be considered after adapt them for their use. It is anticipated that users will recurrence of symptoms following resolution of an include clinical staff, as well as healthcare infection preven- episode of CDI that was treated with appropriate anti- tion and control teams. It is expected that these guidelines will microbials for at least 10 days (conditional). raise awareness of FMT amongst clinicians who care for pa- ii. Consider treatment with extended/pulsed vancomycin tients with recurrent or refractory CDI, but who may be un- and/or fidaxomicin before considering FMT as treatment aware that it is a feasible and accessible treatment option. The for recurrent CDI (conditional). guidelines are also designed to be read by patients with CDI, iii. For those with severe or complicated CDI, which appears helping them to understand whether FMT may be an appro- to be associated with reduced cure rates, consideration priate treatment option for them. should be given to offering patients treatment with medications which are associated with reduced risk of recurrence (e.g. fidaxomicin and bezlotoxumab), before How are the guidelines structured? offering FMT (conditional).

Each section comprises an introduction, a summary of the Post-FMT follow-up, outcomes and adverse events evidence base with levels, and a recommendation graded ac- Management of FMT failure. cording to the available evidence. Recommendation: Further FMT should be offered after initial FMT failure How frequently are the guidelines reviewed and (strong). updated? General approach to follow-up post-FMT. The guidelines will be reviewed at least every four years and Recommendation: updated if changes in the evidence are sufficient to require a All FMT recipients should routinely receive follow-up. Cli- change in practice. nicians should follow-up FMT recipients for long enough to fully establish efficacy/adverse events, and for at least eight weeks in total (strong). Aim Management of the FMT recipient. The primary aim of this report was to assess the current Recommendations: evidence for all aspects relating to provision of an FMT service as treatment for recurrent or refractory CDI. A secondary aim i. Immediate management after endoscopic administration was to review the current evidence for the efficacy of FMT in of FMT should be as per the endoscopy unit protocol treating non-CDI conditions. (strong). ii. Patients should be warned about short term adverse Summary of guidelines events, in particular the possibility of self-limiting GI symptoms. They should be advised that serious adverse Which patients with Clostridium difficile infection events are rare (strong). iii. After enteral tube administration, patients may have the should be considered for faecal microbiota transplant, tube removed and oral water given from 30 minutes post- and how should they be followed up after treatment? administration (strong). Prior to faecal microbiota transplant. Patient selection Recurrent Clostridium difficile infection. Definition of cure post-FMT for CDI. Recommendation: Good practice point: FMT should be offered to patients with recurrent CDI who A decision regarding cure/remission from CDI should be have had at least two recurrences, or those who have had one recorded during follow-up. However, this has no uniformly- recurrence and have risk factors for further episodes, including agreed definition, and should be decided on a case-by-case severe and severe-complicated CDI (strong). basis (strong). B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S5 Definition of treatment failure post-FMT for CDI. counselled about a small but recognised risk of exacer- Good practice point: bation of IBD (strong). Treatment failure/recurrence should be defined on a ii. FMT should be considered for appropriate patients with case-by-case basis. Routine testing for C. difficile toxin after recurrent CDI regardless of other comorbidities FMT is not recommended, but it is appropriate to consider in (conditional). the case of persistent CDI symptoms/suspected relapse (strong). What donor factors influence the outcome of faecal What recipient factors influence the outcome of microbiota transplant when treating people with faecal microbiota transplant when treating people Clostridium difficile infection? with Clostridium difficile infection? General approach to donor selection General approach to co-morbidities and FMT Recommendation: Good practice points: Related or unrelated donors should both be considered acceptable. However, where possible, FMT is best sourced from i. FMT should be avoided in those with anaphylactic food a centralised stool bank, from a healthy unrelated donor allergy (strong). (conditional). ii. FMT should be offered with caution to patients with CDI and decompensated chronic liver disease (conditional). Age and BMI restrictions for potential donors Recommendation: Immunosuppression and FMT People should only be considered as potential FMT donors if Recommendation: they are 18 and 60 years old, and have a BMI of 18 and 30 FMT should be offered with caution to immunosuppressed kg/m2 (conditional). patients, in whom FMT appears efficacious without significant additional adverse effects (strong). General approach to the donor screening assessment Good practice point: Recommendation: Immunocompromised FMT recipients at risk of severe It is mandatory to screen potential donors by questionnaire infection if exposed to EBV or CMV should only receive FMT and personal interview, to establish risk factors for trans- from donors negative for EBV and CMV (strong). missible diseases and factors influencing the gut microbiota (Table 1) (strong). Other comorbidities and FMT Recommendations: Laboratory screening of potential donors Recommendation: i. FMT should be offered to those with recurrent CDI and Blood and stool screening of donors is mandatory (Tables 2 inflammatory bowel disease, but patients should be and 3) (strong).

Table 1 Recommended donor history/questionnaire: A positive response to any of these questions would usually result in exclusion from further consideration as a donor, although this would depend upon the particular circumstances/answers given 1. Receipt of antimicrobials within the past three months. 2. Known prior exposure to HIV and/or viral hepatitis, and known previous or latent tuberculosis. 3. Risk factors for blood-borne viruses - including high risk sexual behaviours, use of illicit drugs, any tattoo/body piercing/needlestick injury/blood transfusion/acupuncture, all within the previous six months. 4. Receipt of a live attenuated virus within the past six months. 5. Underlying gastrointestinal conditions/symptoms (e.g. history of IBD, IBS, chronic diarrhoea, chronic constipation, coeliac disease, bowel resection or bariatric surgery) - also including acute diarrhoea/gastrointestinal symptoms within the past two weeks. 6. Family history of any significant gastrointestinal conditions (e.g. family history of IBD, or colorectal cancer). 7. History of atopy (e.g. asthma, eosinophilic disorders). 8. Any systemic autoimmune conditions. 9. Any metabolic conditions, including diabetes and obesity. 10. Any neurological or psychiatric conditions, or known risk of prion disease. 11. History of chronic pain syndromes, including chronic fatigue syndrome and fibromyalgia. 12. History of any malignancy. 13. Taking particular regular medications, or such medications within the past three months, i.e. antimicrobials, proton pump inhibitors, immunosuppression, chemotherapy 14. History of receiving growth hormone, insulin from cows, or clotting factor concentrates. 15. History of receiving an experimental medicine or vaccine within the past six months. 16. History of travel to tropical countries within the past six months. S6 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31

Table 2 What factors related to the preparation of the Recommended blood screening for stool donors: *EBV and CMV transplant influence the outcome of faecal microbiota testing is only recommended where there is the potential that the transplant when treating people with Clostridium FMT prepared from that donor will be administered to immuno- difficile infection? suppressed patients at risk of severe infection if exposed to CMV and EBV General principles of FMT preparation Pathogen screening: Recommendations: e Hepatitis A IgM e Hepatitis B (HBsAg and HBcAb) i. Donor stool collection should follow a standard protocol e Hepatitis C antibody (strong). e Hepatitis E IgM ii. Donor stool should be processed within 6 hours of e HIV -1 and -2 antibodies defaecation (strong). e HTLV-1 and -2 antibodies iii. Both aerobically and anaerobically prepared FMT treat- e Treponema pallidum antibodies (TPHA, VDRL) ments should be considered suitable when preparing FMT e Epstein-Barr virus IgM and IgG* for the treatment of recurrent CDI (strong). e Cytomegalovirus IgM and IgG* iv. Sterile 0.9% saline should be considered as an appropriate e Strongyloides stercoralis IgG diluent for FMT production, and cryoprotectant such as e Entamoeba histolytica serology glycerol should be added for frozen FMT (strong). General/metabolic screening: v. Use 50g of stool in each FMT preparation (strong). e Full blood count with differential. e Creatinine and electrolytes Good practice points: e Liver enzymes (including albumin, bilirubin, aminotransferases, gamma-glutamyltransferase and alka- i. Stool should be mixed 1:5 with diluent to make the initial line phosphatase). faecal emulsion (conditional). e C-reactive protein ii. Homogenisation and filtration of FMT should be under- taken in a closed disposable system (conditional). Table 3 Recommended stool screening for stool donors: *Whilst CPE and Fresh vs frozen FMT ESBL are the only multi-drug resistant bacteria that are recom- Recommendation: mended to be screened for universally, consider testing for other The use of banked frozen FMT material should be considered resistant organisms (including vancomycin-resistant Enterococci preferable to fresh preparations for CDI (strong). (VRE) and/or methicillin-resistant Staphylococcus aureus (MRSA)) based upon risk assessment and local prevalence Use of frozen FMT Clostridium difficile PCR Recommendation: Campylobacter, Salmonella, and Shigella by standard FMT material stored frozen at -80oC should be regarded as stool culture and/or PCR having a maximum shelf life of six months from preparation Shiga toxin-producing Escherichia coli by PCR. (strong). Multi-drug resistant bacteria, at least carbapenemase- Good practice points: producing Enterobacteriaceae (CPE) and extended- spectrum beta-lactamases (ESBL)*. i. Consider thawing frozen FMT at ambient temperature, Stool ova, cysts and parasite analysis, including for and use within six hours of thawing (conditional). Microsporidia. ii. Do not thaw FMT in warm water baths, due to the Faecal antigen for Cryptosporidium and Giardia. risks of cross contamination with Pseudomonas (and Acid fast stain for Cyclospora and Isospora. other contaminants) and reduced bacterial viability Helicobacter pylori faecal antigen. (strong). Norovirus, Rotavirus PCR.

What factors related to administration of the Repeat donor checks, and donation pathway transplant influence the outcome of faecal microbiota Recommendations: transplant when treating people with Clostridium difficile infection? i. In centres using frozen FMT, before FMT may be used clinically, donors should have successfully completed a Use of specific medications in the period around FMT donor health questionnaire and laboratory screening as- administration says both before and after the period of stool donation. General principles of FMT administration. This is the preferred means of donor screening (strong). Recommendations: ii. In centres using fresh FMT, a repeat health questionnaire should be assessed at the time of each stool donation. To i. Bowel lavage should be administered prior to FMT via the ensure ongoing suitability for inclusion as a donor, the lower GI route, and bowel lavage should be considered donor health questionnaire and laboratory screening prior to FMT via the upper GI route; polyethylene glycol should be repeated regularly (strong). preparation is preferred (conditional). B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S7 ii. For upper GI FMT administration, a proton pump inhibitor ii. Where colonoscopic administration is used, consider should be considered, e.g. the evening before and preferential delivery to the caecum or terminal ileum, as morning of delivery (conditional). this appears to give the highest efficacy rate iii. A single dose of loperamide (or other anti-motility drugs) (conditional). should be considered following lower GI FMT delivery iii. FMT via enema should be used as a lower GI option when (conditional). delivery using colonoscopy or flexible sigmoidoscopy is not possible (strong). Good practice points:

i. Prokinetics (such as metoclopramide) should be consid- Capsulised FMT. ered prior to FMT via the upper GI route (conditional). Recommendation: ii. Best practice for prevention of further transmission of CDI Capsulised FMT holds promise as a treatment option for should be applied throughout when administering FMT to recurrent CDI and should be offered to patients as a potential patients with CDI (nursing with enteric precautions, treatment modality where available. Capsule preparations sporicidal treatment of endoscope, etc). should follow a standard protocol. Further evidence regarding optimal dosing and formulation is required (conditional).

Additional antibiotics pre-FMT. Recommendation: What is the clinical effectiveness of FMT in treating Administer further antimicrobial treatment for CDI for at conditions other than Clostridium difficile infection? least 72 hours prior to FMT (strong). Recommendation: Washout period between antibiotic use and FMT. FMT is not currently recommended as treatment for in- Recommendation: flammatory bowel disease. Apart from CDI, there is insufficient To minimise any deleterious effect of antimicrobials on the evidence to recommend FMT for any other gastrointestinal or FMT material, there should be a minimum washout period of 24 non-gastrointestinal disease (strong). hours between the last dose of antibiotic and treatment with FMT (strong). Basic requirements for implementing a FMT service Good practice point: Consider consultation with infectious disease specialists or General considerations medical microbiologists for advice whenever FMT recipients Good practice points: also have an indication for long-term antibiotics, or have an indication for non-CDI antibiotics within eight weeks of FMT i. The development of FMT centres should be encouraged (conditional). (strong). ii. FMT centres should work to raise awareness about FMT as Route of FMT delivery a treatment option amongst clinicians caring for patients Upper gastrointestinal tract administration of FMT. with CDI, and provide training to relevant healthcare Recommendations: professionals on the practicalities of delivering an FMT service (conditional). i. Upper GI administration of FMT as treatment for recurrent or refractory CDI should be used where clinically appro- priate (strong). Legal aspects and clinical governance ii. Where upper GI administration is considered most Good practice point: appropriate, FMT administration should be via nasogas- In the UK, FMT must be manufactured in accordance with tric, nasoduodenal, or nasojejunal tube, or alternatively MHRA guidance for human medicines regulation. When FMT is via upper GI endoscopy. Administration via a permanent supplied on a named patient basis, within a single organisation, feeding tube is also appropriate (strong). a pharmacy exemption may be used, subject to ensuring proper governance and traceability. All centres that are processing Good practice points: and distributing FMT should seek guidance from the MHRA and where necessary obtain appropriate licenses prior to estab- i. It is recommended that no more than 100ml of FMT is lishing an FMT service. This is a legal requirement. In countries administered to the upper GI tract (conditional). other than the UK, FMT should only be manufactured following ii. Upper GI administration of FMT should be used with appropriate approval from the national authority of that caution in those with swallowing disorders (strong). country (strong).

Lower gastrointestinal tract administration of FMT. Multidisciplinary teams Recommendations: Good practice point: A multidisciplinary team should be formed to deliver FMT i. Colonoscopic administration of FMT as treatment for services (strong). recurrent or refractory CDI should be used where appro- priate (strong). Infrastructure Good practice point: S8 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 Utilise suitable laboratory facilities and infrastructure for including whether recurrent or refractory disease, pre- FMT production (strong). vious antimicrobial courses, and use of bowel purgatives/ other preparatory medications pre-FMT. FMT manufacturing All FMT recipients to have sufficient documentation to Good practice point: allow clear traceability of the exact FMT aliquot trans- Ensure traceability of supply (strong). fused. Records should include identification of the donor, in addition to a frozen FMT aliquot (and original faecal FMT production quality control sample) - as well as serum - from that donor. Good practice point: All FMT recipients for recurrent or refractory CDI to have Monitor, notify and investigate all adverse events and re- documentation during follow-up of treatment success or actions related to FMT (strong). failure (and subsequent treatment plan if failure), together with clear documentation of any adverse events Donor screening governance that may be attributable to FMT. Good practice point: Ensure the clinical governance of donor screening (strong). E-learning tools Implementation of these guidelines Continuing Professional Development questions and their How can these guidelines be used to improve clinical answers are provided for self-assessment in Main Appendix 4. effectiveness?

Primarily, these guidelines will inform the development of Methodology local FMT services and appropriate local operational protocols, and will guide clinical decision-making. They also provide a Evidence appraisal framework for clinical audit, a tool for improving clinical effectiveness. In addition, the future research priorities iden- Questions for review were derived from the Working Party tified by the working group will allow researchers to refine Group, which included patient representatives in accordance applications to funding bodies. with the PICO process [32]. Methods were in accordance with SIGN 50 [33] and the Cochrane Collaboration [34]. How much will it cost to implement these guidelines? Data sources and search strategy Where FMT is being provided under a MHRA license accord- ing to Good Manufacturing Practice (GMP) standards, there are A systematic literature search was undertaken using MED- significant costs associated with initial setup and maintenance LINE and EMBASE databases, and the Cochrane Library, for st st of the service. These include the cost of obtaining the relevant relevant articles published from 1 January 1980 to 1 license, laboratory design and equipment to enable quality January 2018. The MEDLINE and EMBASE strategy is shown in assurance, storage facilities for samples, etc. However, there Main Appendix 2ii. Free text and MESH/index terms for faecal is counterbalance to this, as the expectation of the working microbial transplant and Clostridium difficile or other dis- group is that the publication of this guideline may encourage eases of interest were combined. In addition, conference provision of FMT as treatment for recurrent or refractory CDI. proceedings from microbiology, infectious disease and This has consistently been shown to be cost effective in com- gastroenterology conferences were also searched to identify parison with anti-C. difficile antimicrobial therapy [35e38],so additional studies. overall costs associated with treating the condition may actu- ally decrease. Furthermore, there may be changes to the Study eligibility and selection criteria practice of clinicians already offering the service. For example, encouraging the use of healthy unrelated donors (who can The members of the guideline group determined criteria for provide multiple stool donations after one screening) reduces study inclusion. Two reviewers (BHM, MNQ) screened the titles the cost of screening when compared to the use of an FMT and abstracts of each article for relevance independently; any recipient’s relative as donor, who is likely to provide one disagreements were resolved by discussion with a third donation only. reviewer (JPS). Copies of relevant articles were obtained and assessed for inclusion as evidence in the guideline by all three Summary of audit measures reviewers. The reason for not selecting studies was recorded. Only articles published in English and human clinical studies All donors to have completed initial screening question- were included. For evidence on FMT for CDI, both randomised naires and blood and stool screening results, as well as studies (including randomised controlled trials (RCTs)) and case final health check prior to each stool donation processed series with at least 10 patients were selected. Only randomised to FMT. Results from each subsequent serial round of trials were included as evidence for FMT for non-CDI in- screening also to be documented. dications. Conference abstracts were only included for CDI and All FMT recipients to have clear documentation of details non-CDI indications if they reported a randomised trial; where of their disease course and preparation prior to FMT, abstracts were available reporting data from a randomised trial B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S9 that was subsequently published, only the published paper was Rating of evidence and recommendations reviewed. Evidence tables were presented and discussed by the Data extraction and quality assessment working group, and guidelines were prepared according to the nature and applicability of the evidence regarding efficacy and patient preference and acceptability. For the HIS version of The initial search identified 2658 publications, and of these, this guideline, the strength of evidence was defined by SIGN 802 duplicates were excluded. From here, 1856 studies were [33] (Table 4A), and the strength of recommendation was subsequently screened, from which 78 studies were assessed adopted from GRADE (Grades of Recommendations Assess- by reviewing the full text for eligibility (see Main Appendix 2iii ment, Development and Evaluation) [39] (Table 4B). In addi- and Additional Appendix D). Of these 78 studies, 58 studies tion, where there was no clear evidence or a paucity of were included as the basis of evidence for writing this guide- evidence, good practice recommendations were made by line. In total, 39 were case studies in CDI including at least 10 expert experience and consensus. The section entitled ‘Basic patients (see Additional Appendix C.1), and ten were rando- requirements for implementing an FMT service’ was based on mised studies in CDI (see Additional Appendix C.2). Nine were expert opinion, since this was a key area of the working party’s randomised trials for non-CDI indications (see Additional remit but not one amenable to evaluation by the PICO process. Appendix C.3). Data were extracted for patient demographics, Face-to-face meetings and group teleconferences were held to disease characteristics, donor screening characteristics, stool agree on recommendations. Any disagreements on recom- preparation and administration, clinical outcomes and adverse mendations or the strength of recommendation were resolved events. The quality of randomised studies was assessed with by discussion and, where necessary, voting by the members of the Cochrane Collaboration’s risk of bias tool. Case series were the working group, with consensus achieved when >80% were assessed using the Centre for Reviews and Dissemination in agreement. guidance.

Table 4 Evidence statements and recommendations. A. Levels of evidence for intervention studies; B. Recommendation grading A. Levels of evidence 1þþ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1þ Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias 1 Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2þþ High-quality systematic reviews of case-control or cohort studies High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2þ Well-conducted case-control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2- Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports, case series. 4 Expert opinion B. Recommendations Some recommendations can be made with more certainty than others. The wording used in the recommendations in this guideline denotes the certainty with which the recommendation is made (the ‘strength’ of the recommendation). The ‘strength’ of a recommendation takes into account the quality (level) of the evidence. Although higher-quality evidence is more likely to be associated with strong recommendations than lower-quality evidence, a particular level of quality does not automatically lead to a particular strength of recommendation. Other factors that are taken into account when forming recommendations include: relevance to the NHS in the UK; applicability of published evidence to the target population; consistency of the body of evidence, and the balance of benefits and harms of the options. For ‘strong’ recommendations on interventions that ‘should’ be used, the working group is confident that, for the vast majority of people, the intervention (or interventions) will do more good than harm. For ‘strong’ recommendations on interventions that ‘should not’ be used, the working group is confident that, for the vast majority of people, the intervention (or interventions) will do more harm than good. For ‘conditional’ recommendations on interventions that should be ‘considered’, the working group is confident that the intervention will do more good than harm for most patients. The choice of intervention is therefore more likely to vary depending on a person’s values and preferences, and so the healthcare professional should spend more time discussing the options with the patient. Good practice points are recommended best practice based on the clinical experience of the guideline working group. S10 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 Consultation process FMT using four categories of severity, which also accounted for prior anti-CDI therapy and requirement for hospital- Feedback on draft guidelines was received from the Sci- isation [59]. entific Development Committee (SDC) of HIS, and changes None of the studies directly compared the efficacy of FMT made. These guidelines were then opened to consultation according to the stage at which it was offered (i.e. first with relevant stakeholders (see Main Appendix 3). The draft recurrence vs. two recurrences). A small number of studies report was available on the HIS website for one month. Views [60e62] included patients with severe CDI (defined as hypo- were invited on format, content, local applicability, patient albuminaemia with increased peripheral white cell count and/ acceptability, and recommendations. The working group or abdominal tenderness) or complicated CDI (defined as reviewed stakeholder comments, and collectively agreed re- admission to Intensive Care, altered mental status, hypoten- visions. Final changes were made after repeat reviews from sion, fever, ileus, white blood cell count > 30 109/l, HIS (chair of the SDC and HIS Council) and BSG (BSG CSSC and lactate > 2.2mmol/l, or evidence of end organ damage). A BSG Council), and after further external peer review. single study described an apparent lower rate of treatment success when FMT was used to treat patients with recurrent CDI Rationale for recommendations with disease caused by ribotype 027 [48], but this is the case for all anti-CDI treatment modalities for this ribotype in compari- Which patients with Clostridium difficile infection son with others. The working group agreed that there was should be considered for faecal microbiota transplant, insufficient evidence to suggest that C. difficile ribotype and how should they be followed up after treatment? should influence whether or not FMT is offered. A lower primary cure rate was reported for complicated Prior to faecal microbiota transplant. Patient selection CDI (66%) compared with recurrent CDI (82%) and severe CDI Recurrent Clostridium difficile infection. As already (91%) in one study [60]; in a case series of 17 patients who all described, there is widespread consensus that FMT is an effi- had severe and/or complicated CDI, a primary cure rate of cacious treatment for recurrent CDI. In defining recurrent CDI, 88% was described [62]. A cohort of 328 patients was analysed some studies have relied on a minimum threshold of return of to determine which factors were associated with failure of clinical symptoms (e.g. at least three unformed bowel move- FMT [63]. Higher early (one month) failure rates were found ments within 24 hours, for at least two consecutive days) in patients with severe (72%, n ¼ 18/25) or severe- [12,18] following previous successful CDI treatment; most complicated CDI (52.9%, n ¼ 9/17) than for recurrent CDI studies have also included a requirement for a positive micro- (11.9%, n ¼ 34/286). This study also identified that patients biological test [12,14,18,40e50]. Other studies explicitly state who were treated with FMT as an inpatient were nearly four that a positive test was not required [51]. Recommendations times more likely to fail as those who had FMT as an outpa- for CDI testing are beyond the scope of this guideline, and tient; however, the working group noted that the authors of there are already well-established evidence-based guidelines this study themselves identified that in-patient status is likely [52]. These recommend testing with either a nucleic acid a proxy of severity of CDI and/or co-morbidities. A further amplification test (NAAT) or glutamate dehydrogenase (GDH) similar study, including 64 patients treated with FMT as assay, followed by detection of free toxin (either by toxin A/B treatment for recurrent CDI, also identified severe CDI as the enzyme immunoassay (EIA) or cytotoxin neutralisation assay), strongest independent risk factor for FMT failure on multi- which allows differentiation of patients with active disease as variate analysis [64]. well as those who are likely colonised [52]. However, the The working group discussed their experience of treating working group discussed the importance of the accurate diag- patients with CDI whose disease fitted an intermediate pattern nosis of true recurrent CDI prior to consideration of FMT; in to the typical descriptions given of recurrent or refractory CDI, particular, they noted a study which observed that of 117 pa- e.g. patients with CDI who have some (but incomplete) symp- tients with presumed recurrent CDI referred for work-up for tomatic improvement with anti-CDI antibiotics and worsening FMT, 25% (n ¼ 29/117) were determined to have a non-CDI of disease when these are stopped. The experience of the diagnosis, with irritable bowel syndrome (n ¼ 18) and inflam- working group was that such patients experienced excellent matory bowel disease (n ¼ 3) being the most common alter- responses to FMT, and that these patients should be considered native diagnoses, and younger patients more likely to be for FMT. misdiagnosed [53]. As FMT is currently an unlicensed medicine with poorly- All of the reviewed studies have included patients with studied long term sequelae, the working group considered recurrent CDI but some studies offered FMT to patients at the that it should generally be reserved for patients who have had first recurrence (second episode) [12,15,16,18,40,42, three or more episodes of infection. There are no studies 47,48,51,54], whereas others offered FMT after the second directly comparing its effectiveness with some of the newer recurrence (third episode) [13,14,44,46,49,50,55,56]. Some agents such as fidaxomicin or bezlotoxumab, hence this protocols offered FMT after three or more recurrences [57], recommendation is made on the basis of safety. However, the while others did not define the point at which it was adminis- working group agreed that it may be reasonable in certain tered [45,58]. patient groups with ongoing risk factors for further recurrence The severity of infection has been used as a parameter to offer FMT after the second episode. to decide at which stage FMT is offered. Youngster Evidence: et al. offered FMT to patients with at least three episodes The reviewed literature represents a wide variety of of mild to moderate CDI, or at least two episodes of severe different study designs. However, regardless of design, there is CDI resulting in hospitalisation and associated with signifi- consistent evidence that FMT is an effective therapy for people cant morbidity [17]. Another study selected patients for with recurrent CDI (quality of evidence: 1þ). B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S11 Recommendation: Antimicrobial/antitoxin therapy prior to considering FMT for FMT should be offered to patients with recurrent CDI who patients with CDI. There are now at least two licensed agents have had at least two recurrences, or those who have had one (fidaxomicin and bezlotoxumab) which have been shown to recurrence and have risk factors for further episodes, including significantly reduce the risk of recurrence compared with severe and severe-complicated CDI (strong). vancomycin [68,69]. There is also some evidence that pulsed/ tapered dosing of vancomycin and fidaxomicin (including Refractory Clostridium difficile infection. Two randomised pulsed fidaxomicin [70]) results in fewer recurrences than with trials allowed the recruitment of patients with refractory CDI. standard dosing of these agents [71,72] (although this finding The first defined this as at least three weeks of ongoing severe has not been replicated in all studies [73]). Pre-planned sub- symptoms despite standard antimicrobial therapy for CDI [17]. group analysis of patients with severe CDI in a randomised trial The second required persistent or worsening diarrhoea and one demonstrated a significantly lower recurrence rate when of the following: ongoing abdominal pain, fever > 38oC, or treated with fidaxomicin (13.0%, n ¼ 12/92) than when treated white blood cell count > 15 109/l despite oral vancomycin at with vancomycin (26.6%, n ¼ 29/109) [68]; this finding was a dose of 500mg four times daily for at least five days [16]. Both replicated in another randomised controlled trial, with 8.3% studies included only small numbers of patients with refractory (n ¼ 4/48) and 32.6% (n ¼ 14/43) experiencing a recurrence CDI (n¼4/20 (20%) and n¼15/219 (6.8%), respectively). There respectively [74]. In a further randomised trial, bezlotoxumab did not appear to be any significant difference in primary (together with standard of care antibiotics) was shown to outcome measure (clinical cure) in patients with recurrent or reduce recurrence of severe CDI compared with standard of refractory CDI, although neither study was designed to assess care antibiotics alone (10.9% (n ¼ 6/55) vs 20% (n ¼ 13/65) this difference. There are also a number of case series in which respectively) [69]. FMT was given to patients with refractory CDI; however, As discussed above, the working group noted that there are outcome measures were not reported for these groups indi- no studies comparing FMT with fidaxomicin or bezlotoxumab, vidually in these studies [42,43,59,65]. and only one study comparing a vancomycin taper to FMT [12]. Evidence: The working group agreed that in the absence of this evidence, There is little consensus on the definition of refractory CDI, on the balance of safety and potential risks, consideration with some studies using the terms ‘refractory’ and ‘recurrent’ should be given to using antimicrobial/antitoxin therapy asso- interchangeably (as well as other terms, e.g. ‘salvage ther- ciated with reduced CDI recurrence prior to considering the use apy’). Consequently, the quality of evidence for the utility of of FMT. FMT in refractory cases of CDI is lower than for recurrent CDI. Several studies specify that patients should be treated with Standardisation of definitions will allow more robust compari- anti-C. difficile antibiotics for a minimum period of 10 days son between patient cohorts (quality of evidence: 1-). before diagnosing recurrent CDI and offering FMT Recommendation: [12,15,16,18]. FMT should be considered in cases of refractory CDI Evidence: (conditional). There is evidence that particular antimicrobial agents reduce the likelihood of recurrence of CDI, but data comparing FMT as initial therapy for Clostridium difficile infec- FMT to antimicrobial or antitoxin therapy are lacking (quality of tion. Experience of the use of FMT as initial therapy for CDI is evidence: 3). verylimited.InacaseseriesofpatientswithCDIwithribo- Recommendations: type 027, use of anti-CDI antibiotics together with nasogastric FMT within a week of diagnosis during an initial episode of CDI i. FMT for recurrent CDI should only be considered after was associated with reduced mortality compared to using FMT recurrence of symptoms following resolution of an only after the failure of three courses of antibiotics (mortality episode of CDI that was treated with appropriate anti- of 18.75% (n ¼ 3/16 patients) vs 64.4% (n ¼ 29/45 patients)) microbials for at least 10 days (conditional). [66]. However, 37.5% (n ¼ 6/16) of the patients treated with ii. Consider treatment with extended/pulsed vancomycin FMT within a week of CDI diagnosis required further anti- and/or fidaxomicin before considering FMT as treatment biotics and a second FMT within one month of the first FMT for recurrent CDI (conditional). because of relapse [66]. In a small pilot randomised trial, iii. For those with severe or complicated CDI, which appears patients were randomised to either vancomycin or multi- to be associated with reduced cure rates, consideration donor FMT (administered either via upper or lower GI should be given to offering patients treatment with routes) as initial therapy for CDI; CDI resolution occurred in medications which are associated with reduced risk of 88.9% (8/9) of patients with vancomycin, compared with recurrence (e.g. fidaxomicin and bezlotoxumab), before 57.1% of patients (n ¼ 4/7) with one FMT, and 71.4% of pa- offering FMT (conditional). tients (n ¼ 5/7) after two FMTs [67].Giventhesmallsizeof these studies and equivocal results, the working group Post-FMT follow-up, outcomes and adverse events concluded that the reviewed studies did not support CDI as Management of FMT failure. Where patients were deemed not initial therapy for CDI. to have responded to an initial FMT, many studies have offered Evidence: repeat FMT and success rates have been excellent even in There is very little experience of FMT as use as initial patients with a modest response to a first FMT therapy for CDI (quality of evidence: 3). [14,15,17,18,40,48,51,56,59,75,76]. The success of a second Recommendation: FMT appears to be high whether treatment failure represents FMT should not be administered as initial treatment for CDI non-response to the first FMT, or a late failure (i.e. further (strong). relapse of CDI after an initial response); however, these terms S12 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 have been defined variably between different studies (also see Management of the FMT recipient. Procedural adverse events Section Definition of treatment failure post-FMT for CDI). during administration of FMT have predominantly occurred Second FMTs have been offered as soon as 24e72 hours after an with colonoscopic administration of FMT. These have included initial FMT for presumed non-response [42,77,78]. For FMT mild nausea and vomiting attributed to sedation for the colo- failure in patients with pseudomembranous colitis, repeat FMT noscopy, minor mucosal tears during colonoscopy [54,65], and every three days until resolution of pseudomembranes has microperforation following biopsy of an area of presumed been a successful approach [18]. Good outcomes in pseudo- ischaemic small bowel injury in a patient with chronically membranous disease have also been achieved through a pro- dilated small bowel (which resolved with conservative man- tocol that routinely restarted five days of vancomycin if FMT agement [51]). One death occurred due to witnessed aspiration failed, before offering anther FMT [78]. Other studies have at the time of colonoscopy [65]. Faecal regurgitation and demonstrated potential success in treating initial FMT failure vomiting with temporal association to upper GI FMT adminis- with further antibiotics, including repeat FMT with vancomycin tration has also been described (discussed further in Section between procedures [47], or anti-CDI antibiotics alone Upper gastrointestinal tract administration of FMT) [81]. [40,47,48,50,56,75,76]. Patients unresponsive to two FMTs The predominant short term adverse events post-FMT for have been offered further FMT or antibiotic therapy [16],or CDI are mild: self-limiting GI symptoms have been the most even administration of intravenous immunoglobulin [40]. While frequently reported adverse events. These may be related to the working group collectively agreed that there was strong the route of administration and include belching [15], nausea evidence to recommend repeat FMT after initial FMT failure, [15,16,54,65], abdominal cramps/discomfort/bloating/pain they were not able to recommend a specific protocol for [15,18,54,65,77], and diarrhoea [15,16,18,65]. One patient administering repeat FMT and/or maximum number of FMTs, with a history of autonomic dysfunction experienced dizziness given the wide heterogeneity of approach described within the with diarrhoea after FMT [15]. These symptoms are typically reviewed literature. short-lived, resolving in hours to days [15,16,18,54,77]. Minor Evidence: subsequent adverse events have included a range of GI side Regardless of how failure is defined, there is good evidence effects including self-limiting abdominal discomfort that further FMT is efficacious at treating CDI after initial FMT [14,17,62,80], nausea [14,54,75], flatulence [14,16,17,46,47, failure (quality of evidence 1þþ). 54,62], self-limiting irregular bowel movements [46], Recommendation: C. difficile-toxin negative diarrhoea [57,60], constipation Further FMT should be offered after initial FMT failure [14,15,47,60,75] and constitutional symptoms/temperature (strong). disturbance [14,17]. As such, immediately post-endoscopic administration of General approach to follow-up post-FMT. Follow-up post- FMT, most FMT centres typically manage patients using stan- FMT (in terms of duration, modality and regimen for dard protocols for an endoscopic procedure [46,54], without follow-up) varies considerably between studies, and is any specific adaptations (apart from to reiterate advice about largely dependent on study design. Follow-up regimens vary the possibility of self-limiting GI side effects, and the use of not only between studies but within them too, reflecting the departmental infection control protocols). There is often a retrospective nature of many early FMT studies in CDI, relatively short period of post-procedural observation [15,18]. where follow-up mostly reflected pragmatic routine clinical Most studies allow patients to leave the administration site care. after the period of observation, although overnight observation Modalities of follow-up have included outpatient review was the protocol used for a cohort of very elderly patients with [14,48,63,76,79,80], telephone interview [17,44,48, multiple comorbidities [56]. Where enteral tube administration 51,63,76,79] and case note/database review is used, post-procedure management has ranged between [40,44,45,47,48,50,51,54,56,59,75,76,79].Follow-updura- removal of the tube after 30 minutes (following nasoenteral tion has varied from 60 days [50] to 8 years [41],withvery administration of 500ml of FMT [15]) to prompt post-procedure different durations used in each study. Once again, however, removal and oral water administration (after nasogastric this variability in follow-up largely reflects the retrospective administration of 90ml of FMT [77]), with no direct adverse analysis of case series rather than being justified by any outcomes in either case. The working group felt that removal specific methodology. The working group decided by of the tube at 30 minutes, with administration of water at this consensus that at least eight weeks of follow-up was appro- point, was a pragmatic approach. priate post-FMT to fully assess efficacy and potential adverse The definition of post-FMT serious adverse events has varied events; this figure was also influenced by discussions between studies, but has included significant morbidity regarding the time point after FMT at which a decision could necessitating hospital admission and death in the follow-up be made regarding cure/remission of CDI (see Section period. Many of these events are described as not directly Definitionofcurepost-FMTforCDI). caused by the FMT, including the scenario of post-FMT severe Evidence: CDI recurrences [77] and probable or certain CDI-related The approach to following up patients after FMT varies deaths [16,65,75] occurring in the context of FMT failure, or considerably between studies, and is often pragmatically deaths related to patient comorbidities [17,60]. One patient designed (quality of evidence: 3). was admitted to hospital with self-limiting abdominal pain Recommendation: post-FMT [65], and four patients with flares of inflammatory All FMT recipients should routinely receive follow-up. Cli- bowel disease [65]. Three patients underwent colectomy dur- nicians should follow-up FMT recipients for long enough to fully ing the post-FMT follow-up period, with all related to ulcera- establish efficacy/adverse events, and for at least eight weeks tive colitis and not believed to be due to CDI [65]. Other in total (strong). reported serious adverse events include recurrent urinary tract B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S13 infection [15], fever during haemodialysis [15] and upper recommends ‘resolution of symptoms as a primary end point; gastrointestinal haemorrhage after nasogastric FMT (in a pa- absence within eight weeks of FMT as a secondary end point’ tient taking non-steroidal anti-inflammatory drugs [56]), none [8]. The working group recommended that this definition of which were thought to be strongly linked to FMT. There have should be made on a case-by-case basis; however, they agreed also been a number of new onset autoimmune, inflammatory that an assessment for cure/remission of CDI within eight and metabolic conditions described post-FMT, although these weeks post-FMT was reasonable in most cases, and therefore have been described from single centres only, with these that this was also a reasonable minimum length of time to findings not replicated elsewhere. Such conditions include undertake follow-up post-FMT (see Section General approach microscopic colitis, Sjo¨gren’s syndrome, follicular lymphoma, to follow-up post-FMT). peripheral neuropathy, immune thrombocytopenia and rheu- Evidence: matoid arthritis [58,60]. No universal definition exists regarding cure/remission post- Significant adverse events are therefore rare but well- FMT for CDI (quality of evidence: 4). described. Furthermore, the procedure is relatively novel, Good practice point: and longer-term follow-up data regarding safety are required. A decision regarding cure/remission from CDI should be Therefore, the working group opined that formal follow-up recorded during follow-up. However, this has no uniformly- post-FMT to assess outcome and possible adverse events is agreed definition, and should be decided on a case-by-case essential. basis (strong). The use of questionnaires to compare symptoms pre- and post-FMT is common. Specifically, data collected have included Definition of treatment failure post-FMT for CDI. There is no clinical response to symptom severity [60], stool frequency uniformly-agreed definition of treatment failure/recurrence [15,17,51,60,62,77], stool consistency [14,15,77], abdominal post-FMT for CDI, with varied definitions used in studies. The pain or tenderness [60,62], rating of gastrointestinal symptoms use of C. difficile toxin as a marker of treatment success or [77], general well-being [60,77], days to improvement post- failure is variable, with some studies opting not to test for FMT [62], weight change [77], functional status [60], and C. difficile toxin unless symptoms consistent with CDI recurred changes in medication/use of antibiotics [62,77]. Additionally, [54,57e59,65,77,79]. Some studies have routinely performed certain patients have been given specific advice post-FMT to C. difficile toxin testing without specifying any action taken contact their clinical team if there is recurrence of diarrhoea or after a positive result [14,15,18,41,44,46], while others have symptoms [14,40,46,48]. Where patients underwent outpa- tested for C. difficile PCR but relied on clinical criteria (even if tient clinical evaluation, this was generally undertaken rela- PCR was positive) post-FMT for evaluating FMT efficacy [14].A tively early post-FMT [44,57,80]. In one study, patients were recent prospective study from the USA identified that only 3% additionally given instructions for cleaning and disinfection at (3/129) of patients who were asymptomatic at four weeks post- home, with the aim of reducing the possibility of C. difficile FMT for recurrent CDI had positive C. difficile PCR, again reinfection [48], and counselling on the risk of recurrent CDI emphasising that symptoms rather than laboratory assays are with future antibiotic courses [80]. more useful contributors to establishing FMT success [82]. Evidence: Evidence: Much of the short-term management of the FMT recipient No standard definition exists regarding treatment failure/ describes general principles of best practice related to the recurrence post-FMT for CDI (quality of evidence: 4). route of administration. Many adverse events described Good practice point: following FMT are minor, and/or may not directly relate to the Treatment failure/recurrence should be defined on a case- transplant itself (quality of evidence: 3). by-case basis. Routine testing for C. difficile toxin after FMT Recommendations: is not recommended, but it is appropriate to consider in the case of persistent CDI symptoms/suspected relapse (strong). i. Immediate management after endoscopic administration of FMT should be as per the endoscopy unit protocol (strong). What recipient factors influence the outcome of ii. Patients should be warned about short term adverse faecal microbiota transplant when treating people events, in particular the possibility of self-limiting GI with Clostridium difficile infection? symptoms. They should be advised that serious adverse events are rare (strong). General approach to co-morbidities and FMT iii. After enteral tube administration, patients may have the Most published studies had a core set of general recipient tube removed and oral water given from 30 minutes post- exclusions which included: significant/anaphylactic food al- administration (strong). lergy [14,17], pregnancy [12e15,17,18], breastfeeding [14], admission to intensive care or requirement for vasopressors [12,15,18], chronic diarrhoea or other infectious cause of Definition of cure post-FMT for CDI. It is recognised that diarrhoea [12,14,18,55], inflammatory bowel disease (IBD) and symptoms of CDI resolve relatively promptly after successful irritable bowel syndrome (IBS) [14,41], immunodeficiency due FMT, although this has been variably described (within hours in to recent chemotherapy and/or neutropenia [12,14e18,55], some studies [57], at an average of 4e5 days in others [62,76]). HIV/AIDS [14,17,18], prolonged use of corticosteroids Treatment success post-FMT for CDI has no uniformly-agreed [15,17,18], graft versus host disease [12], and decompensated definition, with the time point at which cure/remission is cirrhosis [14,15,17,18]. defined on clinical grounds varying between 3-5 days [41] up to The working group discussed the reported practice of six months [47]. A consensus document from the USA several centres of treating patients with recurrent CDI and S14 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 food allergies through the use of FMT prepared from a patient- malignancies (remission after one FMT in 11/12 with haema- directed donor instructed to avoid trigger foods before stool tological patients, and 8/10 in solid organ malignancy pa- donation. They agreed that this seemed reasonable for pa- tients). No significant FMT-related complications were tients with true adverse immunological reactions to defined reported [84]. A further case series [50] reported FMT treat- food groups (e.g. gluten-free diet donor for a recipient with ment for 75 patients with recurrent CDI and found no significant coeliac disease). However, the working group noted that food difference in primary cure rates for patients with diabetes allergies are often poorly-defined clinically, and also mellitus, malignancy, or steroid use in the preceding three expressed concerns that there was no means to verify how months. closely a donor had followed an exclusion diet; as such, they The working group discussed the potential impact of donor felt unable to make any specific recommendation about FMT EBV and CMV status for the immunocompromised FMT recipient in patients with food allergies in general. In contrast, while at risk of severe infection if exposed to these viruses. Their the working group were unaware of any reports in the liter- opinion was that such recipients should only receive FMT from ature of anaphylaxis attributable to FMT, they felt that the donors with negative EBV and CMV status. theoretical risk of a serious adverse outcome in patients with Evidence: anaphylactic food allergy merited a specific recommendation The growing pool of experience in using FMT in CDI patients that such individuals should not be offered FMT. Similarly, the with a range of causes of immunosuppression demonstrates working group expressed concern about the theoretical risk of that it appears to be generally as safe and effective as in pa- adverse outcomes when administering FMT to patients with tients without immunosuppression (quality of evidence: 1-). advanced decompensated chronic liver disease (including Recommendation: translocation of microbial material from the intestinal tract FMT should be offered with caution to immunosuppressed into the portal and systemic circulations, and theoretical risk patients, in whom FMT appears efficacious without significant of sepsis), and felt that FMT should be used with caution in additional adverse effects (strong). this patient group. Good practice point: Evidence: Immunocompromised FMT recipients at risk of severe There is a wide range of FMT recipient exclusions listed in infection if exposed to EBV or CMV should only receive FMT different studies, but little evidence on the safety of FMT from donors negative for EBV and CMV (strong). administration in patients with these excluded conditions (quality of evidence: 4). Other comorbidities and FMT Good practice points: Only a limited number of cited studies included specific detail about the presence of comorbidities in patients i. FMT should be avoided in those with anaphylactic food receiving FMT. However, several studies reported median allergy (strong). Charlson comorbidity scores [12,14,15,18,55]. One randomised ii. FMT should be offered with caution to patients with CDI study reported the presence of IBD in 10/17 (59%) FMT re- and decompensated chronic liver disease (conditional). cipients [16], and there did not appear to be any significant difference in primary outcome measures in this group. Another randomised trial included 14/72 (33%) patients with IBD and Immunosuppression and FMT reported clinical cure of CDI in 12/14 (86%) of these patients One randomised study [16] included patients with immu- [13]. This study also included 64/72 (89%) patients with car- nodeficiency (treatment with immunosuppressive therapy diac, respiratory, renal, central nervous system or multi-organ (azathioprine, ciclosporin, infliximab, methotrexate alone, or system comorbidities [13]; however outcomes were not strat- in combination with corticosteroids) (n ¼ 18), renal transplant ified according to co-morbidity. Kelly and coauthors [65] re- (n ¼ 5), chronic haemodialysis (n ¼ 5), solid organ tumours ported an overall cure rate of 94% in a subset of patients with (n ¼ 3) and haematological malignancy (n ¼ 4)) at the time of IBD. A meta-analysis of studies in which patients with IBD FMT. Clinical resolution rates after up to two FMTs were high: received FMT (either primarily as treatment for concurrent 27/29 (93%) for immunocompromised individuals, 5/6 (83%) for recurrent CDI, or with the aim of treating IBD) noted a small risk patients with IBD. of exacerbation of IBD in association with the use of FMT [85]. There are also limited data from case series and single case The working group noted the complexity of the relationship reports describing the use of FMT in immunocompromised pa- between IBD and CDI, given that IBD is itself a risk factor for tients. Agrawal and colleagues [60] included 46/146 (32%) pa- CDI. tients with a history of cancer, and an additional 15/146 (10%) Other exclusions have been more directly related to the patients with non-cancer-related immunologic dysfunction, mode of administration. For upper gastrointestinal delivery, although primary outcome measures are not specifically re- exclusion criteria have included delayed gastric emptying, ported for these groups. Overall cure at 12 weeks in a case chronic aspiration, ‘swallow dysfunction’, and dysphagia series of 80 patients with immunocompromise was reported in [17,55]. Exclusions for lower GI administration have included 71 (89%) patients [65]. Adverse events occurred in 12 (15%) colostomy/ileostomy [16,55], significant bleeding disorders immunocompromised patients; this included two deaths (one [12], untreated colorectal cancer [14,41,59], and ileus/small due to respiratory failure and another due to pneumonia bowel obstruction [55]. resulting from aspiration at the time of FMT administration) In summary, the working group noted that co-morbidities [65]; however, such adverse events have also been reported in among patients with recurrent CDI are common. Most studies non-immunocompromised patient populations [83]. Hefazi and did not analyse primary outcome measures according to co- coauthors described high efficacy rates in a case series of FMT morbidity; however, a small number of studies have analysed for recurrent CDI and a range of haematological or solid organ primary outcome measures (clinical cure) for patients with IBD B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S15 receiving FMT for recurrent CDI and have found no significant A widely-reported case study noted apparent weight gain in difference compared with those without IBD, along with no a recipient of FMT for treatment of CDI when an overweight overall significant worsening of IBD activity. donor was used [95], but any association between a donor with Evidence: a raised BMI and weight gain post-FMT has not been replicated There is growing evidence that FMT is safe and efficacious as elsewhere in the literature [96]. Whereas most randomised treatment for CDI in people with concomitant inflammatory studies did not report donor-specific BMIs, some have excluded bowel disease, but that there is the potential for FMT to cause a those without a ‘normal’ BMI [13,17]. The working group flare in IBD activity (quality of evidence: 1þ). considered an acceptable BMI as between 18 and 30 kg/m2. Recommendations: Evidence: There is considerable variability between studies with i. FMT should be offered to those with recurrent CDI and regards to age and BMI restrictions for donors, and no inflammatory bowel disease, but patients should be comparative studies (quality of evidence: 3). counselled about a small but recognised risk of exacer- Recommendation: bation of IBD (strong). People should only be considered as potential FMT donors if ii. FMT should be considered for appropriate patients with they are 18 and 60 years old, and have a BMI of 18 and 30 recurrent CDI regardless of other comorbidities kg/m2 (conditional). (conditional). General approach to the donor screening assessment There is a clear theoretical risk of the transmission of infection by FMT; furthermore, given the large number of What donor factors influence the outcome of faecal conditions in which perturbation of the gut microbiota has microbiota transplant when treating people with been described [97], there is a concern regarding a risk of Clostridium difficile infection? transmission of microbiota associated with vulnerability to disease. While FMT is efficacious for recurrent CDI, adverse General approach to donor selection events may be associated with its use (discussed further Excellent efficacy has been shown in treating recurrent CDI later), and long-term safety follow-up is lacking. The aim of a using FMT derived from both related [14,41,43,45,46,50, donor screening questionnaire and interview is to minimise 51,54,58,59,62,64,66,86,87] and unrelated [14e17,40,42,43, post-FMT adverse events by excluding potential donors from 46,58,62,64,66,77,79,86e91] donors. To date, there have whom FMT may be associated with risk to recipients. Rando- been no randomised studies comparing differences in efficacy. mised studies performed to date used various pre-screening Case series have tended to rely more on donation of stool from questionnaires, including self-screening questionnaires which healthy family members. In randomised studies using FMT, all focused on high risk behaviours for blood-borne infections donors were healthy unrelated individuals [12e18,92]. Three [12e16], questionnaires that focused on previous potential case series used donor stool from healthcare professionals transferable medical conditions [18], and adaptations from [44,66,89]; no randomised studies have used stool from this the American Association of Blood Banks Donor Questionnaire cohort. However, the working group noted that there were [14,17]. One randomised study used the OpenBiome ques- clear advantages to using FMT from a screened anonymous tionnaire as a screening questionnaire [98]. Some studies have donor, in particular with regards to monitoring and trace- suggested excluding potential donors who have recently ability, as discussed further later. travelled to defined regions (typically tropical areas), varying Evidence: between 3-6 months prior to donation [43,44,54,57, Both related and unrelated donors have been shown to be 60,64,79,91]; this is also the protocol employed in rando- acceptable as donors, but there has been no comparative study mised studies [14,16,18]. Another important point for assess- of the two groups (quality of evidence: 3). ment is recent use of medications by potential donors. In Recommendation: particular, given the profound effects of antimicrobials on the Related or unrelated donors should both be considered gut microbiota [99e102] (along with the theoretical concern acceptable. However, where possible, FMT is best sourced from that recent antimicrobials might precipitate gut colonisation a centralised stool bank, from a healthy unrelated donor with antimicrobial-resistant bacteria that could be transferred (conditional). during FMT) studies advocate either a three month [14,51,58e60,62,66,79] or six month [16,17,104,18,40, Age and BMI restrictions for potential donors 43,44,54,86,89,103] period without antimicrobial use prior to There are no well-defined age restrictions on donors. FMT donation. Randomised studies have used donors of 18 [12,77] and 60 The working group agreed that, given the growing evidence years old [15,17,18] with satisfactory outcomes. Two of the for the contribution of the gut microbiota to the aetiopatho- reviewed case series defined age limitations for donors as 18 genesis of colorectal carcinoma, patients with a significant and 50 years [77,93]. A recent study demonstrated that the personal or family history of (or risk factors for) this condition Bacteroidetes: Firmicutes ratio and microbial diversity was should be excluded as donors (Table 1). However, the working similar for donors older and younger than 60 years, and their group noted an added complexity, in that their recommenda- stool donations had similar clinical efficacy as FMT; however, tion was that potential donors may be up to 60 years of age, but there were losses of the phylum Actinobacteria and family bowel scope screening for colorectal carcinoma currently be- Bifidobactericeae from donors older than 60 years [94].On gins within the UK at 55 years of age, and formal NHS bowel balance, the working group agreed that an age range of 18e60 cancer screening starts at the age of 60 years [105]. The years was appropriate for donors. working group agreed that potential donors living in countries S16 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 with bowel cancer screening programmes that start before the Enterococci (VRE) carriage is relatively common in the com- age of 60 years should have therefore completed appropriate munity (probably related to food consumption) [108], com- screening with negative/normal tests before they are consid- munity strains of VRE are genetically distinct from (and ered further as donors. generally of much lower pathogenicity than) those found The working group was of the opinion that a screening nosocomially [109]; as such, the working group thought that process is mandatory; any positive responses should usually routine screening was not justified. The working group also result in exclusion from donation, although this will depend on noted that methicillin-resistant Staphylococcus aureus (MRSA) the particular circumstances/answers given. A donor screening carriage is very rare in healthy adults in non-healthcare set- questionnaire should be performed both prior to considering a tings (with significant intestinal carriage even rarer), and so did person as a donor, and also at a further point in time (discussed not justify routine screening. However, the working group further in Section Repeat donor checks, and donation acknowledged that the potential infection risk from VRE and pathway). MRSA would vary regionally dependent on local prevalence and Evidence: pathogenicity, and as such recommended that a risk assess- Based on the principles derived from blood transfusion, a ment is performed to assess whether screening for these or- donor screening questionnaire has become standard practice ganisms should be considered. (quality of evidence: 3). A donor laboratory screening should be performed both Recommendation: prior to considering a person as a donor, and also at a further It is mandatory to screen potential donors by questionnaire point in time (discussed further in Section Repeat donor and personal interview, to establish risk factors for trans- checks, and donation pathway). missible diseases and factors influencing the gut microbiota Evidence: (Table 1) (strong). Blood and stool screening is performed uniformly as a part of FMT donor selection, but with varying protocols between Laboratory screening of potential donors studies (quality of evidence: 3). Currently, there are no known confirmed cases of blood- Recommendation: borne pathogens being transmitted by FMT, but strict preven- Blood and stool screening of donors is mandatory (Tables 2 tative measures are important, as the potential risk of trans- and 3) (strong). mission is unknown. Many of the suggestions are extended from established blood screening guidelines [106]. Case series Repeat donor checks, and donation pathway almost universally screen for HIV, hepatitis B and hepatitis C as Almost all reviewed studies have repeated at least some a minimum [40e42,44e47,51,54,57e60,64,66,77,79,86,88,90, elements of the initial donor screening process either at the 91,107]; other studies (including the randomised trials) have time of donation of each stool sample used to prepare FMT, or a more thorough blood screening process [14e18]. Many studies at the end of a period of donation to assess ongoing suitability have also included a ‘metabolic/general blood screen’, to for inclusion. However, protocols have differed widely be- select out donors with hitherto undiagnosed chronic illness. tween studies. Table 2 shows the suggested blood screening protocol of the The opinion of the working group was that when a donor had BSG/HIS working group. met criteria for donation (both with an acceptable health The working group specifically discussed the role of questionnaire and satisfactory laboratory tests), they were screening donors for their EBV and CMV status; the importance suitable to begin donation of stool that may be prepared into of the rationale for this is discussed in Section FMT. Repeat donor screening was also deemed necessary. In Immunosuppression and FMT. They agreed that EBV and CMV centres where frozen FMT is being prepared, stool may be testing was only required where there is the potential that the collected and processed immediately after the first donor FMT prepared from that donor would be administered to screen is successfully completed, but should be stored in immunosuppressed patients at risk of severe infection if ‘quarantine’ pending further donor screening, rather than used exposed to CMV and EBV. immediately for clinical use. At the end of the locally-defined The primary aim of stool screening of potential donors is to period of donation, potential donors should undergo repeat minimise the risk of transmission of pathogens; again, the testing, with a further health questionnaire and laboratory relative novelty of FMT for CDI means that these risks are not screening. If the donor’s health questionnaire remains currently well-defined. Stool screening protocols are universal acceptable and repeat laboratory screening is negative at this among published studies, although widely-variable protocols point, then the frozen FMT may be released from ‘quarantine’, have been used. Table 3 displays the suggested stool screening and used. The working group thought that donor screening both protocol of the working group. The working group discussed before and after donation was the safest route possible, and stool screening for multi-drug resistant bacteria carriage, and that this represented the preferred scenario. A proposed agreed that carbapenemase-producing Enterobacteriaceae summary pathway for donor screening in this scenario is pro- (CPE) should be screened for. Although these bacteria are vided in Figure 1. carried only by a minority of the UK population, transfer into In centres using fresh FMT, the working group agreed that a debilitated patients with CDI is clearly undesirable given that repeat health questionnaire should be completed at the time CPE are potentially so difficult to treat. They also agreed that of donation of each stool sample used to prepare FMT. Formal extended-spectrum beta-lactamase (ESBL)-producing organ- repetition of both the personal interview/health questionnaire isms could also potentially cause severe disease (with limited and laboratory screening tests should occur at regular intervals antimicrobial options) if transplanted into patients with CDI, to ensure ongoing suitability for inclusion as a donor. The and so should also be screened for. While vancomycin-resistant working group’s opinion was that this repetition of the B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S17

Donor personal interview and health questionnaire

Interview and health Inclusion criteria Potential questionnaire results donor not met assessed by clinical team excluded

Inclusion criteria met

Laboratory screening – blood and stool assays ~ 14 days to receive all results Any tests Potential Review laboratory donor unsatisfactory screening excluded

All tests satisfactory

Provisionally accept as donor

• Start stool collection Period of and FMT preparation donation to be • FMT in quaratine/ locally-defined not for use until repeat screening

Repeat donor screening at Inclusion criteria end of donation period: not met, and/ or any Potential donor • Health questionnaire tests unsatisfactory • Laboratory screening excluded

Inclusion criteria still met, and all tests still satisfactory

Release FMT from quarantine for clinical use

Figure 1. Proposed summary pathway for donor screening for centres preparing frozen FMT from recurring donors. S18 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 screening process should occur at least once every four The reviewed randomised studies reported variable months. amounts of stool used in the preparation of each FMT aliquot, Evidence: and the lack of comparative data means that it is not possible Repetition of some or all elements of initial donor screening to link stool mass to outcome from these studies. However, a at a later point is standard practice, though the means of previous systematic review of case series using FMT as treat- assessment differs between studies (quality of evidence: 3). ment for recurrent CDI reported similar rates of treatment Recommendations: efficacy, but an approximate fourfold increase in recurrence rates, if <50g of stool was used compared with 50g [110]. i. In centres using frozen FMT, before FMT may be used Similarly, the initial volume of diluent used to create the clinically, donors should have successfully completed a faecal emulsion is variable between studies, although the donor health questionnaire and laboratory screening as- most common practice appears to be creation of a stool: says both before and after the period of stool donation. diluent ratio of approximately 1:5. The overwhelming major- This is the preferred means of donor screening (strong). ity of the reviewed studies used stool from only a single donor ii. In centres using fresh FMT, a repeat health questionnaire per FMT (rather than stool pooled from a mixture of donors), should be assessed at the time of each stool donation. To and there are no comparative studies of outcomes of CDI from ensure ongoing suitability for inclusion as a donor, the single donor versus pooled donor FMT; as such, the working donor health questionnaire and laboratory screening group found no justification to recommend donor stool pooling should be repeated regularly (strong). for FMT for CDI. The majority of studies have used preservative-free sterile 0.9% saline as the diluent for FMT production, although there have been a handful of reports of other diluents including What factors related to the preparation of the potable water [16,40,48]. There have been no comparative transplant influence the outcome of faecal microbiota studies of FMT diluent. In cases where frozen FMT is prepared, transplant when treating people with Clostridium an appropriate cryoprotective substance should be added prior difficile infection? to freezing. Most studies use glycerol at a final concentration of w10% [16,46]. It has been demonstrated that storing stool at General principles of FMT preparation -80C for up to six months in saline without glycerol decreases There is very little evidence or guidance on the collection of viable aerobic and anaerobic bacterial counts; the reduction donor stool. Critical steps during this process centre on the was statistically significant in all bacterial groups with the reduction of environmental cross-contamination risk, so the exception of E. coli and total anaerobes. When stored with use of clean collection devices and clean collection procedures glycerol, no significant reduction in viable counts was observed is advocated. To promote standardised practice and a safe and [79]. effective product, clear instructions should be provided to the A variety of homogenisation and open filtration systems donor for stool collection (Table 5). have been used, with no apparent major variation in efficacy. Regardless of the methods used to prepare FMT, stool do- Open filtration systems such as gauze [16,42,45,60], filter pa- nations should be processed within six hours of defaecation. per [44] and strainers/sieves [17,46] are unpleasant to use and The period of six hours has been generally applied across many pose a risk of external contamination. In order to best comply successful studies of FMT treatment in CDI [14,18,40,44,48,57], with GMP standards, a sterile, single-use closed homogenisa- although no formal comparative study has been undertaken. tion and filtration system is recommended. An example of such This strategy aims to minimise sample degradation and alter- a system includes the use of sterile filter bags inside a labora- ation over time, which may occur due to the complex meta- tory paddle homogeniser. bolic and environmental requirements of the faecal Evidence: microbiota. The mechanics of stool preparation vary widely between There are no comparative trials of anaerobically versus different studies. There are almost no comparative data for aerobically prepared FMT in the treatment of recurrent CDI. any of these variables (quality of evidence: 3). With the exception of small observational studies [46,79], the Recommendations: vast majority of FMT preparation has been undertaken aero- bically for the treatment of CDI and has proved highly effica- i. Donor stool collection should follow a standard protocol cious. There appears to be no clear need to process (strong). anaerobically, a method which introduces complexity and cost for the treatment of CDI.

Table 5 Criteria for stool collection Clear instructions should be given to donors regarding hand hygiene. Collect stool donations in a sealable clean container. A number of specifically designed devices are available commercially. Stool should ideally be passed directly into the clean container for collection; alternatively, it may be collected in clean tissue and transferred to the clean container. Stool should be transported to the FMT production site as soon as possible post defaecation (and within six hours); however, if a short period of storage is necessary, this should be at 4C. HIS/BSG FMT Guideline: Main Document. B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S19 ii. Donor stool should be processed within 6 hours of Evidence: defaecation (strong). Frozen FMT remains an efficacious treatment for CDI after iii. Both aerobically and anaerobically prepared FMT treat- six months frozen, but it has not been assessed at longer time ments should be considered suitable when preparing FMT points. There are little published data addressing optimal for the treatment of recurrent CDI (strong). thawing of frozen FMT (quality of evidence: 3). iv. Sterile 0.9% saline should be considered as an appropriate Recommendation: diluent for FMT production, and cryoprotectant such as FMT material stored frozen at -80oC should be regarded as glycerol should be added for frozen FMT (strong). having a maximum shelf life of six months from preparation v. Use 50g of stool in each FMT preparation (strong). (strong). Good practice points: Good practice points: 1. Consider thawing frozen FMT at ambient temperature, and i. Stool should be mixed 1:5 with diluent to make the initial use within six hours of thawing (conditional). faecal emulsion (conditional). 2. Do not thaw FMT in warm water baths, due to the risks of ii. Homogenisation and filtration of FMT should be under- cross contamination with Pseudomonas (and other con- taken in a closed disposable system (conditional). taminants) and reduced bacterial viability (strong).

Fresh vs frozen FMT Two randomised studies have examined this area. One What factors related to administration of the double-blind randomised study concluded that enema- transplant influence the outcome of faecal microbiota administered frozen FMT (n ¼ 91) was non-inferior for clinical transplant when treating people with Clostridium resolution of diarrhoea to fresh FMT (n ¼ 87) for the treatment difficile infection? of recurrent or refractory CDI [16] (with frozen FMT in this study stored at -20oC for up to 30 days). A further randomised Use of specific medications in the period around FMT study demonstrated statistically comparable remission rates administration for recurrent CDI with fresh or frozen FMT delivered colono- General principles of FMT administration. Bowel purgatives scopically (n ¼ 25/25 vs 20/24 respectively, p ¼ 0.233) (using have been proposed pre-FMT as a means of removing residual frozen FMT stored at -80oC for up to six months). These data antibiotics that may affect engraftment of transplanted mi- support the findings of earlier small observational studies croorganisms, and as a means of removing any residual [40,46]. Frozen FMT is also preferable to fresh FMT on logistical C. difficile toxin, spores and vegetative cells [114e118]. and cost grounds [16]. Banked frozen FMT also enables the Furthermore, bowel purgatives pre-colonoscopic FMT delivery window period for donor screening to be minimised, allowing facilitate safe endoscopy. Various bowel purgatives have been centres to more closely meet regulatory requirements (also see used in colonoscopic FMT studies, including polyethylene glycol Section Repeat donor checks, and donation pathway). (PEG) (often 4 litres) [14,17,40,46,51,59e61,86,103,119e121], Evidence: MoviPrep [40,46], and macrogol [13,15,18,64]. In those There is randomised trial evidence demonstrating that fresh studies that used an upper GI route for FMT, PEG [59,60,88] and and frozen FMT have comparably high efficacy (quality of evi- Klean-Prep [15,66] were used. FMT without bowel prepara- dence: 1þ). tion has also been used as treatment for recurrent CDI without Recommendation: any apparent reduction in efficacy, including in randomised The use of banked frozen FMT material should be considered studies [16]. preferable to fresh preparations for CDI (strong). The rationale for the use of proton pump inhibitors (PPI) prior to upper GI FMT is to minimise acidity which may Use of frozen FMT impair engraftment of transplanted microorganisms; howev- Frozen FMT has been used up to six months after storage at er, PPIs have been shown to alter the gut microbiota -80oC [17,46,79], with high efficacy rates (>70%) observed in [122,123], and have also been associated with primary and the cases treated. However, there have been no comparative recurrent CDI [124,125]. Some studies advocate the use of trials investigating storage durations. As already described, a PPI prior to receiving FMT via the upper GI route reduction in the viability of certain gut microbiota taxa was [42,44,50,88,89,126,127], but there appears to be compa- noted when faecal aliquots were frozen in 10% glycerol for six rable efficacy data in studies where it has not been used. months [79], and as such, the working group agreed that six Certain studies have also given recipients PPI prior to months was the acceptable limit for freezing of an FMT in receiving colonoscopic FMT [17,91]. glycerol. Storage at -80oC is recommended rather than -20oCto The use of prokinetics (such as metoclopramide) has been minimise sample degradation. described prior to FMT delivery via the upper GI tract route, but Warm water baths have been recommended to speed only in a very small number of studies [89]. Given the potential thawing [6]; however, the working group thought that this risk of regurgitation/aspiration associated with upper GI should be strongly discouraged, as this may introduce risks of administration of FMT, the working group felt that its use cross contamination by Pseudomonas species (and other con- should be considered where appropriate. taminants) from the water bath [111,112], and may reduce A single dose/short course of loperamide has been used bacterial viability in the FMT. Repetitive freeze thawing of FMT following FMT (predominantly for lower GI administration) in samples should be avoided as bacterial numbers will be an attempt to prolong the exposure of the FMT to the mucosa, reduced during this process [113]. and to aid retention of the FMT within the GI tract S20 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 [13,51,54,60,88,127]. One study utilised diphenoxylate with Washout period between antibiotic use and FMT. Nearly all atropine [59] instead. However, no studies have compared FMT studies specified a washout period after completing anti-CDI with and without anti-motility drugs. antibiotics and before administration of FMT. However, this The working group also discussed infection control aspects time period appeared to be arbitrarily selected and varied from as they apply to FMT administration. Specifically, they agreed as little as four [51] or 12 hours [56], up to 72 hours [41]. that recipients should ideally be cared for in a single room The majority of studies specified either 24 hours with en-suite bathroom facilities and, where appropriate, be [15,42,44,45,50,59,131] or 48 hours [46,47,54,65], however placed at the end of an endoscopy list, to facilitate enhanced some allowed a range from 1-3 days [16,49,57,58,60]. One environmental decontamination and prevention of trans- study appeared to allow co-administration of vancomycin with mission of C. difficile spores. Protocols for decontamination bowel preparation, without a washout period [18]. of endoscopes should follow national guidance [128,129], The working group discussed the challenging scenario of using a sporicidal agent. Best practice for prevention of providing FMT to patients with recurrent CDI, but who also had transmission of healthcare-associated infections, as a strong indication for long-term non-anti-CDI antibiotics (e.g. described in national guidelines [130], should also be applied splenectomy, osteomyelitis, or infective endocarditis), or pa- throughout. tients who develop an indication for antibiotics for a reason Evidence: other than CDI shortly after receiving FMT. The concern in this These different classes of medications have all been used instance is that the use of antibiotics may limit engraftment of variably pre-FMT between different studies. They do not microbial communities derived from the FMT, and therefore appear to adversely affect the efficacy of FMT, and there are reduce its effectiveness. The working group discussed a recent sound reasons to expect that they may be beneficial (quality of retrospective study demonstrating that exposure to non-anti- evidence: 3). CDI antimicrobials within eight weeks of FMT is associated Recommendations: with an approximate threefold risk of FMT failure (n ¼ 8/29 failures with antibiotic exposure vs 36/320 failures without i. Bowel lavage should be administered prior to FMT via the antibiotic exposure) [132]. Similarly, the experience of the lower GI route, and bowel lavage should be considered large pan-Netherlands stool bank [133] was that w50% of their prior to FMT via the upper GI route; polyethylene glycol failures of FMT in the treatment of recurrent CDI occurred in preparation is preferred (conditional). patients who had received antibiotics within one month of their ii. For upper GI FMT administration, a proton pump inhibitor FMT. For patients requiring long-term antibiotics, the working should be considered, e.g. the evening before and group’s expert opinion was that such patients should still be morning of delivery (conditional). eligible for FMT, but that the regimen for the use of non-anti- iii. A single dose of loperamide (or other anti-motility drugs) CDI antibiotics should be decided on a case-by-case basis, should be considered following lower GI FMT delivery based on factors including response to FMT and/or strength of (conditional). indication of antibiotics. Both in this scenario, and the scenario in which antibiotics are required shortly after receiving FMT, Good practice point: the working party agreed that infectious diseases specialists/ medical microbiologists should be involved in making decisions i. Prokinetics (such as metoclopramide) should be regarding the choice of agents used. considered prior to FMT via the upper GI route Evidence: (conditional). A washout period between the end of antibiotic use and ii. Best practice for prevention of further transmission of CDI administration of FMT is usually described. However, no formal should be applied throughout when administering FMT to trial assessment as to the optimal length of this period has been patients with CDI (nursing with enteric precautions, undertaken (quality of evidence: 3). sporicidal treatment of endoscope, etc). Recommendation: To minimise any deleterious effect of antimicrobials on the FMT material, there should be a minimum washout period of 24 Additional antibiotics pre-FMT. Many studies have given hours between the last dose of antibiotic and treatment with further courses of conventional antimicrobial C. difficile FMT (strong). treatment prior to FMT. Regimens have included vancomycin Good practice point: alone [12,14,18,40,44,60,64,90,121], metronidazole or vanco- Consider consultation with infectious disease specialists or mycin [45,46,86,126], or alternatively vancomycin, fidax- medical microbiologists for advice whenever FMT recipients omicin or metronidazole [61], with one study using a range of also have an indication for long-term antibiotics, or have an regimens which included rifaximin [127]. The length of treat- indication for non-CDI antibiotics within eight weeks of FMT ment was also variable, ranging from 24 hours [59] up to four (conditional). days prior to receiving FMT [44,50]; however, comparative studies have not been undertaken. Route of FMT delivery Evidence: Introduction. FMT can be delivered via the lower GI route In many studies, additional anti-CDI antibiotics have been (retention enema, colonoscopy), upper GI route (endoscopi- used pre-FMT, with the aim of further reducing the burden of cally, or via nasogastric tube, nasoduodenal or nasojejenal C. difficile (quality of evidence: 3). tube), or via capsules (containing either frozen FMT or lyophi- Recommendation: lised faecal material). Systematic reviews with meta-analysis Administer further antimicrobial treatment for CDI for at suggest that FMT for recurrent CDI via colonoscopy may have least 72 hours prior to FMT (strong). slightly higher efficacy compared with upper GI administration B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S21 [131,134e136] with similar safety profiles, but also note the ii. Where upper GI administration is considered most trend towards using larger amounts of stool or ‘higher con- appropriate, FMT administration should be via nasogas- centration’ FMT in lower GI administration. One systematic tric, nasoduodenal, or nasojejunal tube, or alternatively review (reviewing principally case series, and including only via upper GI endoscopy. Administration via a permanent one randomised study) compared remission rates for CDI using feeding tube is also appropriate (strong). FMT delivered to different areas of the GI tract, and reported that for FMT infused into the stomach, duodenum/jejunum, Good practice points: caecum/ascending colon, and rectum the rates of cure rate were 81%, 86%, 93%, and 84%, respectively [135]. i. It is recommended that no more than 100ml of FMT is In the only randomised study that directly compared upper administered to the upper GI tract (conditional). and lower GI administration, there was no significant differ- ii. Upper GI administration of FMT should be used with ence in overall cure rate (p ¼ 0.53) [17]. caution in those with swallowing disorders (strong).

Upper gastrointestinal tract administration of FMT. FMT has been shown to be safe and efficacious in the treatment of Lower gastrointestinal tract administration of FMT. FMT via C. difficile when administered via nasogastric tube enema: Successful treatment of C. difficile with FMT enema [42,44,50,66,87,127], nasoduodenal tube [15,88,89], entero- has been demonstrated [16,43,47,58,60,87,90] but enema ap- scopy [126,127], or via the infusion channel on a gastroscope pears to have a lower efficacy than other routes of FMT [45,50]. In a randomised trial, nasoduodenal donor FMT has been administration. Specifically, in a randomised study primarily showntobemoreefficaciousthanvancomycinintreatingrecur- comparing the efficacy of fresh and frozen FMT in the treat- rent CDI [15]. Furthermore, it has been shown that FMTcan also be ment of recurrent CDI, only 52.8% of patients in the ‘frozen’ safely and effectively delivered via a percutaneous endoscopic arm and 50.5% of patients in the ‘fresh’ arm of the study gastrostomy tube [50,87]. The working group noted that upper GI (n ¼ 57/108 and 56/111 respectively) experienced resolution of administration of FMT may be particularly suitable for certain symptoms after a single enema, by modified intention to treat patient groups, such as those in whom there are contraindications analysis [16]. However, resolution rates in both arms only or who would find it difficult to tolerate lower GI endoscopy, and/ reached >80% after at least three enemas [16]. A recent or patients unlikely to be unable to retain enemas. randomised study demonstrated similar rates of recurrence of Typically, smaller volumes of faecal suspension are CDI in patients with recurrent CDI treated with either a single administered to the upper GI tract compared with lower GI FMT enema or a six week vancomycin taper (9/16 patients with administration, with quoted volumes ranging from 25ml [44] recurrence vs 5/12 respectively) [12]. Notwithstanding this, up to 150ml [88]- 250ml [42,89]. Up to 500ml of suspension enemas do have specific advantages, such as being a treatment has been given safely and effectively via the upper GI route option where full colonoscopy is contraindicated. It is also [15,81]. However, the working group expressed concerns possible to give multiple infusions relatively easily and outside regarding the risk of regurgitation and aspiration if large vol- a hospital setting. umes of FMT are administered to the upper GI tract, and also FMT via colonoscopy: Randomised study evidence has discussed cases in which this has been described with adverse demonstrated that colonoscopic FMT has higher efficacy in outcomes [83]. This included a reported death from aspira- treating recurrent CDI than vancomycin [18]. Efficacy is similar tion, after 100e150ml of FMT was delivered by enteroscope whether FMT is fresh or frozen, but modestly reduced when into the distal duodenum under general anaesthetic as using a lyophilised FMT product [13]. Colonoscopic delivery of attempted treatment for recurrent CDI [137]. A further report donor FMT into the ileum or caecum was associated with a 91% described a case of fatal aspiration pneumonitis likely related cure rate for recurrent CDI [14]. Observational studies high- to a 500ml FMT via nasoduodenal tube; this patient had a lighted similar success, describing cure rates of 88% (n ¼ 14/16) swallowing disorder following oropharyngeal radiation after [79] and 91% [51] (n ¼ 21/23) in response to infusion of donor surgical removal of a maxillary carcinoma two years previously FMT into the caecum or terminal ileum. A further advantage of [81]. Based on their expert opinion, the working group rec- using colonoscopy to administer FMT has been to allow ommended that upper GI FMT should be used with caution in assessment for the presence of pseudomembranes; in certain those at risk of regurgitation (e.g. known large hiatus hernia, reviewed studies, the presence or absence of pseudomem- gastro-oesophageal reflux disease, etc.) and/or with swal- branes has influenced the FMT regimen used [18,78]. However, lowing disorders (although administration via a gastrostomy the working group noted that many patients with CDI are frail tube would be acceptable). They also recommend that no and elderly, and as such it will not always be safe or feasible to more than 100ml of FMT should be administered to the upper undertake colonoscopy in this particular group of patients. GI tract to minimise these risks. Flexible sigmoidoscopy appears to be an feasible option where Evidence: full colonoscopy cannot be performed e.g. unable to tolerate There is randomised trial evidence demonstrating that up- colonoscopy, severity of colitis [61,65]. per GI administration of FMT for CDI is effective, although The amount of faecal suspension via enema has varied be- there are concerns about the possibility of aspiration and tween 150-500mls [16,43,47,60,90]. The amount of faecal vomiting associated with its use (quality of evidence: 1þ). suspension delivered via colonoscopy has been similarly vari- Recommendation: able, with some studies suggesting as little as 100ml can be used with success rates of 94% [86]. 250ml-400ml had a success i. Upper GI administration of FMT as treatment for recurrent rate of 100% [41], whereas infusions of up to 500e700ml were or refractory CDI should be used where clinically appro- associated with cure rates of 92% [51]. However, the working priate (strong). group noted that it is difficult to compare ‘concentration’ of S22 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 FMT in different studies as different protocols used varied efficacy to other modalities of administration. However, cap- starting amounts of faecal material. Currently, there are no sules are a relatively new modality of administration, and randomised studies that compare concentration/volume of further data are awaited on longer term efficacy and safety, colonoscopic or enema FMT. As such, no recommendation was and the optimal mechanics of preparation and administration made to this regard. (quality of evidence: þ1). Evidence: Recommendation: Randomised trial evidence demonstrates the efficacy of FMT Capsulised FMT holds promise as a treatment option for as treatment for CDI when administrated either as enema or via recurrent CDI and should be offered to patients as a potential colonoscopy (quality of evidence: 1þ). treatment modality where available. Capsule preparations Recommendations: should follow a standard protocol. Further evidence regarding optimal dosing and formulation is required (conditional). i. Colonoscopic administration of FMT as treatment for recurrent or refractory CDI should be used where appro- What is the clinical effectiveness of FMT in treating priate (strong). conditions other than Clostridium difficile infection? ii. Where colonoscopic administration is used, consider preferential delivery to the caecum or terminal ileum, as Introduction this appears to give the highest efficacy rate In current clinical practice, FMT is used predominantly in (conditional). the treatment of recurrent CDI. Its success has led to explo- iii. FMT via enema should be used as a lower GI option when ration of its efficacy in other GI diseases, primarily ulcerative delivery using colonoscopy or flexible sigmoidoscopy is colitis (UC), where perturbation of the gut microbiota has been not possible (strong). observed and implicated in disease pathogenesis [139]. Due to variability of the quality, methodology and cohorts of patients recruited in trials of FMT for non-CDI indications, and in order Capsulised FMT. Capsulised FMT aims to remove some of the to control for significant confounding factors, the working concerns regarding conventional FMT, such as the invasive group only included randomised trials involving patients with means of administration and palatability. The largest case se- well-defined conditions and in which there was a primary ries describing the use of capsules as treatment for recurrent clinical outcome. To date, there have been a total of 71 such CDI [77,93] noted clinical resolution at eight weeks off anti- studies investigating the role of FMT in IBD; of these, only four ¼ biotics for CDI in 82% of cases (n 147/180) after one course of are prospective randomised controlled trials, limited to pa- ¼ capsules, and 91% (n 164/180) after two courses. The cap- tients with ulcerative colitis [140e143]. Five other reviewed sules contained frozen FMT prepared in a diluent of saline with randomised studies investigated the use of FMT in irritable 10% glycerol; 15 capsules were administered each day for two bowel syndrome [144], slow transit constipation [145], hepatic consecutive days (equating to a mean 48g of original crude encephalopathy [146] and metabolic syndrome [147,148]. stool). Other smaller case series have demonstrated compa- rable results [91,127,138], including when lyophilised stool is Use of FMT for ulcerative colitis used instead of frozen whole FMT [138]. Efficacy. All four RCTs, with a total of 277 subjects, included The working group reviewed two randomised studies which patients with mild to moderate UC (Mayo score 3e11 and have examined the efficacy of capsulised FMT in treating endoscopic sub-score of at least 1). Participants were aged recurrent CDI. In one study, published in abstract form [98],a between 27 and 56 years and largely included patients on ‘high dose’ regimen of frozen FMT capsules (30 capsules each stable immunosuppressive therapy (only one study excluded day for two days) was compared with ‘low dose’ (30 capsules patients using biologic treatments and methotrexate within in one day). CDI resolution was comparably high in both arms the preceding two months) [140]. Three studies included pa- ¼ with one treatment course (77% (n 7/9) in the ‘high dose’ tients on oral corticosteroids at the time of FMT, however only ¼ arm vs 70% (n 7/10) in the ‘low dose arm’. Four of five initial two required a mandatory wean of these to meet eligibility. non-responders entered remission after a second capsule Studies generally included patients with all disease distribu- course with the ‘high dose’ regimen [98]. In a recent large tions found in UC. Time to evaluation of response to FMT in randomised trial, patients with recurrent CDI were rando- these studies varied between seven and twelve weeks. Two mised to receive thawed frozen FMT either via colonoscopy or studies used autologous FMT as placebo [140,143]. Three of the via capsules (one treatment of 40 capsules) [11]. On per four studies demonstrated that patients receiving donor FMT protocol analysis, remission at 12 weeks after a single treat- were significantly more likely to achieve clinical and endo- ¼ ment occurred in 96% in both arms (n 51/53 by capsule, scopic remission compared with placebo [141e143]. The ¼ n 50/52 by colonoscopy). pooled rate of combined clinical and endoscopic remission was The working group discussed certain unresolved issues 27.9% for donor FMT and 9.5% for placebo. A pooled risk ratio regarding capsules. Specifically, capsules are often large, and for failure of FMT to achieve these combined outcomes was 0.8 swallowing 30 capsules in a single day may be a significant (95% CI: 0.7e0.9). Deep remission (histological) was only re- undertaking for patients with CDI, such as the frail elderly with ported in one RCT: 18.4% of patients receiving FMT achieved an existing high pill burden. They also noted that follow-up this outcome compared with 2.7% of those receiving placebo data post-capsule administration is relatively short compared [141]. with other modalities of FMT. Evidence: Characteristics of FMT preparation and delivery. The four Case series and RCT evidence demonstrate that capsulised RCTs varied in their FMT preparation and delivery methodol- FMT is efficacious in treating recurrent CDI, with comparable ogy. Two RCTs delivered frozen FMT, one fresh FMT and one B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S23 used a combination. Three RCTs with a positive outcome via nasoduodenal tube of FMT obtained from lean donors. This delivered the FMT via the lower GI route; these studies used a improvement was observed at six weeks post-FMT, but was no high intensity protocol ranging from a total of three infusions in longer present by 18 weeks. No improvement in insulin sensi- one week to 40 FMTs over an eight week period [141e143]. The tivity was identified in patients transplanted with autologous other RCT (that failed to show efficacy of FMT for UC) had FMT (i.e. patients transplanted with their own collected adopted a low intensity protocol of two nasoduodenal infusions faeces). The improvement in peripheral insulin sensitivity in given three weeks apart [140]. Interestingly, the only RCT that the lean donor FMT group was accompanied by a small but prepared stool in anaerobic conditions demonstrated the significant improvement in HbA1c at six weeks [148], but no highest rate of steroid-free clinical remission and steroid-free improvements in other metabolic parameters, such as weight. clinical response with donor FMT [143]. A further interesting While these data are of interest, the working group felt that observation in one study was a trend towards higher rates of the limited, transient nature of the benefits seen and small size remission with one particular donor [141]. of the studies meant that FMT could not be recommended as treatment for metabolic syndrome. Adverse events. Short-lived GI symptoms such as abdominal bloating, cramps, diarrhoea and fever were reported in pa- Future directions for randomised trials of FMT for non- tients receiving FMT for UC. There were no significant differ- CDI indications ences in serious adverse events between patients receiving Currently there are a large number of randomised trials FMT compared with placebo (10 vs 7 respectively). Most of the (including RCTs) being undertaken globally, to evaluate the serious adverse events were a consequence of worsening coli- potential role of FMT as treatment for a wide range of condi- tis: one patient who received FMT required a colectomy [140]. tions. The working group concluded that until there are more In addition, one patient developed concurrent CDI [141].No reliable data to inform decision-making, the best practice deaths were reported in any of the studies. principles described in this document for the governance of an FMT service for recurrent CDI should also be applied to FMT Use of FMT in functional bowel disorders clinical trials for other conditions. However, specific adapta- Two RCTs have investigated the role of FMT in functional tions may be considered depending on the condition being bowel disorders. In a double-blind placebo controlled RCT that studied, e.g. consideration of using anaerobic conditions for recruited 90 patients with IBS with diarrhoea or with diarrhoea the preparation of FMT in trials for the treatment of UC, as and constipation [144], the primary endpoint only just reached described above. statistical significance in inducing symptom relief (as assessed Evidence: by 75 point reduction in IBS-severity scoring system at three FMT has the potential to be an effective treatment option months following a single infusion FMT by colonoscopy) for mild to moderate ulcerative colitis, and appears to be safe (p ¼ 0$049). The second RCT randomised 60 patients with slow despite the use of immunosuppressive therapy. FMT may also transit constipation to either six consecutive days of have a potential role in the treatment of functional bowel nasogastric-delivered FMT or conventional treatment [145]. disorders. However, recommendations for clinical use for both This demonstrated that a significant proportion of patients of these indications cannot be made until there is clearer ev- achieved the primary endpoint of a mean of at least three idence of the most appropriate patient characteristics, prep- complete spontaneous bowel movements per week (53.3% vs. aration methodology, route of delivery and intensity of 20.0%, p ¼ 0.009) along with improvement in stool consistency administration of FMT (quality of evidence: 1þ). The evidence score and colonic transit time. However, the intervention for the use of FMT in hepatic encephalopathy and metabolic group had more treatment-related adverse events than the syndrome is currently limited, and further well-designed RCTs control group (total of 50 vs 4 cases). are needed to evaluate its potential role here (quality of evi- dence: 1-). Use of FMT in hepatic encephalopathy Recommendation: One small study has investigated the role of FMT in the FMT is not currently recommended as treatment for in- management of hepatic encephalopathy (HE) [146]. This RCT flammatory bowel disease. Apart from CDI, there is insufficient randomised 20 male patients with cirrhosis with refractory HE evidence to recommend FMT for any other gastrointestinal or to receive either five days of broad-spectrum antibiotic pre- non-gastrointestinal disease (strong). treatment followed by a single FMT enema or standard of care. Patients in the FMT arm had a significantly lower inci- Basic requirements for implementing a FMT service dence of serious adverse events and improved cognition. The Model for End-Stage Liver Disease (MELD) score, however, As discussed above, there is an absence of published studies transiently worsened post-antibiotics in the FMT arm. The to support the recommendations in this section (although the study was potentially confounded as patients in the FMT arm experience of setting up a nationwide stool bank has recently continued to receive lactulose and/or rifaximin for treatment been reported from the Netherlands [133]). This section is of their HE. therefore based on the working group’s expert opinion and experience of developing FMT services. Use of FMT for metabolic syndrome Two randomised studies [147,148], with a combined total of General considerations 56 patients, demonstrated an improvement in peripheral (but Although it is possible to prepare and administer FMT on not hepatic) insulin sensitivity in Caucasian male obese pa- an individual patient basis in a single hospital, the regulatory tients with metabolic syndrome following one or two infusions requirements are more readily fulfilled by a specialist centre S24 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 approach for the production of a safe FMT product. This Legal aspects and clinical governance particularly applies to record keeping and staff expertise in In the United Kingdom, FMT is now considered a medicinal quality control and production. Recent European consensus product based on the definitions of purpose and efficacy, in The advice suggests that FMT should be administered in a referral Medicines Directive 2001/83 and The Human Medicines Regu- centre [6], however an alternative approach which limits the lations [19]. As the competent authority for medicines regu- need for patient transfer is to undertake controlled pro- lation, the Medicines and Healthcare products Regulatory duction in a large centre and transport treatment to the Agency (MHRA) has indicated that the approach to regulation patient, a supply model which has been well established in will be proportionate, depending on factors such as supply the USA (OpenBiome) [149] and has also been successfully being within or outside a legal entity and FMT production scale. replicated in the UK in a large centre in Birmingham, which Specifically: has supplied FMT to nine NHS Trusts across three regions [28]. This service design only requires that a responsible When FMT is supplied on prescription on a named patient clinician is capable of administering the FMT safely at the basis, then supply under a pharmacy exemption may be satellite clinical site. It also eliminates the need for patient used subject to ensuring proper governance and trace- transfer between clinical sites, which in the case of severe ability [19]. CDI may not be practical. If production scale reaches an ‘industrial’ level, defined The working group encouraged the use of frozen FMT ma- ‘by virtue of the batch sizes, the extent of processing terial supplied from a carefully controlled production site. This and/or whether potential use includes supply between allows donor screening more closely to meet regulatory re- legal entities’ [19], the route to regulation is via adher- quirements, ensuring that the window period between donor ence to HMR and formal Manufacturer’s ‘Specials’ (MS) testing and FMT production is maintained to a minimum. The license. costs of donor screening are substantially reduced using this If a supply is to a clinical trial, then an MIA (IMP) supply model, as a single donor can provide multiple FMT do- manufacturing license is required (further information on nations under a single screening period. license applications [150] and specials [151] is available The working group also noted that given the novelty of FMT, online). awareness of this as a potential treatment option for recurrent or refractory CDI may be low amongst certain groups of clini- Centres establishing an FMT service should undertake steps cians. For instance, clinicians working in primary care, or to ensure practice meets the required compliance levels and those whose practice is not located near to an FMT centre, are seek guidance from the MHRA. If pharmacy exemption is likely to have less knowledge about the potential suitability of applied, there should be justifiable processes in place to FMT for patients with CDI, or be unaware of referral pathways. ensure traceability, health and safety, governance and to As such, there is a responsibility for FMT centres to raise prevent cross-contamination. FMT is regulated as a medicine, awareness and educate as wide a range of clinicians as rather than a tissue, but no products have been licensed possible about the potential role for FMT. Furthermore, following an assessment against the criteria of safety, quality microbiology staff processing stool samples for C. difficile and efficacy, for there is a possible risk that donor screening assays from the community should proactively liaise with pri- protocols will not be sufficiently considered, a step which is mary care teams where recurrent positive tests are received critical to the quality of the product and therefore safety of the from a single patient to raise awareness and suggest the option patient [152]. To mitigate this, it is advisable that donor of FMT. screening protocols are under regularly review and risk Similarly, given the expectation that FMT and/or other assessment, and to ensure that consideration is also given to ‘microbiome therapeutics’ are likely to play an increasing role the Guide to Quality and Safety Assurance for Human Tissues within medicine over future years, there is also an expectation and Cells for Patient Treatment, particularly Annex B related to for FMT centres to not only educate about the potential role for donor testing [153]. When formal licencing is sought, this is FMT, but also to train relevant healthcare professionals in the overseen by a Production Manager and Quality Control Manager practicalities of delivering an FMT service, to enable longer- if under an MS, or by a Qualified Person if under an MIA (IMP). term ongoing provision of services. This is likely to be most of Both should follow the Good Manufacturing Practice (GMP) relevance to specialty trainee and consultant physicians spe- guidelines, found within The Orange Guide Rules and Guidance cialising in gastroenterology, infectious diseases and/or medi- for Pharmaceutical Manufacturers and Distributors 2017 [154], cal microbiology, but potentially to other healthcare or at: https://ec.europa.eu/health/documents/eudralex/vol- professionals too, including infection prevention and control 4_en. nurses, infectious diseases pharmacists, etc. The working group noted that outside the UK, the legal and Evidence: regulatory framework relating to FMT was highly variable be- Working group consensus opinion (quality of evidence: 4). tween different countries. They agreed that FMT should only be Good practice points: administered after appropriate approval from the competent body of each country. i. The development of FMT centres should be encouraged Evidence: (strong). Working group consensus opinion and legal requirement ii. FMT centres should work to raise awareness about FMT as (quality of evidence: 4). a treatment option amongst clinicians caring for patients Good practice point: with CDI, and provide training to relevant healthcare In the UK, FMT must be manufactured in accordance with professionals on the practicalities of delivering an FMT MHRA guidance for human medicines regulation. When FMT is service (conditional). supplied on a named patient basis, within a single organisation, B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S25 a pharmacy exemption may be used, subject to ensuring proper Evidence: governance and traceability. All centres that are processing Working group consensus opinion (quality of evidence: 4). and distributing FMT should seek guidance from the MHRA and Good practice point: where necessary obtain appropriate licenses prior to estab- Utilise suitable laboratory facilities and infrastructure for lishing an FMT service. This is a legal requirement. In countries FMT production (strong). other than the UK, FMT should only be manufactured following appropriate approval from the national authority of that FMT manufacturing country (strong). It is strongly recommended to employ a batch numbering system to track FMT preparations from production to use. It Multidisciplinary teams should be possible from records to identify an individual FMT To promote safe and high quality FMT supply, it is strongly aliquot, trace it to a specific donation, and identify all other recommended that providers adopt a multidisciplinary team FMT aliquots prepared from the same donation. It must also be approach. The choice of the team required is subject to the clear which FMT aliquots patients have received, which should scale of production, but should involve as a minimum a clinical be verifiable from the donor to the patient and vice-versa. It is gastroenterologist, microbiologist/infectious diseases clini- therefore strongly recommended that a treatment directory be cian, state-registered experienced healthcare scientist and maintained documenting all production and use of FMT, and pharmacist. Governance and quality expertise will be required, that an unambiguous record is created in the patients’ clinical which may be provided by consultation. If FMT production is to notes to identify the specific FMT batch number. Further to be under a ‘specials’ licence, the team should be expanded to this, it is also recommended that treatment directories also include a Qualified Person, Quality Manager and Production record clinical outcome, such as that developed in the USA Manager, all with GMP training. [155] and Germany [156] to standardise and improve future Evidence: clinical practice. Working group consensus opinion (quality of evidence: 4). Evidence: Good practice point: Working group consensus opinion (quality of evidence: 4). A multidisciplinary team should be formed to deliver FMT Good practice point: services (strong). Ensure traceability of supply (strong).

Infrastructure FMT production quality control Dedicated laboratory facilities for FMT production are Safety and clinical governance is a central responsibility for recommended to ensure that the process adheres to Health FMT centres, particularly in light of the absence of phase III and Safety requirements, to reducetheriskofcross- licensing trials for FMT, which would normally be required for a contamination, and to facilitate standardisation of the pro- novel medicinal product. Reporting and investigating adverse ductionprocess.Insomestudies,FMThasbeenpreparedina events and reactions contributes to knowledge of the FMT clinical environment [80]; however, this may not be advis- safety profile, while also identifying previously unknown safety ablebecauseoftherisksofcross-contamination.The issues. Governance structures and processes must be in place to manipulation of human stool should be conducted in a monitor, notify and investigate all FMT-related adverse events Containment Level 2 laboratory according to current Health or reactions locally, and FMT users are encouraged to use the and Safety guidance (Health and Safety at Work Act 1974, MHRA Yellow Card Scheme for formal notification. FMT supply COSHH Control of Substances Hazardous to Health Regula- should be suspended if serious adverse events or reactions tions, 2002), and at least within a microbiological safety occur which are directly attributable to FMT, and there should cabinet which provides user protection (Class I) or, ideally, be a clear documented pathway to achieve this. To facilitate a user and product protection (Class II). To meet the re- ‘look-back exercise’ if required, it is advisable to store docu- quirements of GMP, this facility should be sole use or be risk mentation and reference samples, both product-based and assessed for multipurpose use with adequate separation of donor/patient-based. Specifically, retention of production different activities. The working group recommend that the documentation should be for at least five years after the use of facility complies with the new GMP production facility the batch; retention of reference FMT samples (and stool classificationof‘cleannotsterile’.Theuseofpersonal samples from donors and recipients) should be for at least one protective equipment - such as laboratory coat, gloves and year after the last use. Retention of excipient samples should be face mask - is also recommended to prevent production for at least one year after expiry of the excipient. contamination. It is essential to risk assess the process and Evidence: develop control measures to reduce microbial ingress into Working group consensus opinion and legal requirement the facility and monitor the microbiological cleanliness of (quality of evidence: 4). theproductionsuite.FMTpreparation under a ‘specials’ Good practice point: licence should ensure that the production process is inte- Monitor, notify and investigate all adverse events and re- grated into a Quality Management System, to safeguard actions related to FMT (strong). production and maintain the minimum criteria for audit, monitoring, standard operating procedures, document con- Donor screening governance trol, training, facilities, equipment and storage. With regard The testing requirements for donor screening have been to storage, it is essential that the freezer system has real- discussed previously; however, it is worth noting here the time temperature monitoring which provides notification pertinent clinical governance issues which should be outside pre-set limits. addressed. Donor anonymity should be maintained at all times. S26 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 The laboratory undertaking testing of donor samples should be FMT (or any form of ‘bacteriotherapy’) may be inappro- competent for such activity, demonstrable by accreditation priate, including those with very marked immunosup- with the United Kingdom Accreditation Service (UKAS). The pression, and/or multi-organ disease. Despite high levels results of donor testing should remain confidential. There of efficacy, there is a small but appreciable FMT failure should be appropriate standard operating procedures to ensure rate and it is not currently understood whether this is due that the outcome of donor screening is built into a robust FMT to underlying donor or recipient factors. Therefore, a batch release process. To ensure unbiased autonomy during research priority should be in basic and translational donor screening, it is suggested that a clinician independent to studies better to define the mechanisms underlying the the FMT production team is responsible for ratifying FMT do- efficacy of FMT in CDI. This includes comparing the nors prior to donation. Finally, the duration of donor follow-up structure and function of the microbiota of donors to should be considered and extend beyond the period of active patients pre-FMT and post-FMT, via techniques including donation to capture acute and chronic health changes. next-generation microbial sequencing, metabolic Evidence: profiling, and immunological assays. This would allow the Working group consensus opinion (quality of evidence: 4). refinement of FMT from its current state to a more tar- Good practice point: geted therapy, removing the concerns associated with Ensure the clinical governance of donor screening (strong). FMT. The working group identified a need for further well- Conclusions designed RCTs to investigate the potential role of FMT for non-CDI indications. FMT has become an accepted, efficacious treatment for recurrent and/or refractory CDI. In developing this guideline, Appendices. Supplementary data the evidence for the technique has been reviewed in the context of other available treatments. Specific guidance for Supplementary data related to this article can be found at best practice for an FMT service is provided. https://doi.org/10.1016/j.jhin.2018.07.037.

Further research References As described within this guideline, many aspects of the [1] Lawson PA, Citron DM, Tyrrell KL, Finegold SM. Reclassification terminology of CDI are used variably between studies, and of clostridium difficile as clostridioides difficile (hall and o’toole end-points in FMT trials are inconsistent. The working 1935) pre´vot 1938. Anaerobe 2016;40:95e9. https://doi.org/ group noted the need to standardise this terminology to 10.1016/j.anaerobe.2016.06.008. allow more robust comparisons between studies. [2] National Institute for Health and Care Excellence (NICE). Faecal Given the relative novelty of FMT as a procedure, any microbiota transplant for recurrent clostridium difficile infection potential long-term adverse events associated with its j guidance and guidelines j nice. NICE; 2014. https://www.nice. use are poorly-defined. The establishment of formal FMT org.uk/guidance/ipg485. [last accessed 2 October 2017]. [3] Public Health England. Updated guidance on the management registries should be considered. While this would pri- and treatment of clostridium difficile infection. Public Heal marily act as an important tool for defining the safety and Engl 2013:1e29. https://assets.publishing.service.gov.uk/ efficacy of FMT, it would also be a valuable database for government/uploads/system/uploads/attachment_data/file/ researchers within the field. Standardisation of other key 321891/clostridium_difficile_management_and_treatment. documentation related to FMT administration (e.g. pdf. [last accessed 20 March 2017]. establishment of a proforma for assessing eligibility for [4] Debast SB, Bauer MP, Kuijper EJ. European society of clinical FMT and/or follow-up after FMT) would also be advanta- microbiology and infectious diseases: update of the treatment geous for the same reasons. guidance document for clostridium difficile infection. Clin The working group noted the lack of consistency in defi- Microbiol Infect 2014;20:1e26. https://doi.org/10.1111/1469- nitions related to the severity of CDI disease and to 0691.12418. [5] Mcdonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, response or failure to FMT. This limited interpretation of Coffin SE, et al. Clinical practice guidelines for clostridium the published studies. As such, the working group thought difficile infection in adults and children: 2017 update by the that standardisation of these definitions would allow Infectious Diseases Society Of America (IDSA) and Society For more accurate delineation of the factors influencing the Healthcare Epidemiology of America (SHEA). Clin Infect Dis efficacy of FMT for CDI. The working group also noted that 2018;31:431e55. https://doi.org/10.1093/cid/cix1085. only one reviewed study had reported the relationship [6] Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovi c M, Kump P, between C difficile ribotype and FMT outcome, and that Satokari R, et al. European consensus conference on faecal recording of this information should be encouraged better microbiota transplantation in clinical practice. Gut to evaluate its influence. 2017;66:569e80. https://doi.org/10.1136/gutjnl-2016-313017. Further well-designed clinical trials (in particular, RCTs) [7] Ko¨nig J, Siebenhaar A, Ho¨genauer C, Arkkila P, Nieuwdorp M, Nore´n T, et al. Consensus report: faecal microbiota transfer - are required to identify the optimal means of adminis- clinical applications and procedures. Aliment Pharmacol Ther tration of FMT as treatment for recurrent and/or re- 2017;45:222e39. https://doi.org/10.1111/apt.13868. fractory CDI. [8] Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC, The working group noted that even capsulised FMT may Franzos MA, et al. Treating clostridium difficile infection with be associated with potential drawbacks. They also noted fecal microbiota transplantation. Clin Gastroenterol Hepatol that there are many patients with recurrent CDI for whom 2011;9:1044e9. https://doi.org/10.1016/j.cgh.2011.08.014. B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S27

[9]KumpPK,KrauseR,SteiningerC,Gro¨chenig HP, Moschen A, [22] Petrof EO, Gloor GB, Vanner SJ, Weese SJ, Carter D, Madl C, et al. Empfehlungen zur anwendung der fa¨kalen Daigneault MC, et al. Stool substitute transplant therapy for the mikrobiotatransplantation “stuhltransplantation”: konsen- eradication of clostridium difficile infection: “repoopulating” sus der o¨sterreichischen gesellschaft fu¨r gastroenterologie the gut. Microbiome 2013;1:3. https://doi.org/10.1186/2049- und hepatologie (o¨ggh) in zusammenarbeit mit der o¨ster- 2618-1-3. reichischen gesellschaft fu¨r infektiologie und. [23] Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, Z Gastroenterol 2014;52:1485e92. https://doi.org/10.1055/ Grasis JA, et al. Efficacy of sterile fecal filtrate transfer for s-0034-1385562. treating patients with clostridium difficile infection. Gastroen- [10] Sokol H, Galperine T, Kapel N, Bourlioux P, Seksik P, Barbut F, terology 2017;152. https://doi.org/10.1053/j.gastro.2016.11. et al. Faecal microbiota transplantation in recurrent clostridium 010. 799e811.e7. difficile infection: recommendations from the french group of [24] Khanna S, Pardi DS, Kelly CR, Kraft CS, Dhere T, Henn MR, et al. faecal microbiota transplantation. Dig Liver Dis 2016;48:242e7. A novel microbiome therapeutic increases gut microbial di- https://doi.org/10.1016/j.dld.2015.08.017. versity and prevents recurrent clostridium difficile infection. [11] Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect J Infect Dis 2016;214:173e81. https://doi.org/10.1093/infdis/ of oral capsulee vs colonoscopy-delivered fecal microbiota jiv766. transplantation on recurrent clostridium difficile infection. [25] Martin J, Wilcox M. New and emerging therapies for clostridium Jama 2017;318:1985. https://doi.org/10.1001/jama.2017. difficile infection. Curr Opin Infect Dis 2016;29:546e54. https:// 17077. doi.org/10.1097/qco.0000000000000320. [12] Hota SS, Sales V, Tomlinson G, Salpeter MJ, Mcgeer A, Coburn B, [26] Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. et al. Oral vancomycin followed by fecal transplantation versus Patient attitudes toward the use of fecal microbiota trans- tapering oral vancomycin treatment for recurrent clostridium plantation in the treatment of recurrent clostridium difficile difficile infection: an open-label, randomized controlled trial. infection. Clin Infect Dis 2012;55:1652e8. https://doi.org/ Clin Infect Dis 2017;64:265e71. https://doi.org/10.1093/cid/ 10.1093/cid/cis809. ciw731. [27] Kahn SA, Vachon A, Rodriquez D, Goeppinger SR, Surma B, Marks J, [13] Jiang ZD, Ajami NJ, Petrosino JF, Jun G, Hanis CL, Shah M, et al. et al. Patient perceptions of fecal microbiota transplantation for Randomised clinical trial: faecal microbiota transplantation for ulcerative colitis. Inflamm Bowel Dis 2013;19:1506e13. https:// recurrent clostridum difficile infection e fresh, or frozen, or doi.org/10.1097/mib.0b013e318281f520. lyophilised microbiota from a small pool of healthy donors [28] Quraishi MN, Segal J, Mullish B, Mccune Vl, Hawkey P, Colville A, delivered by colonoscopy. Aliment Pharmacol Ther et al. National survey of practice of faecal microbiota trans- 2017;45:899e908. https://doi.org/10.1111/apt.13969. plantation for clostridium difficile infection in the UK. J Hosp [14] Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, Infect 2017;95:444e5. https://doi.org/10.1016/j.jhin.2016.10. et al. Effect of fecal microbiota transplantation on recurrence in 023. multiply recurrent clostridium difficile infection. Ann Intern Med [29] Porter RJ, Fogg C. Faecal microbiota transplantation for clos- 2016;165:609e16. https://doi.org/10.7326/m16-0271. tridium difficile infection in the United Kingdom. Clin Microbiol [15] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, De Infect 2015;21:578e82. https://doi.org/10.1016/j.cmi.2015.01. Vos WM, et al. Duodenal infusion of donor feces for recurrent 020. clostridium difficile. N Engl J Med 2013;368:407e15. https:// [30] Ding NS, Mullish BH, Mclaughlin J, Hart A, Marchesi Jr . Meeting doi.org/10.1056/nejmoa1205037. update: faecal microbiota transplantation - bench, bedside, [16] Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, courtroom? Frontline Gastroenterol 2018;9:45e8. https:// et al. Frozen vs fresh fecal microbiota transplantation and doi.org/10.1136/flgastro-2016-100752. clinical resolution of diarrhea in patients with recurrent clos- [31] Prior AR, Kevans D, Mcdowell L, Cudmore S, Fitzpatrick F. tridium difficile infection a randomized clinical trial. JAMA - J Treatment of clostridium difficile infection: a national survey of Am Med Assoc 2016;315:142e9. https://doi.org/10.1001/ clinician recommendations and the use of faecal microbiota jama.2015.18098. transplantation. J Hosp Infect 2017;95:438e41. https://doi.org/ [17] Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB, 10.1016/j.jhin.2016.10.004. et al. Fecal microbiota transplant for relapsing clostridium [32] Richardson WS, Wilson MC, Nishikwa J, Haywood RSA. The well- difficile infection using a frozen inoculum from unrelated do- built clinical question: a key to evidence-based decisions. 1995 nors: a randomized, open-label, controlled pilot study. Clin Acp J Club 1995;123:a12e3. Infect Dis 2014;58:1515e22. https://doi.org/10.1093/cid/ [33] SIGN. Sign 50. 2015. http://www.sign.ac.uk/assets/sign50_ ciu135. 2015.pdf. [last accessed 18 October 2017]. [18] Cammarota G, Masucci L, Ianiro G, Bibbo` S, Dinoi G, [34] Higgins JPT, Green S. Cochrane handbook for systematic reviews Costamagna G, et al. Randomised clinical trial: faecal micro- of interventions j cochrane training. 2011. http://handbook-5-1. biota transplantation by colonoscopy vs. vancomycin for the cochrane.org. [last accessed 18 October 2017]. treatment of recurrent clostridium difficile infection. Aliment [35] Varier RU, Biltaji E, Smith KJ, Roberts MS, Kyle Jensen M, Pharmacol Ther 2015;41:835e43. https://doi.org/10.1111/ Lafleur J, et al. Cost-effectiveness analysis of fecal microbiota apt.13144. transplantation for recurrent clostridium difficile infection. [19] Medicines and Healthcare Products Regulatory Agency. Faecal Infect Control Hosp Epidemiol 2015;36:438e44. https://doi.org/ Microbiota Transplantation (FMT) mhra’s position n.d. http:// 10.1017/ice.2014.80. www.bsg.org.uk/images/stories/docs/clinical/guidance/fmt_ [36] Konijeti GG, Sauk J, Shrime MG, Gupta M, Ananthakrishnan AN. mhra_position_june2015.pdf [last accessed October 3 2017]. Cost-effectiveness of competing strategies for management of [20] Thomas A. HTA policy on the regulation of faecal microbiota recurrent clostridium difficile infection: a decision analysis. Clin transplant hta-pol-030. 2015. p. 2e3. http://www.bsg.org.uk/ Infect Dis 2014;58:1507e14. https://doi.org/10.1093/cid/ images/stories/docs/clinical/guidance/hta_pol_030_policy_ ciu128. regulation_of_fmt.pdf. [last accessed 3 October 2017]. [37] Baro E, Galperine T, Denies F, Lannoy D, Lenne X, Odou P, et al. [21] Khoruts A, Sadowsky MJ. Understanding the mechanisms of Cost-effectiveness analysis of five competing strategies for the faecal microbiota transplantation. Nat Rev Gastroenterol Hep- management of multiple recurrent community-onset clostridium atol 2016;13:508e16. https://doi.org/10.1038/nrgastro.2016. difficile infection in france. Plos One 2017;12:e0170258. 98. https://doi.org/10.1371/journal.pone.0170258. S28 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31

[38] Lapointe-Shaw L, Tran KL, Coyte PC, Hancock-Howard RL, for clostridium difficile infection. Clin Microbiol Infect Powis J, Poutanen SM, et al. Cost-effectiveness analysis of six 2016;22(suppl 4):s63e81. https://doi.org/10.1016/j.cmi.2016. strategies to treat recurrent clostridium difficile infection. Plos 03.010. One 2016;11:e0149521. https://doi.org/10.1371/journal.pone. [53] Jackson M, Olefson S, Machan JT, kelly CR. A high rate of 0149521. alternative diagnoses in patients referred for presumed clos- [39] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, tridium difficile infection. J Clin Gastroenterol 2016;50:742e6. Alonso-Coello P, et al. Grade: an emerging consensus on rating https://doi.org/10.1097/mcg.0000000000000447. quality of evidence and strength of recommendations. Bmj [54] Ray A, Smith R, Breaux J. Fecal microbiota transplantation for clos- 2008;336:924e6. https://doi.org/10.1136/bmj.39489.470347. tridium difficile infection: the ochsner experience. Ochsner J ad. 2014;14:538e44. https://doi.org/10.1097/mog.0000000000000023. [40] Satokari R, Mattila E, Kainulainen V, Arkkila PET. Simple faecal [55] Kao D, Roach B, Hotte N, Silva M, Madsen K, Beck PLT. preparation and efficacy of frozen inoculum in faecal microbiota A prospective, dual center, randomized trial comparing colo- transplantation for recurrent clostridium difficile infection - an noscopy versus capsule delivered Fecal Microbiota Trans- observational cohort study. Aliment Pharmacol Ther plantation (FMT) in the management of Recurrent Clostridium 2015;41:46e53. https://doi.org/10.1111/apt.13009. Difficile Infection (RCDI). Can J Gastroenterol Hepatol [41] Yoon SS, Brandt LJ. Treatment of refractory/recurrent c. 2016;2016:1e204. https://doi.org/10.1155/2016/4792898. difficile-associated disease by donated stool transplanted via [56] Macconnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal colonoscopy. J Clin Gastroenterol 2010;44:562e6. https:// transplant for recurrent clostridium difficile-associated diar- doi.org/10.1097/mcg.0b013e3181dac035. rhoea: a UK case series. Qjm 2009;102:781e4. https://doi.org/ [42] Zainah H, Hassan M, Shiekh-Sroujieh L, Hassan S, Alangaden G, 10.1093/qjmed/hcp118. Ramesh M. Intestinal microbiota transplantation, a simple and [57] Kelly CR, de Leon L, Jasutkar N. Fecal microbiota trans- effective treatment for severe and refractory clostridium diffi- plantation for relapsing clostridium difficile infection in 26 pa- cile infection. Dig Dis Sci 2014;60:181e5. https://doi.org/ tients. J Clin Gastroenterol 2012;46:145e9. https://doi.org/ 10.1007/s10620-014-3296-y. 10.1097/mcg.0b013e318234570b. [43] Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplant via [58] Brandt LJ, Aroniadis OC, Mellow M, Kanatzar A, Kelly C, Park T, retention enema for refractory or recurrent clostridium difficile et al. Long-term follow-up of colonoscopic fecal microbiota infection. Arch Intern Med 2012;172:191e3. https://doi.org/ transplant for recurrent clostridium difficile infection. Am J 10.1001/archinte.172.2.191. Gastroenterol 2012;107:1079e87. https://doi.org/10.1038/ajg. [44] Aas J, Gessert CE, Bakken JS. Recurrent clostridium difficile 2012.60. colitis: case series involving 18 patients treated with donor stool [59] Pathak R, Enuh HA, Patel A, Wickremesinghe P. Treatment of administered via a nasogastric tube. Clin Infect Dis relapsing clostridium difficile infection using fecal microbiota 2003;36:580e5. https://doi.org/10.1086/367657. transplantation. Clin Exp Gastroenterol 2013;7:1e6. https:// [45] Garborg K, Waagsbø B, Stallemo A, Matre J, Sundøy A. Results of doi.org/10.2147/ceg.s53410. faecal donor instillation therapy for recurrent clostridium [60] Agrawal M, Aroniadis OC, Brandt LJ, Kelly C, Freeman S, difficile-associated diarrhoea. Scand J Infect Dis 2010;42:857e61. Surawicz C, et al. The long-term efficacy and safety of fecal https://doi.org/10.3109/00365548.2010.499541. microbiota transplant for recurrent, severe, and complicated [46] Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Stan- clostridium difficile infection in 146 elderly individuals. J Clin dardized frozen preparation for transplantation of fecal micro- Gastroenterol 2016;50:403e7. https://doi.org/10.1097/mcg. biota for recurrent clostridium difficile infection. Am J 0000000000000410. Gastroenterol 2012;107:761e7. https://doi.org/10.1038/ajg. [61] FischerM, Kao D, Kelly C, Kuchipudi A, Jafri S-M, BlumenkehlM, et al. 2011.482. Fecal microbiota transplantation is safe and efficacious for recur- [47] Lee CH, Belanger JE, Kassam Z, Smieja M, Higgins D, rent or refractory clostridium difficile infection in patients with in- Broukhanski G, et al. The outcome and long-term follow-up of 94 flammatory bowel disease. Inflamm Bowel Dis 2016;22:2402e9. patients with recurrent and refractory clostridium difficile https://doi.org/10.1097/mib.0000000000000908. infection using single to multiple fecal microbiota trans- [62] Aroniadis OC, Brandt LJ, Greenberg A, Borody T, Kelly CR, plantation via retention enema. Eur J Clin Microbiol Infect Dis Mellow M, et al. Long-term follow-up study of fecal microbiota 2014;33:1425e8. https://doi.org/10.1007/s10096-014-2088-9. transplantation for severe and/or complicated clostridium [48] Mattila E, Uusitalo-Seppa¨la¨ R, Wuorela M, Lehtola L, Nurmi H, difficile infection: a multicenter experience. J Clin Gastro- Ristikankare M, et al. Fecal transplantation, through colonos- enterol 2016;50:398e402. https://doi.org/10.1097/mcg. copy, is effective therapy for recurrent clostridium difficile 0000000000000374. infection. Gastroenterology 2012;142:490e6. https://doi.org/ [63] Fischer M, Kao D, Mehta SR, Martin T, Dimitry J, Keshteli AH, 10.1053/j.gastro.2011.11.037. et al. Predictors of early failure after fecal microbiota trans- [49] Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for plantation for the therapy of clostridium difficile infection: a recurrent clostridium difficile infection: results and methodol- multicenter study. Am J Gastroenterol 2016;111:1024e31. ogy. J Clin Gastroenterol 2010;44:567e70. https://doi.org/ https://doi.org/10.1038/ajg.2016.180. 10.1097/mcg.0b013e3181dadb10. [64] Ianiro G, Valerio L, Masucci L, Pecere S, Bibbo` S, Quaranta G, [50] Rubin TA, Gessert CE, Aas J, Bakken JS. Fecal microbiome et al. Predictors of failure after single faecal microbiota trans- transplantation for recurrent clostridium difficile infection: plantation in patients with recurrent clostridium difficile infec- report on a case series. Anaerobe 2013;19:22e6. https:// tion: results from a 3-year, single-centre cohort study. Clin doi.org/10.1016/j.anaerobe.2012.11.004. Microbiol Infect 2017;23:337.e1e3. https://doi.org/10.1016/ [51] Patel NC, Griesbach CL, Dibaise JK, Orenstein R. Fecal micro- j.cmi.2016.12.025. biota transplant for recurrent clostridium difficile infection: [65] Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, mayo clinic in arizona experience. Mayo Clin Proc et al. Fecal microbiota transplant for treatment of clostridium 2013;88:799e805. https://doi.org/10.1016/j.mayocp.2013.04. difficile infection in immunocompromised patients. Am J Gas- 022. troenterol 2014;109:1065e71. https://doi.org/10.1038/ajg. [52] Crobach MJT, Planche T, Eckert C, Barbut F, Terveer EM, 2014.133. Dekkers OM, et al. European society of clinical microbiology and [66] Lagier J-C, Delord M, Million M, Parola P, Stein A, Brouqui P, infectious diseases: update of the diagnostic guidance document et al. Dramatic reduction in clostridium difficile ribotype 027- B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S29

associated mortality with early fecal transplantation by the effective: clinical efficacy and bacterial viability data. Aliment nasogastric route: a preliminary report. Eur J Clin Microbiol Pharmacol Ther 2015;42:1011e8. https://doi.org/10.1111/ Infect Dis 2015;34:1597e601. https://doi.org/10.1007/s10096- apt.13366. 015-2394-x. [80] Allegretti Jr , Korzenik Jr , Hamilton MJ. Fecal microbiota [67] Camacho-Ortiz A, Gutie´rrez-Delgado EM, Garcia-Mazcorro JF, transplantation via colonoscopy for recurrent C. difficile infec- Mendoza-Olazara´n S, Martı´nez-Mele´ndez A, Palau-Davila L, et al. tion. J Vis Exp 2014:52154. https://doi.org/10.3791/52154. Randomized clinical trial to evaluate the effect of fecal micro- [81] van Beurden YH, de Groot PF, van Nood E, Nieuwdorp M, biota transplant for initial clostridium difficile infection in in- Keller JJ, Goorhuis A. Complications, effectiveness, and long testinal microbiome. Plos One 2017;12:e0189768. https:// term follow-up of fecal microbiota transfer by nasoduodenal doi.org/10.1371/journal.pone.0189768. tube for treatment of recurrent clostridium difficile infection. [68] Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, United Eur Gastroenterol J 2017;5:868e79. https://doi.org/ et al. Fidaxomicin versus vancomycin for clostridium difficile 10.1177/2050640616678099. infection. N Engl J Med 2011;364:422e31. https://doi.org/ [82] Allegretti Jr , Allegretti AS, Phelps E, Xu H, Kassam Z, Fischer M. 10.1056/nejmoa0910812. Asymptomatic clostridium difficile carriage rate post-fecal [69] Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, microbiota transplant is low: a prospective clinical and stool et al. Bezlotoxumab for prevention of recurrent clostridium assessment. Clin Microbiol Infect 2018;24:780.e1e3. https:// difficile infection. N Engl J Med 2017;376:305e17. https:// doi.org/10.1016/j.cmi.2017.10.022. doi.org/10.1056/nejmoa1602615. [83] Baxter M, Colville A. Adverse events in faecal microbiota [70] Guery B, Menichetti F, Anttila VJ, Adomakoh N, Aguado JM, transplant: a review of the literature. J Hosp Infect Bisnauthsing K, et al. Extended-pulsed fidaxomicin versus van- 2016;92:117e27. https://doi.org/10.1016/j.jhin.2015.10.024. comycin for clostridium difficile infection in patients 60 years [84] Hefazi M, Patnaik MM, Hogan WJ, Litzow MR, Pardi DS, Khanna S. and older (extend): a randomised, controlled, open-label, phase Safety and efficacy of fecal microbiota transplant for recurrent 3b/4 trial. Lancet Infect Dis 2017;18:296e307. https://doi.org/ clostridium difficile infection in patients with cancer treated 10.1016/s1473-3099(17)30751-x. with cytotoxic chemotherapy: a single-institution retrospective [71] Mcfarland LV, Elmer GW, Surawicz CM. Breaking the cycle: case series. Mayo Clin Proc 2017;92:1617e24. https://doi.org/ treatment strategies for 163 cases of recurrent clostridium 10.1016/j.mayocp.2017.08.016. difficile disease. Am J Gastroenterol 2002;97:1769e75. https:// [85] Qazi T, Amaratunga T, Barnes EL, Fischer M, Kassam Z, doi.org/10.1111/j.1572-0241.2002.05839.x. Allegretti Jr . The risk of inflammatory bowel disease flares after [72] Sirbu BD, Soriano MM, Manzo C, Lum J, Gerding DN, Johnson S. fecal microbiota transplantation: systematic review and meta- Vancomycin taper and pulse regimen with careful follow-up for analysis. Gut Microbes 2017;8:574e88. https://doi.org/10.1080/ patients with recurrent clostridium difficile infection. Clin 19490976.2017.1353848. Infect Dis 2017;65:1396e9. https://doi.org/10.1093/cid/ [86] Mattila E, Uusitalo-Seppa¨la¨ R, Wuorela M, Lehtola L, Nurmi H, cix529. Ristikankare M, et al. Fecal transplantation, through colonos- [73] Gentry CA, Giancola SE, Thind S, Kurdgelashvili G, Skrepnek GH, copy, is effective therapy for recurrent clostridium difficile Williams RJ. A propensity-matched analysis between standard infection. Gastroenterology 2012;142:490e6. https://doi.org/ versus tapered oral vancomycin courses for the management of 10.1053/j.gastro.2011.11.037. recurrent clostridium difficile infection. Open Forum Infect Dis [87] Meighani A, Hart BR, Mittal C, Miller N, John A, Ramesh M. Predictors 2017;4:ofx235. https://doi.org/10.1093/ofid/ofx235. of fecal transplant failure. Eur J Gastroenterol Hepatol [74] Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, 2016;28:826e30. https://doi.org/10.1097/meg.0000000000000614. Weiss K, et al. Fidaxomicin versus vancomycin for infection with [88] Alrabaa S, Jariwala R, Zeitler K, Montero J. Fecal microbiota clostridium difficile in europe, canada, and the usa: a double- transplantation outcomes in immunocompetent and immu- blind, non-inferiority, randomised controlled trial. Lancet nocompromised patients: a single-center experience. Infect Dis 2012;12:281e9. https://doi.org/10.1016/s1473- Transpl Infect Dis 2017;19:e12726. https://doi.org/10.1111/ 3099(11)70374-7. tid.12726. [75] Tauxe WM, Haydek JP, Rebolledo PA, Neish E, Newman Kl, [89] Cohen NA, Livovsky DM, Yaakobovitch S, Ben Yehoyada M, Ben Ward A, et al. Fecal microbiota transplant for clostridium diffi- Ami R, Adler A, et al. A retrospective comparison of fecal mi- cile infection in older adults. Therap Adv Gastroenterol crobial transplantation methods for recurrent clostridium diffi- 2016;9:273e81. https://doi.org/10.1177/1756283x15622600. cile infection. Isr Med Assoc J 2016;18:594e9. [76] Khan MA, Sofi AA, Ahmad U, Alaradi O, Khan AR, Hammad T, [90] Orenstein R, Dubberke E, Hardi R, Ray A, Mullane K, Pardi DS, et al. Efficacy and safety of, and patient satisfaction with, et al. Safety and durability of rbx2660 (microbiota suspension) colonoscopic-administered fecal microbiota transplantation in for recurrent clostridium difficile infection: results of the punch relapsing and refractory community- and hospital-acquired cd study. Clin Infect Dis 2016;62:596e602. https://doi.org/ clostridium difficile infection. Can J Gastroenterol Hepatol 10.1093/cid/civ938. 2014;28:434e8. [91] Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, Honig G. [77] Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Effectiveness of fecal-derived microbiota transfer using orally Hohmann EL. Oral, capsulized, frozen fecal microbiota trans- administered capsules for recurrent clostridium difficile infec- plantation for relapsing clostridium difficile infection. Jama - J tion. Bmc Infect Dis 2015;15:191. https://doi.org/10.1186/ Am Med Assoc 2014;312:1772e8. https://doi.org/10.1001/ s12879-015-0930-z. jama.2014.13875. [92] Kao D, Roach B, Beck P, Hotte N, Madsen K, Louie T. A dual [78] Fischer M, Sipe BW, Rogers NA, Cook GK, Robb BW, center, randomized trial comparing colonoscopy and oral Vuppalanchi R, et al. Faecal microbiota transplantation plus capsule delivered fecal microbiota transplantation in the selected use of vancomycin for severe-complicated clostridium treatment of recurrent clostridium difficile infection: pre- difficile infection: description of a protocol with high success liminary results. Am J Gastroenterol 2015;110:s553. https:// rate. Aliment Pharmacol Ther 2015;42:470e6. https://doi.org/ doi.org/10.1038/ajg.2015.294. 10.1111/apt.13290. [93] Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H, [79] Costello SP, Conlon MA, Vuaran MS, Roberts-Thomson IC, Levin J, et al. Oral, frozen fecal microbiota transplant (fmt) Andrews JM. Faecal microbiota transplant for recurrent clos- capsules for recurrent clostridium difficile infection. Bmc Med tridium difficile infection using long-term frozen stool is 2016;14:134. https://doi.org/10.1186/s12916-016-0680-9. S30 B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31

[94] Anand R, Song Y, Garg S, Girotra M, Sinha A, Sivaraman A, et al. [110] Gough E, Shaikh H, Manges AR. Systematic review of intestinal Effect of aging on the composition of fecal microbiota in donors microbiota transplantation (fecal bacteriotherapy) for recurrent for fmt and its impact on clinical outcomes. Dig Dis Sci clostridium difficile infection. Clin Infect Dis 2011;53:994e1002. 2017;62:1002e8. https://doi.org/10.1007/s10620-017-4449-6. https://doi.org/10.1093/cid/cir632. [95] Alang N, Kelly CR. Weight gain after fecal microbiota trans- [111] Casewell MW, Slater NGP, Cooper JE. Operating theatre water- plantation. Open Forum Infect Dis 2015;2:ofv004. https:// baths as a cause of pseudomonas septicaemia. J Hosp Infect doi.org/10.1093/ofid/ofv004. 1981;2:237e40. https://doi.org/10.1016/0195-6701(81)90043-8. [96] Fischer M, Kao D, Kassam Z, Smith J, Louie T, Sipe B, et al. Stool [112] Muyldermans G, de Smet F, Pierard D, Steenssens L, Stevens D, donor body mass index does not affect recipient weight after a Bougatef A, et al. Neonatal infections with pseudomonas aeru- single fecal microbiota transplantation for clostridium difficile ginosa associated with a water-bath used to thaw fresh frozen infection. Clin Gastroenterol Hepatol 2017. https://doi.org/ plasma. J Hosp Infect 1998;39:309e14. 10.1016/j.cgh.2017.12.007. [113] Sleight SC, Wigginton NS, Lenski RE. Increased susceptibility to [97] Marchesi Jr , Adams DH, Fava F, Hermes GDA, Hirschfield GM, repeated freeze-thaw cycles in escherichia coli following long- Hold G, et al. The gut microbiota and host health: a new clinical term evolution in a benign environment. Bmc Evol Biol frontier. Gut 2016;65:330e9. https://doi.org/10.1136/gutjnl- 2006;6:104. https://doi.org/10.1186/1471-2148-6-104. 2015-309990. [114] O’brien CL, Allison GE, Grimpen F, Pavli P. Impact of colonoscopy [98] Allegretti Jr , Fischer M, Papa E, Elliott RJ, Klank J, Mendolia G, bowel preparation on intestinal microbiota. Plos One et al. su1738 fecal microbiota transplantation delivered via oral 2013;8:e62815. https://doi.org/10.1371/journal.pone.0062815. capsules achieves microbial engraftment similar to traditional [115] Mai V, Stine OC. Bowel preparation for colonoscopy: relevant for delivery modalities: safety, efficacy and engraftment results the gut’s microbiota? Gut 2015;64:1504e5. https://doi.org/ from a multi-center cluster randomized dose-finding study. 10.1136/gutjnl-2014-308937. Gastroenterology 2016;150:s540. https://doi.org/10.1016/ [116] Jalanka J, Salonen A, Saloja¨rvi J, Ritari J, Immonen O, s0016-5085(16)31855-8. Marciani L, et al. Effects of bowel cleansing on the intestinal [99] Langdon A, Crook N, Dantas G. The effects of antibiotics on the microbiota. Gut 2015;64:1562e8. https://doi.org/10.1136/ microbiome throughout development and alternative ap- gutjnl-2014-307240. proaches for therapeutic modulation. Genome Med 2016;8:39. [117] Mai V, Greenwald B, Glenn Morris J, Raufman J-P, Stine OC. https://doi.org/10.1186/s13073-016-0294-z. Effect of bowel preparation and colonoscopy on post-procedure [100] Lange K, Buerger M, Stallmach A, Bruns T. Effects of antibiotics intestinal microbiota composition. Gut 2006;55:1822e3. on gut microbiota. Dig Dis 2016;34:260e8. https://doi.org/ https://doi.org/10.1136/gut.2006.108266. 10.1159/000443360. [118] Harrell L, Wang Y, Antonopoulos D, Young V, Lichtenstein L, [101] Becattini S, Taur Y, Pamer EG. Antibiotic-induced changes in the Huang Y, et al. Standard colonic lavage alters the natural state of intestinal microbiotaand disease.Trends Mol Med 2016;22:458e78. mucosal-associated microbiota in the human colon. Plos One https://doi.org/10.1016/j.molmed.2016.04.003. 2012;7:e32545. https://doi.org/10.1371/journal.pone.0032545. [102] Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators of [119] Chin SM, Sauk J, Mahabamunuge J, Kaplan JL, Hohmann EL, gut microbiota: between good and evil. Gut 2016;65:1906e15. Khalili H. Fecal microbiota transplantation for recurrent clos- https://doi.org/10.1136/gutjnl-2016-312297. tridium difficile infection in patients with inflammatory bowel [103] Allegretti Jr , Korzenik Jr , Hamilton MJ. Tu1361 intestinal disease: a single-center experience. Clin Gastroenterol Hepatol microbiome restoration for recurrent clostridium difficile 2017;15:597e9. https://doi.org/10.1016/j.cgh.2016.11.028. infection in patients with concurrent inflammatory bowel dis- [120] Wang S, Xu M, Wang W, Cao X, Piao M, Khan S, et al. Systematic ease. Gastroenterology 2015;148:s869. https://doi.org/ review: adverse events of fecal microbiota transplantation. Plos 10.1016/s0016-5085(15)32948-6. One 2016;11:e0161174. https://doi.org/10.1371/journal.pone. [104] Dubberke ER, Olsen MA. Burden of clostridium difficile on the 0161174. healthcare system. Clin Infect Dis 2012;55:s88e92. https:// [121] Khoruts A, Rank KM, Newman KM, Viskocil K, Vaughn BP, doi.org/10.1093/cid/cis335. Hamilton MJ, et al. Inflammatory bowel disease affects the [105] National Health Service. Population screening programmes: NHS outcome of fecal microbiota transplantation for recurrent bowel cancer screening (BCSP) Programme - gov.uk n.d. clostridium difficile infection. Clin Gastroenterol Hepatol https://www.gov.uk/topic/population-screening-programmes/ 2016;14:1433e8. https://doi.org/10.1016/j.cgh.2016.02.018. bowel [Accessed June 10 2018]. [122] De Jager CPC, Wever PC, Gemen EFA, van Oijen MGH, van [106] TSO. Guidelines for the blood transfusion services in the United Gageldonk-Lafeber AB, Siersema PD, et al. Proton pump inhib- Kingdom. 7th edition 2005 TSO accredited agents web access n.d. itor therapy predisposes to community-acquired streptococcus https://assets.publishing.service.gov.uk/government/uploads/ pneumoniae pneumonia. Aliment Pharmacol Ther system/uploads/attachment_data/file/228828/0117033715.pdf. 2012;36:941e9. https://doi.org/10.1111/apt.12069. [last accessed 12 July 2018]. [123] Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al. [107] Emanuelsson F, Claesson BEB, Ljungstro¨m L, Tvede M, Ung K-A. Proton pump inhibitors affect the gut microbiome. Gut Faecal microbiota transplantation and bacteriotherapy for 2016;65:740e8. https://doi.org/10.1136/gutjnl-2015-310376. recurrent clostridium difficile infection: a retrospective evalu- [124] Mcdonald EG, Milligan J, Frenette C, Lee TC. Continuous proton ation of 31 patients. Scand J Infect Dis 2014;46:89e97. https:// pump inhibitor therapy and the associated risk of recurrent doi.org/10.3109/00365548.2013.858181. clostridium difficile infection. Jama Intern Med 2015;175:784. [108] Endtz HP, van Den Braak N, van Belkum A, Kluytmans JA, https://doi.org/10.1001/jamainternmed.2015.42. Koeleman JG, Spanjaard L, et al. Fecal carriage of vancomycin- [125] Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium resistant enterococci in hospitalized patients and those living in difficile-associated diarrhea and proton pump inhibitor therapy: the community in the netherlands. J Clin Microbiol a meta-analysis. Am J Gastroenterol 2012;107:1001e10. 1997;35:3026e31. https://doi.org/10.1038/ajg.2012.179. [109] Willems RJL, Top J, van Santen M, Robinson DA, Coque TM, [126] Girotra M, Garg S, Anand R, Song Y, Dutta SK. Fecal microbiota Baquero F, et al. Global spread of vancomycin-resistant transplantation for recurrent clostridium difficile infection in enterococcus faecium from distinct nosocomial genetic com- the elderly: long-term outcomes and microbiota changes. Dig Dis plex. Emerg Infect Dis 2005;11:821e8. https://doi.org/10.3201/ Sci 2016;61:3007e15. https://doi.org/10.1007/s10620-016- eid1106.041204. 4229-8. B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S31

[127] Hagel S, Fischer A, Ehlermann P, Frank T, Tueffers K, Sturm A, transplantation for active ulcerative colitis: a randomised placebo- et al. Fecal microbiota transplant in patients with recurrent controlled trial. Lancet (London, England) 2017;389:1218e28. clostridium difficile infection. Dtsch Arztebl Int 2016;113:583e9. https://doi.org/10.1016/s0140-6736(17)30182-4. https://doi.org/10.3238/arztebl.2016.0583. [143] Costello SP, Waters O, Bryant RV, Katsikeros R, Makanyanga J, [128] Department of Health (UK). Management and decontamination of Schoeman M, et al. Short duration, low intensity, pooled fecal flexible endoscopes (htm 01-06) - gov.uk n.d. https://www.gov.uk/ microbiota transplantation induces remission in patients with government/publications/management-and-decontamination-of- mild-moderately active ulcerative colitis: a randomised flexible-endoscopes [Accessed December 19 2017]. controlled trial. Gastroenterology 2017;152:s198e9. https:// [129] British Society of Gastroenterology. Guidance on decontamina- doi.org/10.1016/s0016-5085(17)30969-1. tion of equipment for gastrointestinal endoscopy. 2017. [144] Johnsen PH, Hilpu¨sch F, Cavanagh JP, Leikanger IS, Kolstad C, edition n.d. https://www.bsg.org.uk/resource/guidance-on- Valle PC, et al. Faecal microbiota transplantation versus pla- decontamination-of-equipment-for-gastrointestinal-endoscopy- cebo for moderate-to-severe irritable bowel syndrome: a 2017-edition.html. [last accessed 19 December 2017]. double-blind, randomised, placebo-controlled, parallel-group, [130] Loveday HP, Wilson JA, Pratt RJ, Golsorkhi M, Tingle A, Bak A, single-centre trial. Lancet Gastroenterol Hepatol 2018;3:17e24. et al. Epic3: national evidence-based guidelines for preventing https://doi.org/10.1016/s2468-1253(17)30338-2. healthcare-associated infections in nhs hospitals in england. [145] Tian H, Ge X, Nie Y, Yang L, Ding C, Mcfarland LV, et al. Fecal J Hosp Infect 2014;86:s1e70. https://doi.org/10.1016/s0195- microbiota transplantation in patients with slow-transit con- 6701(13)60012-2. stipation: a randomized, clinical trial. Plos One 2017;12, [131] Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota trans- e0171308. https://doi.org/10.1371/journal.pone.0171308. plantation for clostridium difficile infection: systematic review [146] Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecal and meta-analysis. Am J Gastroenterol 2013;108:500e8. microbiota transplant from a rational stool donor improves he- https://doi.org/10.1038/ajg.2013.59. patic encephalopathy: a randomized clinical trial. Hepatology [132] Allegretti Jr , Kao D, Sitko J, Fischer M, Kassam Z. Early anti- 2017;66:1727e38. https://doi.org/10.1002/hep.29306. biotic use post-fecal microbiota transplantation increases the [147] Vrieze A, van Nood E, Holleman F, Saloja¨rvi J, Kootte RS, risk of treatment failure. Clin Infect Dis 2017;66:134e5. https:// Bartelsman JFWM, et al. Transfer of intestinal microbiota from doi.org/10.1093/cid/cix684. lean donors increases insulin sensitivity in individuals with [133] Terveer EM, van Beurden YH, Goorhuis A, Seegers JFML, metabolic syndrome. Gastroenterology 2012;143. https:// Bauer MP, van Nood E, et al. How to: establish and run a stool doi.org/10.1053/j.gastro.2012.06.031. 913e916.e7. bank. Clin Microbiol Infect 2017;23:924e30. https://doi.org/ [148] Kootte RS, Levin E, Saloja¨rvi J, Smits LP, Hartstra AV, 10.1016/j.cmi.2017.05.015. Udayappan SD, et al. Improvement of insulin sensitivity after [134] Quraishi MN, Widlak M, Bhala N, Moore D, Price M, Sharma N, lean donor feces in metabolic syndrome is driven by baseline et al. Systematic review with meta-analysis: the efficacy of intestinal microbiota composition. Cell Metab 2017;26. https:// faecal microbiota transplantation for the treatment of recurrent doi.org/10.1016/j.cmet.2017.09.008. 611e619.e6. and refractory clostridium difficile infection. Aliment Pharmacol [149] OpenBiome. Home d openbiome n.d. http://www.openbiome. Ther 2017;46:479e93. https://doi.org/10.1111/apt.14201. org/home/[Accessed October 19 2017]. [135] Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota trans- [150] Medicines and Healthcare Products Regulatory Agency. plantation for the treatment of clostridium difficile infection: a Apply for manufacturer or wholesaler of medicines licences - systematic review. J Clin Gastroenterol 2014;48:693e702. gov.uk n.d. https://www.gov.uk/guidance/apply-for- https://doi.org/10.1097/mcg.0000000000000046. manufacturer-or-wholesaler-of-medicines-licences#apply-for-a- [136] Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A, manufacturerimporter-licence [Accessed February 15 2018]. Macdonald R, et al. Fecal microbiota transplantation for clos- [151] Medicines and Healthcare Products Regulatory Agency. Supply tridium difficile infection a systematic review. Ann Intern Med unlicensed medicinal products (specials) - gov.uk n.d. https:// 2015;162:630e8. https://doi.org/10.7326/m14-2693. www.gov.uk/government/publications/supply-unlicensed- [137] Baxter M, Ahmad T, Colville A, Sheridan R. Fatal aspiration medicinal-products-specials [Accessed February 15 2018]. pneumonia as a complication of fecal microbiota transplant. [152] Edelstein CA, Kassam Z, Daw J, Smith MB, Kelly CR. The regulation Clin Infect Dis 2015;61:136e7. https://doi.org/10.1093/cid/ of fecal microbiota for transplantation: an international perspec- civ247. tivefor policy andpublichealth.Clin ResRegulAff 2015;32:99e107. [138] Hecker MT, Obrenovich ME, Cadnum JL, Jencson AL, Jain AK, https://doi.org/10.3109/10601333.2015.1046602. Ho E, et al. Fecal microbiota transplantation by freeze-dried [153] HTA. Human tissue authority guide to quality and safety assur- oral capsules for recurrent clostridium difficile infection. Open ance for human tissues and cells for patient treatment. 2010. Forum Infect Dis 2016;3:ofw091. https://doi.org/10.1093/ofid/ https://www.hta.gov.uk/sites/default/files/annex_-_guide_ ofw091. to_quality_and_safety_assurance_for_tissues_and_cells_for_ [139] Ni J, Wu GD, Albenberg L, Tomov VT. Gut microbiota and ibd: patient_treatment.pdf. [last accessed 9 October 2017]. causation or correlation? Nat Rev Gastroenterol Hepatol [154] Medicines and Healthcare Products Regulatory Agency. Rules 2017;14:573e84. https://doi.org/10.1038/nrgastro.2017.88. and guidance for pharmaceutical manufacturers and distribu- [140] Rossen NG, Fuentes S, van Der Spek MJ, Tijssen JG, tors 2017 n.d. https://www.pharmpress.com/product.asp? Hartman JHA, Duflou A, et al. Findings from a randomized productid¼mc_orange&affiliateid¼ [Accessed October 9 2017]. controlled trial of fecal transplantation for patients with ul- [155] Kelly CR, Kim AM, Laine L, Wu GD. The aga’s fecal microbiota cerative colitis. Gastroenterology 2015;149. https://doi.org/ transplantation national registry: an important step toward 10.1053/j.gastro.2015.03.045. 110e118.e4. understanding risks and benefits of microbiota therapeutics. [141] Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Gastroenterology 2017;152:681e4. https://doi.org/10.1053/ Onischi C, et al. Fecal microbiota transplantation induces j.gastro.2017.01.028. remission in patients with active ulcerative colitis in a ran- [156] Vehreschild M. MicroTrans - A multicenter registry of fecal domized controlled trial. Gastroenterology 2015;149. https:// microbiota transplantation (MicroTrans) n.d. https:// doi.org/10.1053/j.gastro.2015.04.001. 102e109.e6. clinicaltrials.gov/ct2/show/NCT02681068 [Accessed October 9 [142] Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van Den 2017]. Bogaerde J, Samuel D, et al. Multidonor intensive faecal microbiota