ww.sciencedirect.com

Journal of Hospital Infection 100 (2018) S1eS31

Available online at w

Journal of Hospital Infection

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

Guidelines

The use of faecal microbiota transplant as treatmentfor recurrent or refractory Clostridium difficileinfection and other potential indications: joint BritishSociety of Gastroenterology (BSG) and HealthcareInfection 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. Goldenbergm,n,*,￮

aDivision of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, Faculty of Medicine,Imperial College London, London, UKbDepartments of Gastroenterology and Hepatology, St Mary’s Hospital, Imperial College Healthcare NHS Trust, Paddington,London, UKcDepartment of Gastroenterology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS FoundationTrust, Birmingham, UKd Inflammatory Bowel Disease Unit, St Mark’s Hospital, Harrow, London, UKe Public Health England, Public Health Laboratory Birmingham, Birmingham, UKf Institute of Microbiology and Infection, University of Birmingham, Birmingham, UKgDepartment of Microbiology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UKhHealthcare Infection Society, London, UKi Institute of Applied Health Research, University of Birmingham, Birmingham, UKj Institute of Translational Medicine, University of Birmingham, Edgbaston, Birmingham, UKkDepartment of Microbiology, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UKlC diff Support, UKmCentre for Clinical Infection and Diagnostics Research, King’s College London, London, UKnDepartment 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 forrecurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) andHealthcare Infection Society (HIS) guidelines’. The NICE accreditation of HIS methodology is valid for 5 years from March 2015. More information onaccreditation 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 allrelevant 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: simon.goldenberg@gstt.nhs.uk (S.D. Goldenberg).

y Joint first authors.￮ Joint senior authors.

https://doi.org/10.1016/j.jhin.2018.07.0370195-6701/ª 2018 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S2

A R T I C L E I N F O

Article history:Received 2 July 2018Accepted 23 July 2018

Keywords:microbiotafaecal transplantClostridium difficileinflammatory bowel disease

about 25% of patients, and some may suffer multiplerecurrences.

evidence-based recommendations wherever possible, andconsensus multi-disciplinary expert opinion where specific

Executive summary

Interest in the therapeutic potential of faecal microbiotatransplant (FMT) has been increasing globally in recent years,particularly as a result of randomised studies in which it hasbeen used as an intervention. The main focus of these studieshas been the treatment of recurrent or refractory Clostridiumdifficile infection (CDI), but there is also an emerging evi-dence base regarding potential applications in non-CDI set-tings. The key clinical stakeholders for the provision andgovernance of FMT services in the United Kingdom (UK) havetended to be in two major specialty areas: gastroenterologyand microbiology/infectious diseases. While the NationalInstitute for Health and Care Excellence (NICE) guidance(2014) for use of FMT for recurrent or refractory CDI hasbecome accepted in the UK, clear evidence-based UK guide-lines for FMT have been lacking. This resulted in discussionsbetween the British Society of Gastroenterology (BSG) andHealthcare Infection Society (HIS), and a joint BSG/HIS FMTworking group was established. This guideline document is theculmination of that joint dialogue.

Lay summary

Faecal microbiota transplant (FMT) involves the transferof a sample of faeces from a healthy donor to a recipient.There are several different ways to administer the trans-plant, including via endoscopy, rectally as an enema, vianasogastric/nasoenteral tube (tube passed through the noseinto the stomach/upper part of the small intestine), or viaoral ingestion of capsules that contain faecal material. Thetransplant may either be administered fresh (i.e. immedi-ately after preparation), or may be prepared in advance,stored in a freezer and thawed when required. FMT is anaccepted and effective treatment for recurrent infection byClostridium difficile, a bacterium which can cause severeillness with diarrhoea, most commonly in frail elderly pop-ulations as a complication of antibiotic use. Despiteadequate treatment, Clostridium difficile infection recurs in

This guideline reviews the evidence for FMT as a treatmentfor Clostridium difficile infection (CDI) and other conditions.Recommendations are made for: which patients are mostlikely to benefit, how donors should be selected and screened,how FMT should be prepared and administered, how patientsshould be followed up, and how FMT services should beconfigured.

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 definedbest practice in all aspects of a FMT service, by providing

published evidence is currently lacking. This included theevaluation of the use of FMT in the treatment of Clostridiumdifficile infection (CDI; also referred to as Clostridioidesdifficile [1]), and also in potential non-CDI indications. Rele-vant guidance published to date includes the interventionalprocedure guidance from the National Institute for Health andCare Excellence (NICE) [2], UK, European and US microbiolog-ical guidelines on the treatment of CDI [3e5], and recentexpert consensus documents on FMT in clinical practice [6,7].Furthermore, there have also been national recommendationsregarding FMT produced by working groups in several differentcountries [8e10]. Principally as a result of randomised studiesthat have been published in recent years [11e18], FMT hasbecome an accepted treatment for recurrent/refractory CDI.

The unique remit and objectives of this guideline whencommissioned by the BSG and HIS were:

i. To review the rapidly-growing body of randomised trialevidence for the efficacy of FMT in the treatment ofadults (�18 years), both in CDI and in other clinical con-ditions, much of which has been published after thepublication of current CDI treatment algorithms [3,4].

ii. To provide specific guidance about best practice for anFMT service within the context of the regulatory frame-work for the intervention as it currently exists in the UK[19,20].

The elucidation of the mechanisms underlying the efficacyof FMT in treating CDI remains an active area of globalresearch, with the aim of rationalising FMT from its currentcrude form to a more targeted, refined therapeutic modality[21]. Previous research has demonstrated that commensalbacteria cultured from the stool of healthy donors [22],sterile faecal filtrate [23], and/or spores of Firmicutesderived from ethanol-treated stool from healthy donors [24]may have similar efficacy to conventional FMT in treatingCDI, although results of the latter approach produced disap-pointing outcome data when extended to a Phase II clinicaltrial [25]. For the purposes of this guideline, the BSG/HISworking group considered only studies that used the admin-istration of manipulated whole stool (including encapsulatedfaeces). 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), ormicrobiota suspensions, to be in the pre-clinical researchstage, without firm evidence.

FMT has been shown to be very acceptable to patients, bothin the setting of CDI [11,26] and in non-CDI settings, e.g. ul-cerative colitis [27]. However, the absence of appropriateprotocols [28e31] specifically taking into account UK clinicalpractice and regulation of FMT has been perceived as a barrierto the use of FMT in the UK and Ireland: these guidelines seek torectify this problem.

Guideline development team

Acknowledgements

The authors would like to acknowledge the support of theGut Microbiota for Health Expert Panel of the British Society ofGastroenterology, along with that of the Healthcare InfectionSociety. They would also like to thank Ian Rees from the MHRAfor contributions regarding the legal aspects and clinicalgovernance of FMT within the UK and beyond.

Source of funding

There was no external funding for this work. BHM is therecipient of a Medical Research Council (MRC) Clinical ResearchTraining Fellowship (grant reference: MR/R000875/1). BHM andHRTW receive support from the National Institute for HealthResearch (NIHR) Imperial Biomedical Research Centre (BRC)based at Imperial College Healthcare NHS Trust and ImperialCollege London.

Disclosure of potential conflict of interest

� THI: Acted as consultant, advisor or speaker for Pharma-cosmos and Shield Therapeutics.

� ALH: Acted as consultant, advisory board member orspeaker for AbbVie, Atlantic, Bristol-Myers Squibb,Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceu-ticals, Pfizer, Pharmacosmos, Shire and Takeda. ALH alsoserves on the Global Steering Committee for Genentech.

� SDG: Received consultancy fees, speaker fees andresearch grant support from Astellas between 2015-2017;received consultancy fees and speaker fees from MSDbetween 2015-2017; and received consultancy fees in2017 from Pfizer.

� All other authors declared no conflict of interest.

Relationship of authors with sponsor

BSG and HIS commissioned the authors to undertake theWorking Party Report. The authors represent the membershipof both societies.

Responsibility for guidelines

The views expressed in this publication are those of theauthors, and have been endorsed by BSG and HIS followingconsultation.

Working Party Report

What is the Working Party Report?

The report is a set of recommendations covering key aspectsof safe and efficacious delivery of a FMT service for recurrent/refractory CDI. The guidelines also review the evidence for theuse of FMT for non-CDI indications.

The diagnosis and management of Clostridium difficileinfection in general are outside of the remit of theseguidelines.

The working group recommendations have been developedsystematically through multi-disciplinary discussions based onpublished evidence. They should be used in the development oflocal protocols for all relevant healthcare settings.

Why do we need a Working Party Report for this topic?

There is widespread and growing interest in the use of FMTas a treatment for recurrent CDI. The previous absence ofrandomised trials and lack of evidence-based guidelinesdescribing best practice related to its use has led to uncer-tainty as to how to establish an FMT service. Existing servicesmay be providing suboptimal clinical care. There is now adeveloping portfolio of randomised study evidence (includingrandomised controlled trial data) regarding the use of FMT inCDI and non-CDI indications, providing the opportunity todevelop an evidence-based guideline for its use. There havealso been recent changes to the UK regulatory framework forFMT (see Section Basic requirements for implementing a FMTservice), which are not well-understood by clinicians.

What is the purpose of the Working Party Report’srecommendations?

The main purpose is to inform clinicians about the use ofFMT (and about the establishment of an FMT service) for thetreatment of recurrent and refractory CDI, and other possiblefuture indications. The recommendations provide an evidence-based approach to a high quality clinical service, with appro-priate governance structures. This document also serves toillustrate areas in which there are current gaps in knowledge,which will help to direct future areas of research.

What is the scope of the guidelines?

The main scope of the guidelines is to provide guidance forthe 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 toadult patients (�18 years); the working party did not considerthe role of FMT in the treatment of either CDI or non-CDI in-dications in children or young people. The guidelines werewritten with a focus on UK practice, but also with considerationof more global practice as it applied.

What is the evidence for these guidelines?

Questions for review were derived from the Working PartyGroup, which included patient representatives in accordancewith the PICO process [32]. To prepare these

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S4

recommendations, the working group collectively reviewedrelevant peer-reviewed research. Methods are described fullybelow; they were in accordance with SIGN 50 [33] and theCochrane Collaboration [34].

Who developed these guidelines?

The working group included gastroenterologists, infectiousdiseases/microbiology clinicians, a clinical scientist, a sys-tematic reviewer, and patient representatives.

Who are these guidelines for?

Any healthcare practitioner may use these guidelines andadapt them for their use. It is anticipated that users willinclude clinical staff, as well as healthcare infection preven-tion and control teams. It is expected that these guidelines willraise awareness of FMT amongst clinicians who care for pa-tients with recurrent or refractory CDI, but who may be un-aware that it is a feasible and accessible treatment option. Theguidelines are also designed to be read by patients with CDI,helping them to understand whether FMT may be an appro-priate treatment option for them.

How are the guidelines structured?

Each section comprises an introduction, a summary of theevidence base with levels, and a recommendation graded ac-cording to the available evidence.

How frequently are the guidelines reviewed andupdated?

The guidelines will be reviewed at least every four years andupdated if changes in the evidence are sufficient to require achange in practice.

Aim

The primary aim of this report was to assess the currentevidence for all aspects relating to provision of an FMT serviceas treatment for recurrent or refractory CDI. A secondary aimwas to review the current evidence for the efficacy of FMT intreating non-CDI conditions.

Summary of guidelines

Which patients with Clostridium difficile infectionshould be considered for faecal microbiota transplant,and how should they be followed up after treatment?

Prior to faecal microbiota transplant. Patient selectionRecurrent Clostridium difficile infection.Recommendation:

FMT should be offered to patients with recurrent CDI whohave had at least two recurrences, or those who have had onerecurrence and have risk factors for further episodes, includingsevere and severe-complicated CDI (strong).

Refractory Clostridium difficile infection.Recommendation:

FMT should be considered in cases of refractory CDI(conditional).

FMT as initial therapy for Clostridium difficile infection.Recommendation:

FMT should not be administered as initial treatment for CDI(strong).

Antimicrobial/antitoxin therapy prior to considering FMT forpatients with CDI.Recommendations:

i. FMT for recurrent CDI should only be considered afterrecurrence of symptoms following resolution of anepisode of CDI that was treated with appropriate anti-microbials for at least 10 days (conditional).

ii. Consider treatment with extended/pulsed vancomycinand/or fidaxomicin before considering FMT as treatmentfor recurrent CDI (conditional).

iii. For those with severe or complicated CDI, which appearsto be associated with reduced cure rates, considerationshould be given to offering patients treatment withmedications which are associated with reduced risk ofrecurrence (e.g. fidaxomicin and bezlotoxumab), beforeoffering FMT (conditional).

Post-FMT follow-up, outcomes and adverse eventsManagement of FMT failure.Recommendation:

Further FMT should be offered after initial FMT failure(strong).

General approach to follow-up post-FMT.Recommendation:

All FMT recipients should routinely receive follow-up. Cli-nicians should follow-up FMT recipients for long enough to fullyestablish efficacy/adverse events, and for at least eight weeksin total (strong).

Management of the FMT recipient.Recommendations:

i. Immediate management after endoscopic administrationof FMT should be as per the endoscopy unit protocol(strong).

ii. Patients should be warned about short term adverseevents, in particular the possibility of self-limiting GIsymptoms. They should be advised that serious adverseevents are rare (strong).

iii. After enteral tube administration, patients may have thetube removed and oral water given from 30 minutes post-administration (strong).

Definition of cure post-FMT for CDI.Good practice point:

A decision regarding cure/remission from CDI should berecorded during follow-up. However, this has no uniformly-agreed definition, and should be decided on a case-by-casebasis (strong).

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S5

Definition of treatment failure post-FMT for CDI.Good practice point:

Treatment failure/recurrence should be defined on acase-by-case basis. Routine testing for C. difficile toxin afterFMT is not recommended, but it is appropriate to consider inthe case of persistent CDI symptoms/suspected relapse(strong).

What recipient factors influence the outcome offaecal microbiota transplant when treating peoplewith Clostridium difficile infection?

General approach to co-morbidities and FMTGood practice points:

i. FMT should be avoided in those with anaphylactic foodallergy (strong).

ii. FMT should be offered with caution to patients with CDIand decompensated chronic liver disease (conditional).

Immunosuppression and FMTRecommendation:FMT should be offered with caution to immunosuppressed

patients, in whom FMT appears efficacious without significantadditional adverse effects (strong).

Good practice point:Immunocompromised FMT recipients at risk of severe

infection if exposed to EBV or CMV should only receive FMTfrom donors negative for EBV and CMV (strong).

Other comorbidities and FMTRecommendations:

i. FMT should be offered to those with recurrent CDI andinflammatory bowel disease, but patients should be

Table 1

Recommended donor history/questionnaire: A positive response to anconsideration as a donor, although this would depend upon the particu

1. Receipt of antimicrobials within the past three months.2. Known prior exposure to HIV and/or viral hepatitis, and known p3. Risk factors for blood-borne viruses - including high risk sexual beh

injury/blood transfusion/acupuncture, all within the previous six4. Receipt of a live attenuated virus within the past six months.5. Underlying gastrointestinal conditions/symptoms (e.g. history of

bowel resection or bariatric surgery) - also including acute diarrh6. Family history of any significant gastrointestinal conditions (e.g.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 prion11. History of chronic pain syndromes, including chronic fatigue synd12. History of any malignancy.13. Taking particular regular medications, or such medications wi

inhibitors, immunosuppression, chemotherapy14. History of receiving growth hormone, insulin from cows, or clott15. History of receiving an experimental medicine or vaccine within16. History of travel to tropical countries within the past six months

counselled about a small but recognised risk of exacer-bation of IBD (strong).

ii. FMT should be considered for appropriate patients withrecurrent CDI regardless of other comorbidities(conditional).

What donor factors influence the outcome of faecalmicrobiota transplant when treating people withClostridium difficile infection?

General approach to donor selectionRecommendation:Related or unrelated donors should both be considered

acceptable. However, where possible, FMT is best sourced froma centralised stool bank, from a healthy unrelated donor(conditional).

Age and BMI restrictions for potential donorsRecommendation:People should only be considered as potential FMT donors if

they are�18 and�60 years old, and have a BMI of�18 and�30kg/m2 (conditional).

General approach to the donor screening assessmentRecommendation:It is mandatory to screen potential donors by questionnaire

and personal interview, to establish risk factors for trans-missible diseases and factors influencing the gut microbiota(Table 1) (strong).

Laboratory screening of potential donorsRecommendation:Blood and stool screening of donors is mandatory (Tables 2

and 3) (strong).

y of these questions would usually result in exclusion from furtherlar circumstances/answers given

revious or latent tuberculosis.aviours, use of illicit drugs, any tattoo/body piercing/needlestickmonths.

IBD, IBS, chronic diarrhoea, chronic constipation, coeliac disease,oea/gastrointestinal symptoms within the past two weeks.family history of IBD, or colorectal cancer).

disease.rome and fibromyalgia.

thin the past three months, i.e. antimicrobials, proton pump

ing factor concentrates.the past six months..

Table 3

Recommended stool screening for stool donors: *Whilst CPE andESBL are the only multi-drug resistant bacteria that are recom-mended to be screened for universally, consider testing for otherresistant organisms (including vancomycin-resistant Enterococci(VRE) and/or methicillin-resistant Staphylococcus aureus (MRSA))based upon risk assessment and local prevalence

� Clostridium difficile PCR� Campylobacter, Salmonella, and Shigella by standard

stool culture and/or PCR� Shiga toxin-producing Escherichia coli by PCR.� Multi-drug resistant bacteria, at least carbapenemase-

producing Enterobacteriaceae (CPE) and extended-spectrum beta-lactamases (ESBL)*.

� Stool ova, cysts and parasite analysis, including forMicrosporidia.

� Faecal antigen for Cryptosporidium and Giardia.� Acid fast stain for Cyclospora and Isospora.� Helicobacter pylori faecal antigen.� Norovirus, Rotavirus PCR.

Table 2

Recommended blood screening for stool donors: *EBV and CMVtesting is only recommended where there is the potential that theFMT prepared from that donor will be administered to immuno-suppressed patients at risk of severe infection if exposed to CMVand EBV

Pathogen screening:e Hepatitis A IgMe Hepatitis B (HBsAg and HBcAb)e Hepatitis C antibodye Hepatitis E IgMe HIV -1 and -2 antibodiese HTLV-1 and -2 antibodiese Treponema pallidum antibodies (TPHA, VDRL)e Epstein-Barr virus IgM and IgG*e Cytomegalovirus IgM and IgG*e Strongyloides stercoralis IgGe Entamoeba histolytica serology

General/metabolic screening:e Full blood count with differential.e Creatinine and electrolytese Liver enzymes (including albumin, bilirubin,

aminotransferases, gamma-glutamyltransferase and alka-line phosphatase).

e C-reactive protein

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S6

Repeat donor checks, and donation pathwayRecommendations:

i. In centres using frozen FMT, before FMT may be usedclinically, donors should have successfully completed adonor health questionnaire and laboratory screening as-says both before and after the period of stool donation.This is the preferred means of donor screening (strong).

ii. In centres using fresh FMT, a repeat health questionnaireshould be assessed at the time of each stool donation. Toensure ongoing suitability for inclusion as a donor, thedonor health questionnaire and laboratory screeningshould be repeated regularly (strong).

What factors related to the preparation of thetransplant influence the outcome of faecal microbiotatransplant when treating people with Clostridiumdifficile infection?

General principles of FMT preparationRecommendations:

i. Donor stool collection should follow a standard protocol(strong).

ii. Donor stool should be processed within 6 hours ofdefaecation (strong).

iii. Both aerobically and anaerobically prepared FMT treat-ments should be considered suitable when preparing FMTfor the treatment of recurrent CDI (strong).

iv. Sterile 0.9% saline should be considered as an appropriatediluent for FMT production, and cryoprotectant such asglycerol should be added for frozen FMT (strong).

v. Use �50g of stool in each FMT preparation (strong).

Good practice points:

i. Stool should be mixed 1:5 with diluent to make the initialfaecal emulsion (conditional).

ii. Homogenisation and filtration of FMT should be under-taken in a closed disposable system (conditional).

Fresh vs frozen FMTRecommendation:The use of banked frozen FMTmaterial should be considered

preferable to fresh preparations for CDI (strong).

Use of frozen FMTRecommendation:FMT material stored frozen at -80oC should be regarded as

having a maximum shelf life of six months from preparation(strong).

Good practice points:

i. Consider thawing frozen FMT at ambient temperature,and use within six hours of thawing (conditional).

ii. Do not thaw FMT in warm water baths, due to therisks of cross contamination with Pseudomonas (andother contaminants) and reduced bacterial viability(strong).

What factors related to administration of thetransplant influence the outcome of faecal microbiotatransplant when treating people with Clostridiumdifficile infection?

Use of specific medications in the period around FMTadministrationGeneral principles of FMT administration.Recommendations:

i. Bowel lavage should be administered prior to FMT via thelower GI route, and bowel lavage should be consideredprior to FMT via the upper GI route; polyethylene glycolpreparation 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 inhibitorshould be considered, e.g. the evening before andmorning of delivery (conditional).

iii. A single dose of loperamide (or other anti-motility drugs)should be considered following lower GI FMT delivery(conditional).

Good practice points:

i. Prokinetics (such as metoclopramide) should be consid-ered prior to FMT via the upper GI route (conditional).

ii. Best practice for prevention of further transmission of CDIshould be applied throughout when administering FMT topatients with CDI (nursing with enteric precautions,sporicidal treatment of endoscope, etc).

Additional antibiotics pre-FMT.Recommendation:

Administer further antimicrobial treatment for CDI for atleast 72 hours prior to FMT (strong).

Washout period between antibiotic use and FMT.Recommendation:

To minimise any deleterious effect of antimicrobials on theFMT material, there should be a minimum washout period of 24hours between the last dose of antibiotic and treatment withFMT (strong).

Good practice point:Consider consultation with infectious disease specialists or

medical microbiologists for advice whenever FMT recipientsalso have an indication for long-term antibiotics, or have anindication for non-CDI antibiotics within eight weeks of FMT(conditional).

Route of FMT deliveryUpper gastrointestinal tract administration of FMT.Recommendations:

i. Upper GI administration of FMTas treatment for recurrentor refractory CDI should be used where clinically appro-priate (strong).

ii. Where upper GI administration is considered mostappropriate, FMT administration should be via nasogas-tric, nasoduodenal, or nasojejunal tube, or alternativelyvia upper GI endoscopy. Administration via a permanentfeeding tube is also appropriate (strong).

Good practice points:

i. It is recommended that no more than 100ml of FMT isadministered to the upper GI tract (conditional).

ii. Upper GI administration of FMT should be used withcaution in those with swallowing disorders (strong).

Lower gastrointestinal tract administration of FMT.Recommendations:

i. Colonoscopic administration of FMT as treatment forrecurrent or refractory CDI should be used where appro-priate (strong).

ii. Where colonoscopic administration is used, considerpreferential delivery to the caecum or terminal ileum, asthis appears to give the highest efficacy rate(conditional).

iii. FMT via enema should be used as a lower GI option whendelivery using colonoscopy or flexible sigmoidoscopy isnot possible (strong).

Capsulised FMT.Recommendation:

Capsulised FMT holds promise as a treatment option forrecurrent CDI and should be offered to patients as a potentialtreatment modality where available. Capsule preparationsshould follow a standard protocol. Further evidence regardingoptimal dosing and formulation is required (conditional).

What is the clinical effectiveness of FMT in treatingconditions other than Clostridium difficile infection?

Recommendation:FMT is not currently recommended as treatment for in-

flammatory bowel disease. Apart from CDI, there is insufficientevidence to recommend FMT for any other gastrointestinal ornon-gastrointestinal disease (strong).

Basic requirements for implementing a FMT service

General considerationsGood practice points:

i. The development of FMT centres should be encouraged(strong).

ii. FMT centres should work to raise awareness about FMT asa treatment option amongst clinicians caring for patientswith CDI, and provide training to relevant healthcareprofessionals on the practicalities of delivering an FMTservice (conditional).

Legal aspects and clinical governanceGood practice point:In the UK, FMT must be manufactured in accordance with

MHRA guidance for human medicines regulation. When FMT issupplied on a named patient basis, within a single organisation,a pharmacy exemption may be used, subject to ensuring propergovernance and traceability. All centres that are processingand distributing FMT should seek guidance from the MHRA andwhere necessary obtain appropriate licenses prior to estab-lishing an FMT service. This is a legal requirement. In countriesother than the UK, FMT should only be manufactured followingappropriate approval from the national authority of thatcountry (strong).

Multidisciplinary teamsGood practice point:A multidisciplinary team should be formed to deliver FMT

services (strong).

InfrastructureGood practice point:

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S8

Utilise suitable laboratory facilities and infrastructure forFMT production (strong).

FMT manufacturingGood practice point:Ensure traceability of supply (strong).

FMT production quality controlGood practice point:Monitor, notify and investigate all adverse events and re-

actions related to FMT (strong).

Donor screening governanceGood practice point:Ensure the clinical governance of donor screening (strong).

Implementation of these guidelines

How can these guidelines be used to improve clinicaleffectiveness?

Primarily, these guidelines will inform the development oflocal FMT services and appropriate local operational protocols,and will guide clinical decision-making. They also provide aframework for clinical audit, a tool for improving clinicaleffectiveness. In addition, the future research priorities iden-tified by the working group will allow researchers to refineapplications to funding bodies.

How much will it cost to implement these guidelines?

Where FMT is being provided under a MHRA license accord-ing to Good Manufacturing Practice (GMP) standards, there aresignificant costs associated with initial setup and maintenanceof the service. These include the cost of obtaining the relevantlicense, laboratory design and equipment to enable qualityassurance, storage facilities for samples, etc. However, thereis counterbalance to this, as the expectation of the workinggroup is that the publication of this guideline may encourageprovision of FMT as treatment for recurrent or refractory CDI.This has consistently been shown to be cost effective in com-parison with anti-C. difficile antimicrobial therapy [35e38], sooverall costs associated with treating the condition may actu-ally decrease. Furthermore, there may be changes to thepractice of clinicians already offering the service. For example,encouraging the use of healthy unrelated donors (who canprovide multiple stool donations after one screening) reducesthe cost of screening when compared to the use of an FMTrecipient’s relative as donor, who is likely to provide onedonation only.

Summary of audit measures

� All donors to have completed initial screening question-naires and blood and stool screening results, as well asfinal health check prior to each stool donation processedto FMT. Results from each subsequent serial round ofscreening also to be documented.

� All FMT recipients to have clear documentation of detailsof their disease course and preparation prior to FMT,

including whether recurrent or refractory disease, pre-vious antimicrobial courses, and use of bowel purgatives/other preparatory medications pre-FMT.

� All FMT recipients to have sufficient documentation toallow clear traceability of the exact FMT aliquot trans-fused. Records should include identification of the donor,in addition to a frozen FMT aliquot (and original faecalsample) - as well as serum - from that donor.

� All FMT recipients for recurrent or refractory CDI to havedocumentation during follow-up of treatment success orfailure (and subsequent treatment plan if failure),together with clear documentation of any adverse eventsthat may be attributable to FMT.

E-learning tools

Continuing Professional Development questions and theiranswers are provided for self-assessment in Main Appendix 4.

Methodology

Evidence appraisal

Questions for review were derived from the Working PartyGroup, which included patient representatives in accordancewith the PICO process [32]. Methods were in accordance withSIGN 50 [33] and the Cochrane Collaboration [34].

Data sources and search strategy

A systematic literature search was undertaken using MED-LINE and EMBASE databases, and the Cochrane Library, forrelevant articles published from 1st January 1980 to 1st

January 2018. The MEDLINE and EMBASE strategy is shown inMain Appendix 2ii. Free text and MESH/index terms for faecalmicrobial transplant and Clostridium difficile or other dis-eases of interest were combined. In addition, conferenceproceedings from microbiology, infectious disease andgastroenterology conferences were also searched to identifyadditional studies.

Study eligibility and selection criteria

The members of the guideline group determined criteria forstudy inclusion. Two reviewers (BHM, MNQ) screened the titlesand abstracts of each article for relevance independently; anydisagreements were resolved by discussion with a thirdreviewer (JPS). Copies of relevant articles were obtained andassessed for inclusion as evidence in the guideline by all threereviewers. The reason for not selecting studies was recorded.Only articles published in English and human clinical studieswere included. For evidence on FMT for CDI, both randomisedstudies (including randomised controlled trials (RCTs)) and caseseries with at least 10 patients were selected. Only randomisedtrials were included as evidence for FMT for non-CDI in-dications. Conference abstracts were only included for CDI andnon-CDI indications if they reported a randomised trial; whereabstracts 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 wasreviewed.

Data extraction and quality assessment

The initial search identified 2658 publications, and of these,802 duplicates were excluded. From here, 1856 studies weresubsequently screened, from which 78 studies were assessedby reviewing the full text for eligibility (see Main Appendix 2iiiand Additional Appendix D). Of these 78 studies, 58 studieswere included as the basis of evidence for writing this guide-line. In total, 39 were case studies in CDI including at least 10patients (see Additional Appendix C.1), and ten were rando-mised studies in CDI (see Additional Appendix C.2). Nine wererandomised trials for non-CDI indications (see AdditionalAppendix C.3). Data were extracted for patient demographics,disease characteristics, donor screening characteristics, stoolpreparation and administration, clinical outcomes and adverseevents. The quality of randomised studies was assessed withthe Cochrane Collaboration’s risk of bias tool. Case series wereassessed using the Centre for Reviews and Disseminationguidance.

Table 4

Evidence statements and recommendations. A. Levels of evidence fo

A. Levels of evidence1þþ High

very1þ Well-

risk o1� Meta2þþ High-

High-confocausa

2þ Well-confocausa

2- Case-and a

3 Non-a4 Expe

B. Recommendations

Some recommendations can be made with more certainty than othedenotes the certainty with which the recommendation is made (th

The ‘strength’ of a recommendation takes into account the quality (likely to be associated with strong recommendations than lower-qualead to a particular strength of recommendation.

Other factors that are taken into account when forming recommendapublished evidence to the target population; consistency of the booptions.

For ‘strong’ recommendations on interventions that ‘should’ be usedpeople, the intervention (or interventions) will do more good than hnot’ be used, the working group is confident that, for the vast majharm than good.

For ‘conditional’ recommendations on interventions that should be ‘will do more good than harm for most patients. The choice of intervalues and preferences, and so the healthcare professional should

Good practice points are recommended best practice based on the

Rating of evidence and recommendations

Evidence tables were presented and discussed by theworking group, and guidelines were prepared according to thenature and applicability of the evidence regarding efficacy andpatient preference and acceptability. For the HIS version ofthis guideline, the strength of evidence was defined by SIGN[33] (Table 4A), and the strength of recommendation wasadopted from GRADE (Grades of Recommendations Assess-ment, Development and Evaluation) [39] (Table 4B). In addi-tion, where there was no clear evidence or a paucity ofevidence, good practice recommendations were made byexpert experience and consensus. The section entitled ‘Basicrequirements for implementing an FMT service’ was based onexpert opinion, since this was a key area of the working party’sremit but not one amenable to evaluation by the PICO process.Face-to-face meetings and group teleconferences were held toagree on recommendations. Any disagreements on recom-mendations or the strength of recommendation were resolvedby discussion and, where necessary, voting by the members ofthe working group, with consensus achieved when >80% werein agreement.

r intervention studies; B. Recommendation grading

quality meta-analyses, systematic reviews of RCTs, or RCTs with alow risk of biasconducted meta-analyses, systematic reviews, or RCTs with a lowf bias-analyses, systematic reviews, or RCTs with a high risk of biasquality systematic reviews of case-control or cohort studiesquality case-control or cohort studies with a very low risk ofunding or bias and a high probability that the relationship islconducted case-control or cohort studies with a low risk ofunding or bias and a moderate probability that the relationship islcontrol or cohort studies with a high risk of confounding or biassignificant risk that the relationship is not causalnalytic studies, e.g. case reports, case series.rt opinion

rs. The wording used in the recommendations in this guidelinee ‘strength’ of the recommendation).level) of the evidence. Although higher-quality evidence is morelity evidence, a particular level of quality does not automatically

tions include: relevance to the NHS in the UK; applicability ofdy of evidence, and the balance of benefits and harms of the

, the working group is confident that, for the vast majority ofarm. For ‘strong’ recommendations on interventions that ‘shouldority of people, the intervention (or interventions) will do more

considered’, the working group is confident that the interventionvention is therefore more likely to vary depending on a person’sspend more time discussing the options with the patient.

clinical experience of the guideline working group.

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S10

Consultation process

Feedback on draft guidelines was received from the Sci-entific Development Committee (SDC) of HIS, and changesmade. These guidelines were then opened to consultationwith relevant stakeholders (see Main Appendix 3). The draftreport was available on the HIS website for one month. Viewswere invited on format, content, local applicability, patientacceptability, and recommendations. The working groupreviewed stakeholder comments, and collectively agreed re-visions. Final changes were made after repeat reviews fromHIS (chair of the SDC and HIS Council) and BSG (BSG CSSC andBSG Council), and after further external peer review.

Rationale for recommendations

Which patients with Clostridium difficile infectionshould be considered for faecal microbiota transplant,and how should they be followed up after treatment?

Prior to faecal microbiota transplant. Patient selectionRecurrent Clostridium difficile infection. As alreadydescribed, there is widespread consensus that FMT is an effi-cacious treatment for recurrent CDI. In defining recurrent CDI,some studies have relied on a minimum threshold of return ofclinical symptoms (e.g. at least three unformed bowel move-ments within 24 hours, for at least two consecutive days)[12,18] following previous successful CDI treatment; moststudies have also included a requirement for a positive micro-biological test [12,14,18,40e50]. Other studies explicitly statethat a positive test was not required [51]. Recommendationsfor CDI testing are beyond the scope of this guideline, andthere are already well-established evidence-based guidelines[52]. These recommend testing with either a nucleic acidamplification test (NAAT) or glutamate dehydrogenase (GDH)assay, followed by detection of free toxin (either by toxin A/Benzyme immunoassay (EIA) or cytotoxin neutralisation assay),which allows differentiation of patients with active disease aswell as those who are likely colonised [52]. However, theworking group discussed the importance of the accurate diag-nosis of true recurrent CDI prior to consideration of FMT; inparticular, they noted a study which observed that of 117 pa-tients with presumed recurrent CDI referred for work-up forFMT, 25% (n ¼ 29/117) were determined to have a non-CDIdiagnosis, with irritable bowel syndrome (n ¼ 18) and inflam-matory bowel disease (n ¼ 3) being the most common alter-native diagnoses, and younger patients more likely to bemisdiagnosed [53].

All of the reviewed studies have included patients withrecurrent CDI but some studies offered FMT to patients at thefirst recurrence (second episode) [12,15,16,18,40,42,47,48,51,54], whereas others offered FMT after the secondrecurrence (third episode) [13,14,44,46,49,50,55,56]. Someprotocols offered FMT after three or more recurrences [57],while others did not define the point at which it was adminis-tered [45,58].

The severity of infection has been used as a parameterto decide at which stage FMT is offered. Youngsteret al. offered FMT to patients with at least three episodesof mild to moderate CDI, or at least two episodes of severeCDI resulting in hospitalisation and associated with signifi-cant morbidity [17]. Another study selected patients for

FMT using four categories of severity, which also accountedfor prior anti-CDI therapy and requirement for hospital-isation [59].

None of the studies directly compared the efficacy of FMTaccording to the stage at which it was offered (i.e. firstrecurrence vs. � two recurrences). A small number of studies[60e62] included patients with severe CDI (defined as hypo-albuminaemia with increased peripheral white cell count and/or abdominal tenderness) or complicated CDI (defined asadmission to Intensive Care, altered mental status, hypoten-sion, fever, ileus, white blood cell count > 30 � 109/l,lactate > 2.2mmol/l, or evidence of end organ damage). Asingle study described an apparent lower rate of treatmentsuccess when FMTwas used to treat patients with recurrent CDIwith disease caused by ribotype 027 [48], but this is the case forall anti-CDI treatment modalities for this ribotype in compari-son with others. The working group agreed that there wasinsufficient evidence to suggest that C. difficile ribotypeshould influence whether or not FMT is offered.

A lower primary cure rate was reported for complicatedCDI (66%) compared with recurrent CDI (82%) and severe CDI(91%) in one study [60]; in a case series of 17 patients who allhad severe and/or complicated CDI, a primary cure rate of88% was described [62]. A cohort of 328 patients was analysedto determine which factors were associated with failure ofFMT [63]. Higher early (one month) failure rates were foundin patients with severe (72%, n ¼ 18/25) or severe-complicated CDI (52.9%, n ¼ 9/17) than for recurrent CDI(11.9%, n ¼ 34/286). This study also identified that patientswho were treated with FMT as an inpatient were nearly fourtimes more likely to fail as those who had FMT as an outpa-tient; however, the working group noted that the authors ofthis study themselves identified that in-patient status is likelya proxy of severity of CDI and/or co-morbidities. A furthersimilar study, including 64 patients treated with FMT astreatment for recurrent CDI, also identified severe CDI as thestrongest independent risk factor for FMT failure on multi-variate analysis [64].

The working group discussed their experience of treatingpatients with CDI whose disease fitted an intermediate patternto the typical descriptions given of recurrent or refractory CDI,e.g. patients with CDI who have some (but incomplete) symp-tomatic improvement with anti-CDI antibiotics and worseningof disease when these are stopped. The experience of theworking group was that such patients experienced excellentresponses to FMT, and that these patients should be consideredfor FMT.

As FMT is currently an unlicensed medicine with poorly-studied long term sequelae, the working group consideredthat it should generally be reserved for patients who have hadthree or more episodes of infection. There are no studiesdirectly comparing its effectiveness with some of the neweragents such as fidaxomicin or bezlotoxumab, hence thisrecommendation is made on the basis of safety. However, theworking group agreed that it may be reasonable in certainpatient groups with ongoing risk factors for further recurrenceto offer FMT after the second episode.

Evidence:The reviewed literature represents a wide variety of

different study designs. However, regardless of design, there isconsistent evidence that FMT is an effective therapy for peoplewith recurrent CDI (quality of evidence: 1þ).

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S11

Recommendation:FMT should be offered to patients with recurrent CDI who

have had at least two recurrences, or those who have had onerecurrence and have risk factors for further episodes, includingsevere and severe-complicated CDI (strong).

Refractory Clostridium difficile infection. Two randomisedtrials allowed the recruitment of patients with refractory CDI.The first defined this as at least three weeks of ongoing severesymptoms despite standard antimicrobial therapy for CDI [17].The second required persistent or worsening diarrhoea and oneof the following: ongoing abdominal pain, fever > 38oC, orwhite blood cell count > 15 � 109/l despite oral vancomycin ata dose of 500mg four times daily for at least five days [16]. Bothstudies included only small numbers of patients with refractoryCDI (n¼4/20 (20%) and n¼15/219 (6.8%), respectively). Theredid not appear to be any significant difference in primaryoutcome measure (clinical cure) in patients with recurrent orrefractory CDI, although neither study was designed to assessthis difference. There are also a number of case series in whichFMT was given to patients with refractory CDI; however,outcome measures were not reported for these groups indi-vidually in these studies [42,43,59,65].

Evidence:There is little consensus on the definition of refractory CDI,

with some studies using the terms ‘refractory’ and ‘recurrent’interchangeably (as well as other terms, e.g. ‘salvage ther-apy’). Consequently, the quality of evidence for the utility ofFMT in refractory cases of CDI is lower than for recurrent CDI.Standardisation of definitions will allow more robust compari-son between patient cohorts (quality of evidence: 1-).

Recommendation:FMT should be considered in cases of refractory CDI

(conditional).

FMT as initial therapy for Clostridium difficile infec-tion. Experience of the use of FMT as initial therapy for CDI isvery limited. In a case series of patients with CDI with ribo-type 027, use of anti-CDI antibiotics together with nasogastricFMTwithin a week of diagnosis during an initial episode of CDIwas associated with reduced mortality compared to using FMTonly after the failure of three courses of antibiotics (mortalityof 18.75% (n ¼ 3/16 patients) vs 64.4% (n ¼ 29/45 patients))[66]. However, 37.5% (n ¼ 6/16) of the patients treated withFMT within a week of CDI diagnosis required further anti-biotics and a second FMT within one month of the first FMTbecause of relapse [66]. In a small pilot randomised trial,patients were randomised to either vancomycin or multi-donor FMT (administered either via upper or lower GIroutes) as initial therapy for CDI; CDI resolution occurred in88.9% (8/9) of patients with vancomycin, compared with57.1% of patients (n ¼ 4/7) with one FMT, and 71.4% of pa-tients (n ¼ 5/7) after two FMTs [67]. Given the small size ofthese studies and equivocal results, the working groupconcluded that the reviewed studies did not support CDI asinitial therapy for CDI.

Evidence:There is very little experience of FMT as use as initial

therapy for CDI (quality of evidence: 3).Recommendation:FMT should not be administered as initial treatment for CDI

(strong).

Antimicrobial/antitoxin therapy prior to considering FMT forpatients with CDI. There are now at least two licensed agents(fidaxomicin and bezlotoxumab) which have been shown tosignificantly reduce the risk of recurrence compared withvancomycin [68,69]. There is also some evidence that pulsed/tapered dosing of vancomycin and fidaxomicin (includingpulsed fidaxomicin [70]) results in fewer recurrences than withstandard dosing of these agents [71,72] (although this findinghas not been replicated in all studies [73]). Pre-planned sub-group analysis of patients with severe CDI in a randomised trialdemonstrated a significantly lower recurrence rate whentreated with fidaxomicin (13.0%, n ¼ 12/92) than when treatedwith vancomycin (26.6%, n ¼ 29/109) [68]; this finding wasreplicated in another randomised controlled trial, with 8.3%(n ¼ 4/48) and 32.6% (n ¼ 14/43) experiencing a recurrencerespectively [74]. In a further randomised trial, bezlotoxumab(together with standard of care antibiotics) was shown toreduce recurrence of severe CDI compared with standard ofcare antibiotics alone (10.9% (n ¼ 6/55) vs 20% (n ¼ 13/65)respectively) [69].

As discussed above, the working group noted that there areno studies comparing FMT with fidaxomicin or bezlotoxumab,and only one study comparing a vancomycin taper to FMT [12].The working group agreed that in the absence of this evidence,on the balance of safety and potential risks, considerationshould be given to using antimicrobial/antitoxin therapy asso-ciated with reduced CDI recurrence prior to considering the useof FMT.

Several studies specify that patients should be treated withanti-C. difficile antibiotics for a minimum period of 10 daysbefore diagnosing recurrent CDI and offering FMT[12,15,16,18].

Evidence:There is evidence that particular antimicrobial agents

reduce the likelihood of recurrence of CDI, but data comparingFMT to antimicrobial or antitoxin therapy are lacking (quality ofevidence: 3).

Recommendations:

i. FMT for recurrent CDI should only be considered afterrecurrence of symptoms following resolution of anepisode of CDI that was treated with appropriate anti-microbials for at least 10 days (conditional).

ii. Consider treatment with extended/pulsed vancomycinand/or fidaxomicin before considering FMT as treatmentfor recurrent CDI (conditional).

iii. For those with severe or complicated CDI, which appearsto be associated with reduced cure rates, considerationshould be given to offering patients treatment withmedications which are associated with reduced risk ofrecurrence (e.g. fidaxomicin and bezlotoxumab), beforeoffering FMT (conditional).

Post-FMT follow-up, outcomes and adverse eventsManagement of FMT failure. Where patients were deemed notto have responded to an initial FMT, many studies have offeredrepeat FMT and success rates have been excellent even inpatients with a modest response to a first FMT[14,15,17,18,40,48,51,56,59,75,76]. The success of a secondFMT appears to be high whether treatment failure representsnon-response to the first FMT, or a late failure (i.e. furtherrelapse of CDI after an initial response); however, these terms

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S12

have been defined variably between different studies (also seeSection Definition of treatment failure post-FMT for CDI).Second FMTs have been offered as soon as 24e72 hours after aninitial FMT for presumed non-response [42,77,78]. For FMTfailure in patients with pseudomembranous colitis, repeat FMTevery three days until resolution of pseudomembranes hasbeen a successful approach [18]. Good outcomes in pseudo-membranous disease have also been achieved through a pro-tocol that routinely restarted five days of vancomycin if FMTfailed, before offering anther FMT [78]. Other studies havedemonstrated potential success in treating initial FMT failurewith further antibiotics, including repeat FMTwith vancomycinbetween procedures [47], or anti-CDI antibiotics alone[40,47,48,50,56,75,76]. Patients unresponsive to two FMTshave been offered further FMT or antibiotic therapy [16], oreven administration of intravenous immunoglobulin [40]. Whilethe working group collectively agreed that there was strongevidence to recommend repeat FMT after initial FMT failure,they were not able to recommend a specific protocol foradministering repeat FMT and/or maximum number of FMTs,given the wide heterogeneity of approach described within thereviewed literature.

Evidence:Regardless of how failure is defined, there is good evidence

that further FMT is efficacious at treating CDI after initial FMTfailure (quality of evidence 1þþ).

Recommendation:Further FMT should be offered after initial FMT failure

(strong).

General approach to follow-up post-FMT. Follow-up post-FMT (in terms of duration, modality and regimen forfollow-up) varies considerably between studies, and islargely dependent on study design. Follow-up regimens varynot only between studies but within them too, reflecting theretrospective nature of many early FMT studies in CDI,where follow-up mostly reflected pragmatic routine clinicalcare.

Modalities of follow-up have included outpatient review[14,48,63,76,79,80], telephone interview [17,44,48,51,63,76,79] and case note/database review[40,44,45,47,48,50,51,54,56,59,75,76,79]. Follow-up dura-tion has varied from 60 days [50] to 8 years [41], with verydifferent durations used in each study. Once again, however,this variability in follow-up largely reflects the retrospectiveanalysis of case series rather than being justified by anyspecific methodology. The working group decided byconsensus that at least eight weeks of follow-up was appro-priate post-FMT to fully assess efficacy and potential adverseevents; this figure was also influenced by discussionsregarding the time point after FMT at which a decision couldbe made regarding cure/remission of CDI (see SectionDefinition of cure post-FMT for CDI).

Evidence:The approach to following up patients after FMT varies

considerably between studies, and is often pragmaticallydesigned (quality of evidence: 3).

Recommendation:All FMT recipients should routinely receive follow-up. Cli-

nicians should follow-up FMT recipients for long enough to fullyestablish efficacy/adverse events, and for at least eight weeksin total (strong).

Management of the FMT recipient. Procedural adverse eventsduring administration of FMT have predominantly occurredwith colonoscopic administration of FMT. These have includedmild nausea and vomiting attributed to sedation for the colo-noscopy, minor mucosal tears during colonoscopy [54,65], andmicroperforation following biopsy of an area of presumedischaemic small bowel injury in a patient with chronicallydilated small bowel (which resolved with conservative man-agement [51]). One death occurred due to witnessed aspirationat the time of colonoscopy [65]. Faecal regurgitation andvomiting with temporal association to upper GI FMT adminis-tration has also been described (discussed further in SectionUpper gastrointestinal tract administration of FMT) [81].

The predominant short term adverse events post-FMT forCDI are mild: self-limiting GI symptoms have been the mostfrequently reported adverse events. These may be related tothe route of administration and include belching [15], nausea[15,16,54,65], abdominal cramps/discomfort/bloating/pain[15,18,54,65,77], and diarrhoea [15,16,18,65]. One patientwith a history of autonomic dysfunction experienced dizzinesswith diarrhoea after FMT [15]. These symptoms are typicallyshort-lived, resolving in hours to days [15,16,18,54,77]. Minorsubsequent adverse events have included a range of GI sideeffects including self-limiting abdominal discomfort[14,17,62,80], nausea [14,54,75], flatulence [14,16,17,46,47,54,62], self-limiting irregular bowel movements [46],C. difficile-toxin negative diarrhoea [57,60], constipation[14,15,47,60,75] and constitutional symptoms/temperaturedisturbance [14,17].

As such, immediately post-endoscopic administration ofFMT, most FMT centres typically manage patients using stan-dard protocols for an endoscopic procedure [46,54], withoutany specific adaptations (apart from to reiterate advice aboutthe possibility of self-limiting GI side effects, and the use ofdepartmental infection control protocols). There is often arelatively short period of post-procedural observation [15,18].Most studies allow patients to leave the administration siteafter the period of observation, although overnight observationwas the protocol used for a cohort of very elderly patients withmultiple comorbidities [56]. Where enteral tube administrationis used, post-procedure management has ranged betweenremoval of the tube after 30 minutes (following nasoenteraladministration of 500ml of FMT [15]) to prompt post-procedureremoval and oral water administration (after nasogastricadministration of 90ml of FMT [77]), with no direct adverseoutcomes in either case. The working group felt that removalof the tube at 30 minutes, with administration of water at thispoint, was a pragmatic approach.

The definition of post-FMT serious adverse events has variedbetween studies, but has included significant morbiditynecessitating hospital admission and death in the follow-upperiod. Many of these events are described as not directlycaused by the FMT, including the scenario of post-FMT severeCDI recurrences [77] and probable or certain CDI-relateddeaths [16,65,75] occurring in the context of FMT failure, ordeaths related to patient comorbidities [17,60]. One patientwas admitted to hospital with self-limiting abdominal painpost-FMT [65], and four patients with flares of inflammatorybowel disease [65]. Three patients underwent colectomy dur-ing the post-FMT follow-up period, with all related to ulcera-tive colitis and not believed to be due to CDI [65]. Otherreported 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 uppergastrointestinal haemorrhage after nasogastric FMT (in a pa-tient taking non-steroidal anti-inflammatory drugs [56]), noneof which were thought to be strongly linked to FMT. There havealso been a number of new onset autoimmune, inflammatoryand metabolic conditions described post-FMT, although thesehave been described from single centres only, with thesefindings not replicated elsewhere. Such conditions includemicroscopic colitis, Sjogren’s syndrome, follicular lymphoma,peripheral neuropathy, immune thrombocytopenia and rheu-matoid arthritis [58,60].

Significant adverse events are therefore rare but well-described. Furthermore, the procedure is relatively novel,and longer-term follow-up data regarding safety are required.Therefore, the working group opined that formal follow-uppost-FMT to assess outcome and possible adverse events isessential.

The use of questionnaires to compare symptoms pre- andpost-FMT is common. Specifically, data collected have includedclinical response to symptom severity [60], stool frequency[15,17,51,60,62,77], stool consistency [14,15,77], abdominalpain or tenderness [60,62], rating of gastrointestinal symptoms[77], general well-being [60,77], days to improvement post-FMT [62], weight change [77], functional status [60], andchanges in medication/use of antibiotics [62,77]. Additionally,certain patients have been given specific advice post-FMT tocontact their clinical team if there is recurrence of diarrhoea orsymptoms [14,40,46,48]. Where patients underwent outpa-tient clinical evaluation, this was generally undertaken rela-tively early post-FMT [44,57,80]. In one study, patients wereadditionally given instructions for cleaning and disinfection athome, with the aim of reducing the possibility of C. difficilereinfection [48], and counselling on the risk of recurrent CDIwith future antibiotic courses [80].

Evidence:Much of the short-term management of the FMT recipient

describes general principles of best practice related to theroute of administration. Many adverse events describedfollowing FMT are minor, and/or may not directly relate to thetransplant itself (quality of evidence: 3).

Recommendations:

i. Immediate management after endoscopic administrationof FMT should be as per the endoscopy unit protocol(strong).

ii. Patients should be warned about short term adverseevents, in particular the possibility of self-limiting GIsymptoms. They should be advised that serious adverseevents are rare (strong).

iii. After enteral tube administration, patients may have thetube removed and oral water given from 30 minutes post-administration (strong).

Definition of cure post-FMT for CDI. It is recognised thatsymptoms of CDI resolve relatively promptly after successfulFMT, although this has been variably described (within hours insome studies [57], at an average of 4e5 days in others [62,76]).Treatment success post-FMT for CDI has no uniformly-agreeddefinition, with the time point at which cure/remission isdefined on clinical grounds varying between 3-5 days [41] up tosix months [47]. A consensus document from the USA

recommends ‘resolution of symptoms as a primary end point;absence within eight weeks of FMT as a secondary end point’[8]. The working group recommended that this definitionshould be made on a case-by-case basis; however, they agreedthat an assessment for cure/remission of CDI within eightweeks post-FMT was reasonable in most cases, and thereforethat this was also a reasonable minimum length of time toundertake follow-up post-FMT (see Section General approachto follow-up post-FMT).

Evidence:No universal definition exists regarding cure/remission post-

FMT for CDI (quality of evidence: 4).Good practice point:A decision regarding cure/remission from CDI should be

recorded during follow-up. However, this has no uniformly-agreed definition, and should be decided on a case-by-casebasis (strong).

Definition of treatment failure post-FMT for CDI. There is nouniformly-agreed definition of treatment failure/recurrencepost-FMT for CDI, with varied definitions used in studies. Theuse of C. difficile toxin as a marker of treatment success orfailure is variable, with some studies opting not to test forC. difficile toxin unless symptoms consistent with CDI recurred[54,57e59,65,77,79]. Some studies have routinely performedC. difficile toxin testing without specifying any action takenafter a positive result [14,15,18,41,44,46], while others havetested for C. difficile PCR but relied on clinical criteria (even ifPCR was positive) post-FMT for evaluating FMT efficacy [14]. Arecent prospective study from the USA identified that only 3%(3/129) of patients who were asymptomatic at four weeks post-FMT for recurrent CDI had positive C. difficile PCR, againemphasising that symptoms rather than laboratory assays aremore useful contributors to establishing FMT success [82].

Evidence:No standard definition exists regarding treatment failure/

recurrence post-FMT for CDI (quality of evidence: 4).Good practice point:Treatment failure/recurrence should be defined on a case-

by-case basis. Routine testing for C. difficile toxin after FMTis not recommended, but it is appropriate to consider in thecase of persistent CDI symptoms/suspected relapse (strong).

What recipient factors influence the outcome offaecal microbiota transplant when treating peoplewith Clostridium difficile infection?

General approach to co-morbidities and FMTMost published studies had a core set of general recipient

exclusions which included: significant/anaphylactic food al-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 ofdiarrhoea [12,14,18,55], inflammatory bowel disease (IBD) andirritable bowel syndrome (IBS) [14,41], immunodeficiency dueto recent chemotherapy and/or neutropenia [12,14e18,55],HIV/AIDS [14,17,18], prolonged use of corticosteroids[15,17,18], graft versus host disease [12], and decompensatedcirrhosis [14,15,17,18].

The working group discussed the reported practice ofseveral centres of treating patients with recurrent CDI and

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S14

food allergies through the use of FMT prepared from a patient-directed donor instructed to avoid trigger foods before stooldonation. They agreed that this seemed reasonable for pa-tients with true adverse immunological reactions to definedfood groups (e.g. gluten-free diet donor for a recipient withcoeliac disease). However, the working group noted that foodallergies are often poorly-defined clinically, and alsoexpressed concerns that there was no means to verify howclosely a donor had followed an exclusion diet; as such, theyfelt unable to make any specific recommendation about FMTin patients with food allergies in general. In contrast, whilethe working group were unaware of any reports in the liter-ature of anaphylaxis attributable to FMT, they felt that thetheoretical risk of a serious adverse outcome in patients withanaphylactic food allergy merited a specific recommendationthat such individuals should not be offered FMT. Similarly, theworking group expressed concern about the theoretical risk ofadverse outcomes when administering FMT to patients withadvanced decompensated chronic liver disease (includingtranslocation of microbial material from the intestinal tractinto the portal and systemic circulations, and theoretical riskof sepsis), and felt that FMT should be used with caution inthis patient group.

Evidence:There is a wide range of FMT recipient exclusions listed in

different studies, but little evidence on the safety of FMTadministration in patients with these excluded conditions(quality of evidence: 4).

Good practice points:

i. FMT should be avoided in those with anaphylactic foodallergy (strong).

ii. FMT should be offered with caution to patients with CDIand decompensated chronic liver disease (conditional).

Immunosuppression and FMTOne randomised study [16] included patients with immu-

nodeficiency (treatment with immunosuppressive therapy(azathioprine, ciclosporin, infliximab, methotrexate alone, orin combination with corticosteroids) (n ¼ 18), renal transplant(n ¼ 5), chronic haemodialysis (n ¼ 5), solid organ tumours(n ¼ 3) and haematological malignancy (n ¼ 4)) at the time ofFMT. Clinical resolution rates after up to two FMTs were high:27/29 (93%) for immunocompromised individuals, 5/6 (83%) forpatients with IBD.

There are also limited data from case series and single casereports describing the use of FMT in immunocompromised pa-tients. Agrawal and colleagues [60] included 46/146 (32%) pa-tients with a history of cancer, and an additional 15/146 (10%)patients with non-cancer-related immunologic dysfunction,although primary outcome measures are not specifically re-ported for these groups. Overall cure at 12 weeks in a caseseries of 80 patients with immunocompromise was reported in71 (89%) patients [65]. Adverse events occurred in 12 (15%)immunocompromised patients; this included two deaths (onedue to respiratory failure and another due to pneumoniaresulting from aspiration at the time of FMT administration)[65]; however, such adverse events have also been reported innon-immunocompromised patient populations [83]. Hefazi andcoauthors described high efficacy rates in a case series of FMTfor recurrent CDI and a range of haematological or solid organ

malignancies (remission after one FMT in 11/12 with haema-tological patients, and 8/10 in solid organ malignancy pa-tients). No significant FMT-related complications werereported [84]. A further case series [50] reported FMT treat-ment for 75 patients with recurrent CDI and found no significantdifference in primary cure rates for patients with diabetesmellitus, malignancy, or steroid use in the preceding threemonths.

The working group discussed the potential impact of donorEBV and CMV status for the immunocompromised FMT recipientat risk of severe infection if exposed to these viruses. Theiropinion was that such recipients should only receive FMT fromdonors with negative EBV and CMV status.

Evidence:The growing pool of experience in using FMT in CDI patients

with a range of causes of immunosuppression demonstratesthat it appears to be generally as safe and effective as in pa-tients without immunosuppression (quality of evidence: 1-).

Recommendation:FMT should be offered with caution to immunosuppressed

patients, in whom FMT appears efficacious without significantadditional adverse effects (strong).

Good practice point:Immunocompromised FMT recipients at risk of severe

infection if exposed to EBV or CMV should only receive FMTfrom donors negative for EBV and CMV (strong).

Other comorbidities and FMTOnly a limited number of cited studies included specific

detail about the presence of comorbidities in patientsreceiving FMT. However, several studies reported medianCharlson comorbidity scores [12,14,15,18,55]. One randomisedstudy reported the presence of IBD in 10/17 (59%) FMT re-cipients [16], and there did not appear to be any significantdifference in primary outcome measures in this group. Anotherrandomised trial included 14/72 (33%) patients with IBD andreported clinical cure of CDI in 12/14 (86%) of these patients[13]. This study also included 64/72 (89%) patients with car-diac, respiratory, renal, central nervous system or multi-organsystem comorbidities [13]; however outcomes were not strat-ified according to co-morbidity. Kelly and coauthors [65] re-ported an overall cure rate of 94% in a subset of patients withIBD. A meta-analysis of studies in which patients with IBDreceived FMT (either primarily as treatment for concurrentrecurrent CDI, or with the aim of treating IBD) noted a small riskof exacerbation of IBD in association with the use of FMT [85].The working group noted the complexity of the relationshipbetween IBD and CDI, given that IBD is itself a risk factor forCDI.

Other exclusions have been more directly related to themode of administration. For upper gastrointestinal delivery,exclusion criteria have included delayed gastric emptying,chronic aspiration, ‘swallow dysfunction’, and dysphagia[17,55]. Exclusions for lower GI administration have includedcolostomy/ileostomy [16,55], significant bleeding disorders[12], untreated colorectal cancer [14,41,59], and ileus/smallbowel obstruction [55].

In summary, the working group noted that co-morbiditiesamong patients with recurrent CDI are common. Most studiesdid not analyse primary outcome measures according to co-morbidity; however, a small number of studies have analysedprimary 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 significantdifference compared with those without IBD, along with nooverall significant worsening of IBD activity.

Evidence:There is growing evidence that FMT is safe and efficacious as

treatment for CDI in people with concomitant inflammatorybowel disease, but that there is the potential for FMT to cause aflare in IBD activity (quality of evidence: 1þ).

Recommendations:

i. FMT should be offered to those with recurrent CDI andinflammatory bowel disease, but patients should becounselled about a small but recognised risk of exacer-bation of IBD (strong).

ii. FMT should be considered for appropriate patients withrecurrent CDI regardless of other comorbidities(conditional).

What donor factors influence the outcome of faecalmicrobiota transplant when treating people withClostridium difficile infection?

General approach to donor selectionExcellent efficacy has been shown in treating recurrent CDI

using FMT derived from both related [14,41,43,45,46,50,51,54,58,59,62,64,66,86,87] and unrelated [14e17,40,42,43,46,58,62,64,66,77,79,86e91] donors. To date, there havebeen no randomised studies comparing differences in efficacy.Case series have tended to rely more on donation of stool fromhealthy family members. In randomised studies using FMT, alldonors were healthy unrelated individuals [12e18,92]. Threecase series used donor stool from healthcare professionals[44,66,89]; no randomised studies have used stool from thiscohort. However, the working group noted that there wereclear advantages to using FMT from a screened anonymousdonor, in particular with regards to monitoring and trace-ability, as discussed further later.

Evidence:Both related and unrelated donors have been shown to be

acceptable as donors, but there has been no comparative studyof the two groups (quality of evidence: 3).

Recommendation:Related or unrelated donors should both be considered

acceptable. However, where possible, FMT is best sourced froma centralised stool bank, from a healthy unrelated donor(conditional).

Age and BMI restrictions for potential donorsThere are no well-defined age restrictions on donors.

Randomised studies have used donors of �18 [12,77] and �60years old [15,17,18] with satisfactory outcomes. Two of thereviewed case series defined age limitations for donors as �18and � 50 years [77,93]. A recent study demonstrated that theBacteroidetes: Firmicutes ratio and microbial diversity wassimilar for donors older and younger than 60 years, and theirstool donations had similar clinical efficacy as FMT; however,there were losses of the phylum Actinobacteria and familyBifidobactericeae from donors older than 60 years [94]. Onbalance, the working group agreed that an age range of 18e60years was appropriate for donors.

A widely-reported case study noted apparent weight gain ina recipient of FMT for treatment of CDI when an overweightdonor was used [95], but any association between a donor witha raised BMI and weight gain post-FMT has not been replicatedelsewhere in the literature [96]. Whereas most randomisedstudies did not report donor-specific BMIs, some have excludedthose without a ‘normal’ BMI [13,17]. The working groupconsidered an acceptable BMI as between �18 and �30 kg/m2.

Evidence:There is considerable variability between studies with

regards to age and BMI restrictions for donors, and nocomparative studies (quality of evidence: 3).

Recommendation:People should only be considered as potential FMT donors if

they are�18 and�60 years old, and have a BMI of�18 and�30kg/m2 (conditional).

General approach to the donor screening assessmentThere is a clear theoretical risk of the transmission of

infection by FMT; furthermore, given the large number ofconditions in which perturbation of the gut microbiota hasbeen described [97], there is a concern regarding a risk oftransmission of microbiota associated with vulnerability todisease. While FMT is efficacious for recurrent CDI, adverseevents may be associated with its use (discussed furtherlater), and long-term safety follow-up is lacking. The aim of adonor screening questionnaire and interview is to minimisepost-FMT adverse events by excluding potential donors fromwhom FMT may be associated with risk to recipients. Rando-mised studies performed to date used various pre-screeningquestionnaires, including self-screening questionnaires whichfocused on high risk behaviours for blood-borne infections[12e16], questionnaires that focused on previous potentialtransferable medical conditions [18], and adaptations fromthe American Association of Blood Banks Donor Questionnaire[14,17]. One randomised study used the OpenBiome ques-tionnaire as a screening questionnaire [98]. Some studies havesuggested excluding potential donors who have recentlytravelled to defined regions (typically tropical areas), varyingbetween 3-6 months prior to donation [43,44,54,57,60,64,79,91]; this is also the protocol employed in rando-mised studies [14,16,18]. Another important point for assess-ment is recent use of medications by potential donors. Inparticular, given the profound effects of antimicrobials on thegut microbiota [99e102] (along with the theoretical concernthat recent antimicrobials might precipitate gut colonisationwith antimicrobial-resistant bacteria that could be transferredduring FMT) studies advocate either a three month[14,51,58e60,62,66,79] or six month [16,17,104,18,40,43,44,54,86,89,103] period without antimicrobial use prior toFMT donation.

The working group agreed that, given the growing evidencefor the contribution of the gut microbiota to the aetiopatho-genesis of colorectal carcinoma, patients with a significantpersonal or family history of (or risk factors for) this conditionshould be excluded as donors (Table 1). However, the workinggroup noted an added complexity, in that their recommenda-tion was that potential donors may be up to 60 years of age, butbowel scope screening for colorectal carcinoma currently be-gins within the UK at 55 years of age, and formal NHS bowelcancer screening starts at the age of 60 years [105]. Theworking group agreed that potential donors living in countries

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S16

with bowel cancer screening programmes that start before theage of 60 years should have therefore completed appropriatescreening with negative/normal tests before they are consid-ered further as donors.

The working group was of the opinion that a screeningprocess is mandatory; any positive responses should usuallyresult in exclusion from donation, although this will depend onthe particular circumstances/answers given. A donor screeningquestionnaire should be performed both prior to considering aperson as a donor, and also at a further point in time (discussedfurther in Section Repeat donor checks, and donationpathway).

Evidence:Based on the principles derived from blood transfusion, a

donor screening questionnaire has become standard practice(quality of evidence: 3).

Recommendation:It is mandatory to screen potential donors by questionnaire

and personal interview, to establish risk factors for trans-missible diseases and factors influencing the gut microbiota(Table 1) (strong).

Laboratory screening of potential donorsCurrently, there are no known confirmed cases of blood-

borne pathogens being transmitted by FMT, but strict preven-tative measures are important, as the potential risk of trans-mission is unknown. Many of the suggestions are extended fromestablished blood screening guidelines [106]. Case seriesalmost universally screen for HIV, hepatitis B and hepatitis C asa minimum [40e42,44e47,51,54,57e60,64,66,77,79,86,88,90,91,107]; other studies (including the randomised trials) haveamore thorough blood screening process [14e18]. Many studieshave also included a ‘metabolic/general blood screen’, toselect out donors with hitherto undiagnosed chronic illness.Table 2 shows the suggested blood screening protocol of theBSG/HIS working group.

The working group specifically discussed the role ofscreening donors for their EBV and CMV status; the importanceof the rationale for this is discussed in SectionImmunosuppression and FMT. They agreed that EBV and CMVtesting was only required where there is the potential that theFMT prepared from that donor would be administered toimmunosuppressed patients at risk of severe infection ifexposed to CMV and EBV.

The primary aim of stool screening of potential donors is tominimise the risk of transmission of pathogens; again, therelative novelty of FMT for CDI means that these risks are notcurrently well-defined. Stool screening protocols are universalamong published studies, although widely-variable protocolshave been used. Table 3 displays the suggested stool screeningprotocol of the working group. The working group discussedstool screening for multi-drug resistant bacteria carriage, andagreed that carbapenemase-producing Enterobacteriaceae(CPE) should be screened for. Although these bacteria arecarried only by a minority of the UK population, transfer intodebilitated patients with CDI is clearly undesirable given thatCPE are potentially so difficult to treat. They also agreed thatextended-spectrum beta-lactamase (ESBL)-producing organ-isms could also potentially cause severe disease (with limitedantimicrobial options) if transplanted into patients with CDI,and so should also be screened for. While vancomycin-resistant

Enterococci (VRE) carriage is relatively common in the com-munity (probably related to food consumption) [108], com-munity strains of VRE are genetically distinct from (andgenerally of much lower pathogenicity than) those foundnosocomially [109]; as such, the working group thought thatroutine screening was not justified. The working group alsonoted that methicillin-resistant Staphylococcus aureus (MRSA)carriage is very rare in healthy adults in non-healthcare set-tings (with significant intestinal carriage even rarer), and so didnot justify routine screening. However, the working groupacknowledged that the potential infection risk from VRE andMRSA would vary regionally dependent on local prevalence andpathogenicity, and as such recommended that a risk assess-ment is performed to assess whether screening for these or-ganisms should be considered.

A donor laboratory screening should be performed bothprior to considering a person as a donor, and also at a furtherpoint in time (discussed further in Section Repeat donorchecks, and donation pathway).

Evidence:Blood and stool screening is performed uniformly as a part of

FMT donor selection, but with varying protocols betweenstudies (quality of evidence: 3).

Recommendation:Blood and stool screening of donors is mandatory (Tables 2

and 3) (strong).

Repeat donor checks, and donation pathwayAlmost all reviewed studies have repeated at least some

elements of the initial donor screening process either at thetime of donation of each stool sample used to prepare FMT, orat the end of a period of donation to assess ongoing suitabilityfor inclusion. However, protocols have differed widely be-tween studies.

The opinion of the working group was that when a donor hadmet criteria for donation (both with an acceptable healthquestionnaire and satisfactory laboratory tests), they weresuitable to begin donation of stool that may be prepared intoFMT. Repeat donor screening was also deemed necessary. Incentres where frozen FMT is being prepared, stool may becollected and processed immediately after the first donorscreen is successfully completed, but should be stored in‘quarantine’ pending further donor screening, rather than usedimmediately for clinical use. At the end of the locally-definedperiod of donation, potential donors should undergo repeattesting, with a further health questionnaire and laboratoryscreening. If the donor’s health questionnaire remainsacceptable and repeat laboratory screening is negative at thispoint, then the frozen FMT may be released from ‘quarantine’,and used. The working group thought that donor screening bothbefore and after donation was the safest route possible, andthat this represented the preferred scenario. A proposedsummary pathway for donor screening in this scenario is pro-vided in Figure 1.

In centres using fresh FMT, the working group agreed that arepeat health questionnaire should be completed at the timeof donation of each stool sample used to prepare FMT. Formalrepetition of both the personal interview/health questionnaireand laboratory screening tests should occur at regular intervalsto ensure ongoing suitability for inclusion as a donor. Theworking group’s opinion was that this repetition of the

Donor personal interviewand health questionnaire

Interview and healthquestionnaire results

assessed by clinical team

Laboratory screening –blood and stool assays

Review laboratoryscreening

Provisionally accept asdonor

Start stool collectionand FMT preparationFMT in quaratine/not for use until repeatscreening

Repeat donor screening atend of donation period:

Health questionnaireLaboratory screening

Release FMT fromquarantine for clinical use

Period ofdonation to be

locally-defined

~ 14 days toreceive all

results

Inclusion criterianot met

Any testsunsatisfactory

Inclusion criterianot met, and/ or any

tests unsatisfactory

Inclusioncriteria met

All testssatisfactory

Inclusion criteriastill met, and all

tests stillsatisfactory

Potentialdonor

excluded

Potentialdonor

excluded

Potentialdonor

excluded

•

•

••

Figure 1. Proposed summary pathway for donor screening for centres preparing frozen FMT from recurring donors.

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S17

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S18

screening process should occur at least once every fourmonths.

Evidence:Repetition of some or all elements of initial donor screening

at a later point is standard practice, though the means ofassessment differs between studies (quality of evidence: 3).

Recommendations:

i. In centres using frozen FMT, before FMT may be usedclinically, donors should have successfully completed adonor health questionnaire and laboratory screening as-says both before and after the period of stool donation.This is the preferred means of donor screening (strong).

ii. In centres using fresh FMT, a repeat health questionnaireshould be assessed at the time of each stool donation. Toensure ongoing suitability for inclusion as a donor, thedonor health questionnaire and laboratory screeningshould be repeated regularly (strong).

What factors related to the preparation of thetransplant influence the outcome of faecal microbiotatransplant when treating people with Clostridiumdifficile infection?

General principles of FMT preparationThere is very little evidence or guidance on the collection of

donor stool. Critical steps during this process centre on thereduction of environmental cross-contamination risk, so theuse of clean collection devices and clean collection proceduresis advocated. To promote standardised practice and a safe andeffective product, clear instructions should be provided to thedonor for stool collection (Table 5).

Regardless of the methods used to prepare FMT, stool do-nations should be processed within six hours of defaecation.The period of six hours has been generally applied across manysuccessful studies of FMT treatment in CDI [14,18,40,44,48,57],although no formal comparative study has been undertaken.This strategy aims to minimise sample degradation and alter-ation over time, which may occur due to the complex meta-bolic and environmental requirements of the faecalmicrobiota.

There are no comparative trials of anaerobically versusaerobically prepared FMT in the treatment of recurrent CDI.With the exception of small observational studies [46,79], thevast majority of FMT preparation has been undertaken aero-bically for the treatment of CDI and has proved highly effica-cious. There appears to be no clear need to processanaerobically, a method which introduces complexity and costfor 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 spStool should ideally be passed directly into the clean container for ctransferred to the clean container.

Stool should be transported to the FMT production site as soon as posperiod of storage is necessary, this should be at 4�C.

HIS/BSG FMT Guideline: Main Document.

The reviewed randomised studies reported variableamounts of stool used in the preparation of each FMT aliquot,and the lack of comparative data means that it is not possibleto link stool mass to outcome from these studies. However, aprevious systematic review of case series using FMT as treat-ment for recurrent CDI reported similar rates of treatmentefficacy, but an approximate fourfold increase in recurrencerates, if <50g of stool was used compared with �50g [110].Similarly, the initial volume of diluent used to create thefaecal emulsion is variable between studies, although themost common practice appears to be creation of a stool:diluent ratio of approximately 1:5. The overwhelming major-ity of the reviewed studies used stool from only a single donorper FMT (rather than stool pooled from a mixture of donors),and there are no comparative studies of outcomes of CDI fromsingle donor versus pooled donor FMT; as such, the workinggroup found no justification to recommend donor stool poolingfor FMT for CDI.

The majority of studies have used preservative-free sterile0.9% saline as the diluent for FMT production, although therehave been a handful of reports of other diluents includingpotable water [16,40,48]. There have been no comparativestudies of FMT diluent. In cases where frozen FMT is prepared,an appropriate cryoprotective substance should be added priorto freezing. Most studies use glycerol at a final concentration ofw10% [16,46]. It has been demonstrated that storing stool at-80�C for up to six months in saline without glycerol decreasesviable aerobic and anaerobic bacterial counts; the reductionwas statistically significant in all bacterial groups with theexception of E. coli and total anaerobes. When stored withglycerol, no significant reduction in viable counts was observed[79].

A variety of homogenisation and open filtration systemshave been used, with no apparent major variation in efficacy.Open filtration systems such as gauze [16,42,45,60], filter pa-per [44] and strainers/sieves [17,46] are unpleasant to use andpose a risk of external contamination. In order to best complywith GMP standards, a sterile, single-use closed homogenisa-tion and filtration system is recommended. An example of sucha system includes the use of sterile filter bags inside a labora-tory paddle homogeniser.

Evidence:The mechanics of stool preparation vary widely between

different studies. There are almost no comparative data forany of these variables (quality of evidence: 3).

Recommendations:

i. Donor stool collection should follow a standard protocol(strong).

ecifically designed devices are available commercially.ollection; alternatively, it may be collected in clean tissue and

sible post defaecation (and within six hours); however, if a short

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31 S19

ii. Donor stool should be processed within 6 hours ofdefaecation (strong).

iii. Both aerobically and anaerobically prepared FMT treat-ments should be considered suitable when preparing FMTfor the treatment of recurrent CDI (strong).

iv. Sterile 0.9% saline should be considered as an appropriatediluent for FMT production, and cryoprotectant such asglycerol should be added for frozen FMT (strong).

v. Use �50g of stool in each FMT preparation (strong).

Good practice points:

i. Stool should be mixed 1:5 with diluent to make the initialfaecal emulsion (conditional).

ii. Homogenisation and filtration of FMT should be under-taken in a closed disposable system (conditional).

Fresh vs frozen FMTTwo randomised studies have examined this area. One

double-blind randomised study concluded that enema-administered frozen FMT (n ¼ 91) was non-inferior for clinicalresolution of diarrhoea to fresh FMT (n ¼ 87) for the treatmentof recurrent or refractory CDI [16] (with frozen FMT in thisstudy stored at -20oC for up to 30 days). A further randomisedstudy demonstrated statistically comparable remission ratesfor recurrent CDI with fresh or frozen FMT delivered colono-scopically (n ¼ 25/25 vs 20/24 respectively, p ¼ 0.233) (usingfrozen FMT stored at -80oC for up to six months). These datasupport the findings of earlier small observational studies[40,46]. Frozen FMT is also preferable to fresh FMT on logisticaland cost grounds [16]. Banked frozen FMT also enables thewindow period for donor screening to be minimised, allowingcentres to more closely meet regulatory requirements (also seeSection Repeat donor checks, and donation pathway).

Evidence:There is randomised trial evidence demonstrating that fresh

and frozen FMT have comparably high efficacy (quality of evi-dence: 1þ).

Recommendation:The use of banked frozen FMTmaterial should be considered

preferable to fresh preparations for CDI (strong).

Use of frozen FMTFrozen FMT has been used up to six months after storage at

-80oC [17,46,79], with high efficacy rates (>70%) observed inthe cases treated. However, there have been no comparativetrials investigating storage durations. As already described, areduction in the viability of certain gut microbiota taxa wasnoted when faecal aliquots were frozen in 10% glycerol for sixmonths [79], and as such, the working group agreed that sixmonths was the acceptable limit for freezing of an FMT inglycerol. Storage at -80oC is recommended rather than -20oC tominimise sample degradation.

Warm water baths have been recommended to speedthawing [6]; however, the working group thought that thisshould be strongly discouraged, as this may introduce risks ofcross contamination by Pseudomonas species (and other con-taminants) from the water bath [111,112], and may reducebacterial viability in the FMT. Repetitive freeze thawing of FMTsamples should be avoided as bacterial numbers will bereduced during this process [113].

Evidence:Frozen FMT remains an efficacious treatment for CDI after

six months frozen, but it has not been assessed at longer timepoints. There are little published data addressing optimalthawing of frozen FMT (quality of evidence: 3).

Recommendation:FMT material stored frozen at -80oC should be regarded as

having a maximum shelf life of six months from preparation(strong).

Good practice points:

1. Consider thawing frozen FMT at ambient temperature, anduse within six hours of thawing (conditional).

2. Do not thaw FMT in warm water baths, due to the risks ofcross contamination with Pseudomonas (and other con-taminants) and reduced bacterial viability (strong).

What factors related to administration of thetransplant influence the outcome of faecal microbiotatransplant when treating people with Clostridiumdifficile infection?

Use of specific medications in the period around FMTadministrationGeneral principles of FMT administration. Bowel purgativeshave been proposed pre-FMT as a means of removing residualantibiotics that may affect engraftment of transplanted mi-croorganisms, and as a means of removing any residualC. difficile toxin, spores and vegetative cells [114e118].Furthermore, bowel purgatives pre-colonoscopic FMT deliveryfacilitate safe endoscopy. Various bowel purgatives have beenused in colonoscopic FMT studies, including polyethylene glycol(PEG) (often 4 litres) [14,17,40,46,51,59e61,86,103,119e121],MoviPrep� [40,46], and macrogol [13,15,18,64]. In thosestudies that used an upper GI route for FMT, PEG [59,60,88] andKlean-Prep� [15,66] were used. FMT without bowel prepara-tion has also been used as treatment for recurrent CDI withoutany apparent reduction in efficacy, including in randomisedstudies [16].

The rationale for the use of proton pump inhibitors (PPI)prior to upper GI FMT is to minimise acidity which mayimpair engraftment of transplanted microorganisms; howev-er, PPIs have been shown to alter the gut microbiota[122,123], and have also been associated with primary andrecurrent CDI [124,125]. Some studies advocate the use ofPPI prior to receiving FMT via the upper GI route[42,44,50,88,89,126,127], but there appears to be compa-rable efficacy data in studies where it has not been used.Certain studies have also given recipients PPI prior toreceiving colonoscopic FMT [17,91].

The use of prokinetics (such as metoclopramide) has beendescribed prior to FMT delivery via the upper GI tract route, butonly in a very small number of studies [89]. Given the potentialrisk of regurgitation/aspiration associated with upper GIadministration of FMT, the working group felt that its useshould be considered where appropriate.

A single dose/short course of loperamide has been usedfollowing FMT (predominantly for lower GI administration) inan attempt to prolong the exposure of the FMT to the mucosa,and to aid retention of the FMT within the GI tract

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S20

[13,51,54,60,88,127]. One study utilised diphenoxylate withatropine [59] instead. However, no studies have compared FMTwith and without anti-motility drugs.

The working group also discussed infection control aspectsas they apply to FMT administration. Specifically, they agreedthat recipients should ideally be cared for in a single roomwith en-suite bathroom facilities and, where appropriate, beplaced at the end of an endoscopy list, to facilitate enhancedenvironmental decontamination and prevention of trans-mission of C. difficile spores. Protocols for decontaminationof endoscopes should follow national guidance [128,129],using a sporicidal agent. Best practice for prevention oftransmission of healthcare-associated infections, asdescribed in national guidelines [130], should also be appliedthroughout.

Evidence:These different classes of medications have all been used

variably pre-FMT between different studies. They do notappear to adversely affect the efficacy of FMT, and there aresound reasons to expect that they may be beneficial (quality ofevidence: 3).

Recommendations:

i. Bowel lavage should be administered prior to FMT via thelower GI route, and bowel lavage should be consideredprior to FMT via the upper GI route; polyethylene glycolpreparation is preferred (conditional).

ii. For upper GI FMT administration, a proton pump inhibitorshould be considered, e.g. the evening before andmorning of delivery (conditional).

iii. A single dose of loperamide (or other anti-motility drugs)should be considered following lower GI FMT delivery(conditional).

Good practice point:

i. Prokinetics (such as metoclopramide) should beconsidered prior to FMT via the upper GI route(conditional).

ii. Best practice for prevention of further transmission of CDIshould be applied throughout when administering FMT topatients with CDI (nursing with enteric precautions,sporicidal treatment of endoscope, etc).

Additional antibiotics pre-FMT. Many studies have givenfurther courses of conventional antimicrobial C. difficiletreatment prior to FMT. Regimens have included vancomycinalone [12,14,18,40,44,60,64,90,121], metronidazole or vanco-mycin [45,46,86,126], or alternatively vancomycin, fidax-omicin or metronidazole [61], with one study using a range ofregimens which included rifaximin [127]. The length of treat-ment was also variable, ranging from 24 hours [59] up to fourdays prior to receiving FMT [44,50]; however, comparativestudies have not been undertaken.

Evidence:In many studies, additional anti-CDI antibiotics have been

used pre-FMT, with the aim of further reducing the burden ofC. difficile (quality of evidence: 3).

Recommendation:Administer further antimicrobial treatment for CDI for atleast 72 hours prior to FMT (strong).

Washout period between antibiotic use and FMT. Nearly allstudies specified a washout period after completing anti-CDIantibiotics and before administration of FMT. However, thistime period appeared to be arbitrarily selected and varied fromas little as four [51] or 12 hours [56], up to 72 hours [41].The majority of studies specified either 24 hours[15,42,44,45,50,59,131] or 48 hours [46,47,54,65], howeversome allowed a range from 1-3 days [16,49,57,58,60]. Onestudy appeared to allow co-administration of vancomycin withbowel preparation, without a washout period [18].

The working group discussed the challenging scenario ofproviding FMT to patients with recurrent CDI, but who also hada strong indication for long-term non-anti-CDI antibiotics (e.g.splenectomy, osteomyelitis, or infective endocarditis), or pa-tients who develop an indication for antibiotics for a reasonother than CDI shortly after receiving FMT. The concern in thisinstance is that the use of antibiotics may limit engraftment ofmicrobial communities derived from the FMT, and thereforereduce its effectiveness. The working group discussed a recentretrospective study demonstrating that exposure to non-anti-CDI antimicrobials within eight weeks of FMT is associatedwith an approximate threefold risk of FMT failure (n ¼ 8/29failures with antibiotic exposure vs 36/320 failures withoutantibiotic exposure) [132]. Similarly, the experience of thelarge pan-Netherlands stool bank [133] was that w50% of theirfailures of FMT in the treatment of recurrent CDI occurred inpatients who had received antibiotics within onemonth of theirFMT. For patients requiring long-term antibiotics, the workinggroup’s expert opinion was that such patients should still beeligible for FMT, but that the regimen for the use of non-anti-CDI antibiotics should be decided on a case-by-case basis,based on factors including response to FMT and/or strength ofindication of antibiotics. Both in this scenario, and the scenarioin which antibiotics are required shortly after receiving FMT,the working party agreed that infectious diseases specialists/medical microbiologists should be involved in making decisionsregarding the choice of agents used.

Evidence:A washout period between the end of antibiotic use and

administration of FMT is usually described. However, no formaltrial assessment as to the optimal length of this period has beenundertaken (quality of evidence: 3).

Recommendation:To minimise any deleterious effect of antimicrobials on the

FMT material, there should be a minimum washout period of 24hours between the last dose of antibiotic and treatment withFMT (strong).

Good practice point:Consider consultation with infectious disease specialists or

medical microbiologists for advice whenever FMT recipientsalso have an indication for long-term antibiotics, or have anindication for non-CDI antibiotics within eight weeks of FMT(conditional).

Route of FMT deliveryIntroduction. FMT can be delivered via the lower GI route(retention enema, colonoscopy), upper GI route (endoscopi-cally, or via nasogastric tube, nasoduodenal or nasojejenaltube), or via capsules (containing either frozen FMT or lyophi-lised faecal material). Systematic reviews with meta-analysissuggest that FMT for recurrent CDI via colonoscopy may haveslightly 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 thetrend towards using larger amounts of stool or ‘higher con-centration’ FMT in lower GI administration. One systematicreview (reviewing principally case series, and including onlyone randomised study) compared remission rates for CDI usingFMT delivered to different areas of the GI tract, and reportedthat for FMT infused into the stomach, duodenum/jejunum,caecum/ascending colon, and rectum the rates of cure ratewere 81%, 86%, 93%, and 84%, respectively [135].

In the only randomised study that directly compared upperand lower GI administration, there was no significant differ-ence in overall cure rate (p ¼ 0.53) [17].

Upper gastrointestinal tract administration of FMT. FMT hasbeen shown to be safe and efficacious in the treatment ofC. difficile when administered via nasogastric tube[42,44,50,66,87,127], nasoduodenal tube [15,88,89], entero-scopy [126,127], or via the infusion channel on a gastroscope[45,50]. In a randomised trial, nasoduodenal donor FMT has beenshown to be more efficacious than vancomycin in treating recur-rentCDI [15]. Furthermore, it hasbeen shown thatFMTcanalsobesafely and effectively delivered via a percutaneous endoscopicgastrostomy tube [50,87]. The working group noted that upper GIadministration of FMT may be particularly suitable for certainpatient groups, such as those inwhom there are contraindicationsor whowould find it difficult to tolerate lower GI endoscopy, and/or patients unlikely to be unable to retain enemas.

Typically, smaller volumes of faecal suspension areadministered to the upper GI tract compared with lower GIadministration, with quoted volumes ranging from 25ml [44]up to 150ml [88]- 250ml [42,89]. Up to 500ml of suspensionhas been given safely and effectively via the upper GI route[15,81]. However, the working group expressed concernsregarding the risk of regurgitation and aspiration if large vol-umes of FMT are administered to the upper GI tract, and alsodiscussed cases in which this has been described with adverseoutcomes [83]. This included a reported death from aspira-tion, after 100e150ml of FMT was delivered by enteroscopeinto the distal duodenum under general anaesthetic asattempted treatment for recurrent CDI [137]. A further reportdescribed a case of fatal aspiration pneumonitis likely relatedto a 500ml FMT via nasoduodenal tube; this patient had aswallowing disorder following oropharyngeal radiation aftersurgical removal of a maxillary carcinoma two years previously[81]. Based on their expert opinion, the working group rec-ommended that upper GI FMT should be used with caution inthose at risk of regurgitation (e.g. known large hiatus hernia,gastro-oesophageal reflux disease, etc.) and/or with swal-lowing disorders (although administration via a gastrostomytube would be acceptable). They also recommend that nomore than 100ml of FMT should be administered to the upperGI tract to minimise these risks.

Evidence:There is randomised trial evidence demonstrating that up-

per GI administration of FMT for CDI is effective, althoughthere are concerns about the possibility of aspiration andvomiting associated with its use (quality of evidence: 1þ).

Recommendation:

i. Upper GI administration of FMTas treatment for recurrentor refractory CDI should be used where clinically appro-priate (strong).

ii. Where upper GI administration is considered mostappropriate, FMT administration should be via nasogas-tric, nasoduodenal, or nasojejunal tube, or alternativelyvia upper GI endoscopy. Administration via a permanentfeeding tube is also appropriate (strong).

Good practice points:

i. It is recommended that no more than 100ml of FMT isadministered to the upper GI tract (conditional).

ii. Upper GI administration of FMT should be used withcaution in those with swallowing disorders (strong).

Lower gastrointestinal tract administration of FMT. FMT viaenema: Successful treatment of C. difficile with FMT enemahas been demonstrated [16,43,47,58,60,87,90] but enema ap-pears to have a lower efficacy than other routes of FMTadministration. Specifically, in a randomised study primarilycomparing the efficacy of fresh and frozen FMT in the treat-ment of recurrent CDI, only 52.8% of patients in the ‘frozen’arm and 50.5% of patients in the ‘fresh’ arm of the study(n¼ 57/108 and 56/111 respectively) experienced resolution ofsymptoms after a single enema, by modified intention to treatanalysis [16]. However, resolution rates in both arms onlyreached >80% after at least three enemas [16]. A recentrandomised study demonstrated similar rates of recurrence ofCDI in patients with recurrent CDI treated with either a singleFMT enema or a six week vancomycin taper (9/16 patients withrecurrence vs 5/12 respectively) [12]. Notwithstanding this,enemas do have specific advantages, such as being a treatmentoption where full colonoscopy is contraindicated. It is alsopossible to give multiple infusions relatively easily and outsidea hospital setting.

FMT via colonoscopy: Randomised study evidence hasdemonstrated that colonoscopic FMT has higher efficacy intreating recurrent CDI than vancomycin [18]. Efficacy is similarwhether FMT is fresh or frozen, but modestly reduced whenusing a lyophilised FMT product [13]. Colonoscopic delivery ofdonor FMT into the ileum or caecum was associated with a 91%cure rate for recurrent CDI [14]. Observational studies high-lighted similar success, describing cure rates of 88% (n¼ 14/16)[79] and 91% [51] (n ¼ 21/23) in response to infusion of donorFMT into the caecum or terminal ileum. A further advantage ofusing colonoscopy to administer FMT has been to allowassessment for the presence of pseudomembranes; in certainreviewed studies, the presence or absence of pseudomem-branes has influenced the FMT regimen used [18,78]. However,the working group noted that many patients with CDI are frailand elderly, and as such it will not always be safe or feasible toundertake colonoscopy in this particular group of patients.Flexible sigmoidoscopy appears to be an feasible option wherefull colonoscopy cannot be performed e.g. unable to toleratecolonoscopy, severity of colitis [61,65].

The amount of faecal suspension via enema has varied be-tween 150-500mls [16,43,47,60,90]. The amount of faecalsuspension delivered via colonoscopy has been similarly vari-able, with some studies suggesting as little as 100ml can beused with success rates of 94% [86]. 250ml-400ml had a successrate of 100% [41], whereas infusions of up to 500e700ml wereassociated with cure rates of 92% [51]. However, the workinggroup noted that it is difficult to compare ‘concentration’ of

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S22

FMT in different studies as different protocols used variedstarting amounts of faecal material. Currently, there are norandomised studies that compare concentration/volume ofcolonoscopic or enema FMT. As such, no recommendation wasmade to this regard.

Evidence:Randomised trial evidence demonstrates the efficacy of FMT

as treatment for CDI when administrated either as enema or viacolonoscopy (quality of evidence: 1þ).

Recommendations:

i. Colonoscopic administration of FMT as treatment forrecurrent or refractory CDI should be used where appro-priate (strong).

ii. Where colonoscopic administration is used, considerpreferential delivery to the caecum or terminal ileum, asthis appears to give the highest efficacy rate(conditional).

iii. FMT via enema should be used as a lower GI option whendelivery using colonoscopy or flexible sigmoidoscopy isnot possible (strong).

Capsulised FMT. Capsulised FMT aims to remove some of theconcerns regarding conventional FMT, such as the invasivemeans of administration and palatability. The largest case se-ries describing the use of capsules as treatment for recurrentCDI [77,93] noted clinical resolution at eight weeks off anti-biotics for CDI in 82% of cases (n ¼ 147/180) after one course ofcapsules, and 91% (n ¼ 164/180) after two courses. The cap-sules contained frozen FMT prepared in a diluent of saline with10% glycerol; 15 capsules were administered each day for twoconsecutive days (equating to a mean 48g of original crudestool). Other smaller case series have demonstrated compa-rable results [91,127,138], including when lyophilised stool isused instead of frozen whole FMT [138].

The working group reviewed two randomised studies whichhave examined the efficacy of capsulised FMT in treatingrecurrent CDI. In one study, published in abstract form [98], a‘high dose’ regimen of frozen FMT capsules (30 capsules eachday for two days) was compared with ‘low dose’ (30 capsulesin one day). CDI resolution was comparably high in both armswith one treatment course (77% (n ¼ 7/9) in the ‘high dose’arm vs 70% (n ¼ 7/10) in the ‘low dose arm’. Four of five initialnon-responders entered remission after a second capsulecourse with the ‘high dose’ regimen [98]. In a recent largerandomised trial, patients with recurrent CDI were rando-mised to receive thawed frozen FMT either via colonoscopy orvia capsules (one treatment of 40 capsules) [11]. On perprotocol analysis, remission at 12 weeks after a single treat-ment occurred in 96% in both arms (n ¼ 51/53 by capsule,n ¼ 50/52 by colonoscopy).

The working group discussed certain unresolved issuesregarding capsules. Specifically, capsules are often large, andswallowing 30 capsules in a single day may be a significantundertaking for patients with CDI, such as the frail elderly withan existing high pill burden. They also noted that follow-updata post-capsule administration is relatively short comparedwith other modalities of FMT.

Evidence:Case series and RCT evidence demonstrate that capsulised

FMT is efficacious in treating recurrent CDI, with comparable

efficacy to other modalities of administration. However, cap-sules are a relatively new modality of administration, andfurther data are awaited on longer term efficacy and safety,and the optimal mechanics of preparation and administration(quality of evidence: þ1).

Recommendation:Capsulised FMT holds promise as a treatment option for

recurrent CDI and should be offered to patients as a potentialtreatment modality where available. Capsule preparationsshould follow a standard protocol. Further evidence regardingoptimal dosing and formulation is required (conditional).

What is the clinical effectiveness of FMT in treatingconditions other than Clostridium difficile infection?

IntroductionIn current clinical practice, FMT is used predominantly in

the treatment of recurrent CDI. Its success has led to explo-ration of its efficacy in other GI diseases, primarily ulcerativecolitis (UC), where perturbation of the gut microbiota has beenobserved and implicated in disease pathogenesis [139]. Due tovariability of the quality, methodology and cohorts of patientsrecruited in trials of FMT for non-CDI indications, and in orderto control for significant confounding factors, the workinggroup only included randomised trials involving patients withwell-defined conditions and in which there was a primaryclinical outcome. To date, there have been a total of 71 suchstudies investigating the role of FMT in IBD; of these, only fourare prospective randomised controlled trials, limited to pa-tients with ulcerative colitis [140e143]. Five other reviewedrandomised studies investigated the use of FMT in irritablebowel syndrome [144], slow transit constipation [145], hepaticencephalopathy [146] and metabolic syndrome [147,148].

Use of FMT for ulcerative colitisEfficacy. All four RCTs, with a total of 277 subjects, includedpatients with mild to moderate UC (Mayo score 3e11 andendoscopic sub-score of at least 1). Participants were agedbetween 27 and 56 years and largely included patients onstable immunosuppressive therapy (only one study excludedpatients using biologic treatments and methotrexate withinthe preceding two months) [140]. Three studies included pa-tients on oral corticosteroids at the time of FMT, however onlytwo required a mandatory wean of these to meet eligibility.Studies generally included patients with all disease distribu-tions found in UC. Time to evaluation of response to FMT inthese studies varied between seven and twelve weeks. Twostudies used autologous FMT as placebo [140,143]. Three of thefour studies demonstrated that patients receiving donor FMTwere significantly more likely to achieve clinical and endo-scopic remission compared with placebo [141e143]. Thepooled rate of combined clinical and endoscopic remission was27.9% for donor FMT and 9.5% for placebo. A pooled risk ratiofor failure of FMT to achieve these combined outcomes was 0.8(95% CI: 0.7e0.9). Deep remission (histological) was only re-ported in one RCT: 18.4% of patients receiving FMT achievedthis outcome compared with 2.7% of those receiving placebo[141].

Characteristics of FMT preparation and delivery. The fourRCTs varied in their FMT preparation and delivery methodol-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 outcomedelivered the FMT via the lower GI route; these studies used ahigh intensity protocol ranging from a total of three infusions inone week to 40 FMTs over an eight week period [141e143]. Theother RCT (that failed to show efficacy of FMT for UC) hadadopted a low intensity protocol of two nasoduodenal infusionsgiven three weeks apart [140]. Interestingly, the only RCT thatprepared stool in anaerobic conditions demonstrated thehighest rate of steroid-free clinical remission and steroid-freeclinical response with donor FMT [143]. A further interestingobservation in one study was a trend towards higher rates ofremission with one particular donor [141].

Adverse events. Short-lived GI symptoms such as abdominalbloating, cramps, diarrhoea and fever were reported in pa-tients receiving FMT for UC. There were no significant differ-ences in serious adverse events between patients receivingFMT compared with placebo (10 vs 7 respectively). Most of theserious adverse events were a consequence of worsening coli-tis: one patient who received FMT required a colectomy [140].In addition, one patient developed concurrent CDI [141]. Nodeaths were reported in any of the studies.

Use of FMT in functional bowel disordersTwo RCTs have investigated the role of FMT in functional

bowel disorders. In a double-blind placebo controlled RCT thatrecruited 90 patients with IBS with diarrhoea or with diarrhoeaand constipation [144], the primary endpoint only just reachedstatistical significance in inducing symptom relief (as assessedby 75 point reduction in IBS-severity scoring system at threemonths following a single infusion FMT by colonoscopy)(p ¼ 0$049). The second RCT randomised 60 patients with slowtransit constipation to either six consecutive days ofnasogastric-delivered FMT or conventional treatment [145].This demonstrated that a significant proportion of patientsachieved the primary endpoint of a mean of at least threecomplete spontaneous bowel movements per week (53.3% vs.20.0%, p ¼ 0.009) along with improvement in stool consistencyscore and colonic transit time. However, the interventiongroup had more treatment-related adverse events than thecontrol group (total of 50 vs 4 cases).

Use of FMT in hepatic encephalopathyOne small study has investigated the role of FMT in the

management of hepatic encephalopathy (HE) [146]. This RCTrandomised 20 male patients with cirrhosis with refractory HEto receive either five days of broad-spectrum antibiotic pre-treatment followed by a single FMT enema or standard ofcare. Patients in the FMT arm had a significantly lower inci-dence of serious adverse events and improved cognition. TheModel for End-Stage Liver Disease (MELD) score, however,transiently worsened post-antibiotics in the FMT arm. Thestudy was potentially confounded as patients in the FMT armcontinued to receive lactulose and/or rifaximin for treatmentof their HE.

Use of FMT for metabolic syndromeTwo randomised studies [147,148], with a combined total of

56 patients, demonstrated an improvement in peripheral (butnot hepatic) insulin sensitivity in Caucasian male obese pa-tients with metabolic syndrome following one or two infusions

via nasoduodenal tube of FMT obtained from lean donors. Thisimprovement was observed at six weeks post-FMT, but was nolonger present by 18 weeks. No improvement in insulin sensi-tivity was identified in patients transplanted with autologousFMT (i.e. patients transplanted with their own collectedfaeces). The improvement in peripheral insulin sensitivity inthe lean donor FMT group was accompanied by a small butsignificant improvement in HbA1c at six weeks [148], but noimprovements in other metabolic parameters, such as weight.While these data are of interest, the working group felt thatthe limited, transient nature of the benefits seen and small sizeof the studies meant that FMT could not be recommended astreatment for metabolic syndrome.

Future directions for randomised trials of FMT for non-CDI indications

Currently there are a large number of randomised trials(including RCTs) being undertaken globally, to evaluate thepotential role of FMT as treatment for a wide range of condi-tions. The working group concluded that until there are morereliable data to inform decision-making, the best practiceprinciples described in this document for the governance of anFMT service for recurrent CDI should also be applied to FMTclinical trials for other conditions. However, specific adapta-tions may be considered depending on the condition beingstudied, e.g. consideration of using anaerobic conditions forthe preparation of FMT in trials for the treatment of UC, asdescribed above.

Evidence:FMT has the potential to be an effective treatment option

for mild to moderate ulcerative colitis, and appears to be safedespite the use of immunosuppressive therapy. FMT may alsohave a potential role in the treatment of functional boweldisorders. However, recommendations for clinical use for bothof these indications cannot be made until there is clearer ev-idence of the most appropriate patient characteristics, prep-aration methodology, route of delivery and intensity ofadministration of FMT (quality of evidence: 1þ). The evidencefor the use of FMT in hepatic encephalopathy and metabolicsyndrome is currently limited, and further well-designed RCTsare needed to evaluate its potential role here (quality of evi-dence: 1-).

Recommendation:FMT is not currently recommended as treatment for in-

flammatory bowel disease. Apart from CDI, there is insufficientevidence to recommend FMT for any other gastrointestinal ornon-gastrointestinal disease (strong).

Basic requirements for implementing a FMT service

As discussed above, there is an absence of published studiesto support the recommendations in this section (although theexperience of setting up a nationwide stool bank has recentlybeen reported from the Netherlands [133]). This section istherefore based on the working group’s expert opinion andexperience of developing FMT services.

General considerationsAlthough it is possible to prepare and administer FMT on

an individual patient basis in a single hospital, the regulatoryrequirements are more readily fulfilled by a specialist centre

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S24

approach for the production of a safe FMT product. Thisparticularly applies to record keeping and staff expertise inquality control and production. Recent European consensusadvice suggests that FMT should be administered in a referralcentre [6], however an alternative approach which limits theneed for patient transfer is to undertake controlled pro-duction in a large centre and transport treatment to thepatient, a supply model which has been well established inthe USA (OpenBiome) [149] and has also been successfullyreplicated in the UK in a large centre in Birmingham, whichhas supplied FMT to nine NHS Trusts across three regions[28]. This service design only requires that a responsibleclinician is capable of administering the FMT safely at thesatellite clinical site. It also eliminates the need for patienttransfer between clinical sites, which in the case of severeCDI may not be practical.

The working group encouraged the use of frozen FMT ma-terial supplied from a carefully controlled production site. Thisallows donor screening more closely to meet regulatory re-quirements, ensuring that the window period between donortesting and FMT production is maintained to a minimum. Thecosts of donor screening are substantially reduced using thissupply model, as a single donor can provide multiple FMT do-nations under a single screening period.

The working group also noted that given the novelty of FMT,awareness of this as a potential treatment option for recurrentor refractory CDI may be low amongst certain groups of clini-cians. For instance, clinicians working in primary care, orthose whose practice is not located near to an FMT centre, arelikely to have less knowledge about the potential suitability ofFMT for patients with CDI, or be unaware of referral pathways.As such, there is a responsibility for FMT centres to raiseawareness and educate as wide a range of clinicians aspossible about the potential role for FMT. Furthermore,microbiology staff processing stool samples for C. difficileassays from the community should proactively liaise with pri-mary care teams where recurrent positive tests are receivedfrom a single patient to raise awareness and suggest the optionof FMT.

Similarly, given the expectation that FMT and/or other‘microbiome therapeutics’ are likely to play an increasing rolewithin medicine over future years, there is also an expectationfor FMTcentres to not only educate about the potential role forFMT, but also to train relevant healthcare professionals in thepracticalities of delivering an FMT service, to enable longer-term ongoing provision of services. This is likely to be most ofrelevance to specialty trainee and consultant physicians spe-cialising in gastroenterology, infectious diseases and/or medi-cal microbiology, but potentially to other healthcareprofessionals too, including infection prevention and controlnurses, infectious diseases pharmacists, etc.

Evidence:Working group consensus opinion (quality of evidence: 4).Good practice points:

i. The development of FMT centres should be encouraged(strong).

ii. FMT centres should work to raise awareness about FMT asa treatment option amongst clinicians caring for patientswith CDI, and provide training to relevant healthcareprofessionals on the practicalities of delivering an FMTservice (conditional).

Legal aspects and clinical governanceIn the United Kingdom, FMT is now considered a medicinal

product based on the definitions of purpose and efficacy, in TheMedicines Directive 2001/83 and The Human Medicines Regu-lations [19]. As the competent authority for medicines regu-lation, the Medicines and Healthcare products RegulatoryAgency (MHRA) has indicated that the approach to regulationwill be proportionate, depending on factors such as supplybeing within or outside a legal entity and FMT production scale.Specifically:

� When FMT is supplied on prescription on a named patientbasis, then supply under a pharmacy exemption may beused subject to ensuring proper governance and trace-ability [19].

� If production scale reaches an ‘industrial’ level, defined‘by virtue of the batch sizes, the extent of processingand/or whether potential use includes supply betweenlegal entities’ [19], the route to regulation is via adher-ence to HMR and formal Manufacturer’s ‘Specials’ (MS)license.

� If a supply is to a clinical trial, then an MIA (IMP)manufacturing license is required (further information onlicense applications [150] and specials [151] is availableonline).

Centres establishing an FMT service should undertake stepsto ensure practice meets the required compliance levels andseek guidance from the MHRA. If pharmacy exemption isapplied, there should be justifiable processes in place toensure traceability, health and safety, governance and toprevent cross-contamination. FMT is regulated as a medicine,rather than a tissue, but no products have been licensedfollowing an assessment against the criteria of safety, qualityand efficacy, for there is a possible risk that donor screeningprotocols will not be sufficiently considered, a step which iscritical to the quality of the product and therefore safety of thepatient [152]. To mitigate this, it is advisable that donorscreening protocols are under regularly review and riskassessment, and to ensure that consideration is also given tothe Guide to Quality and Safety Assurance for Human Tissuesand Cells for Patient Treatment, particularly Annex B related todonor testing [153]. When formal licencing is sought, this isoverseen by a Production Manager and Quality Control Managerif under an MS, or by a Qualified Person if under an MIA (IMP).Both should follow the Good Manufacturing Practice (GMP)guidelines, found within The Orange Guide Rules and Guidancefor Pharmaceutical Manufacturers and Distributors 2017 [154],or at: https://ec.europa.eu/health/documents/eudralex/vol-4_en.

The working group noted that outside the UK, the legal andregulatory framework relating to FMT was highly variable be-tween different countries. They agreed that FMT should only beadministered after appropriate approval from the competentbody of each country.

Evidence:Working group consensus opinion and legal requirement

(quality of evidence: 4).Good practice point:In the UK, FMT must be manufactured in accordance with

MHRA guidance for human medicines regulation. When FMT issupplied 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 propergovernance and traceability. All centres that are processingand distributing FMT should seek guidance from the MHRA andwhere necessary obtain appropriate licenses prior to estab-lishing an FMT service. This is a legal requirement. In countriesother than the UK, FMT should only be manufactured followingappropriate approval from the national authority of thatcountry (strong).

Multidisciplinary teamsTo promote safe and high quality FMT supply, it is strongly

recommended that providers adopt a multidisciplinary teamapproach. The choice of the team required is subject to thescale of production, but should involve as a minimum a clinicalgastroenterologist, microbiologist/infectious diseases clini-cian, state-registered experienced healthcare scientist andpharmacist. Governance and quality expertise will be required,which may be provided by consultation. If FMT production is tobe under a ‘specials’ licence, the team should be expanded toinclude a Qualified Person, Quality Manager and ProductionManager, all with GMP training.

Evidence:Working group consensus opinion (quality of evidence: 4).Good practice point:A multidisciplinary team should be formed to deliver FMT

services (strong).

InfrastructureDedicated laboratory facilities for FMT production are

recommended to ensure that the process adheres to Healthand Safety requirements, to reduce the risk of cross-contamination, and to facilitate standardisation of the pro-duction process. In some studies, FMT has been prepared in aclinical environment [80]; however, this may not be advis-able because of the risks of cross-contamination. Themanipulation of human stool should be conducted in aContainment Level 2 laboratory according to current Healthand Safety guidance (Health and Safety at Work Act 1974,COSHH Control of Substances Hazardous to Health Regula-tions, 2002), and at least within a microbiological safetycabinet which provides user protection (Class I) or, ideally,user and product protection (Class II). To meet the re-quirements of GMP, this facility should be sole use or be riskassessed for multipurpose use with adequate separation ofdifferent activities. The working group recommend that thefacility complies with the new GMP production facilityclassification of ‘clean not sterile’. The use of personalprotective equipment - such as laboratory coat, gloves andface mask - is also recommended to prevent productioncontamination. It is essential to risk assess the process anddevelop control measures to reduce microbial ingress intothe facility and monitor the microbiological cleanliness ofthe production suite. FMT preparation under a ‘specials’licence should ensure that the production process is inte-grated into a Quality Management System, to safeguardproduction and maintain the minimum criteria for audit,monitoring, standard operating procedures, document con-trol, training, facilities, equipment and storage. With regardto storage, it is essential that the freezer system has real-time temperature monitoring which provides notificationoutside pre-set limits.

Evidence:Working group consensus opinion (quality of evidence: 4).Good practice point:Utilise suitable laboratory facilities and infrastructure for

FMT production (strong).

FMT manufacturingIt is strongly recommended to employ a batch numbering

system to track FMT preparations from production to use. Itshould be possible from records to identify an individual FMTaliquot, trace it to a specific donation, and identify all otherFMT aliquots prepared from the same donation. It must also beclear which FMT aliquots patients have received, which shouldbe verifiable from the donor to the patient and vice-versa. It istherefore strongly recommended that a treatment directory bemaintained documenting all production and use of FMT, andthat an unambiguous record is created in the patients’ clinicalnotes to identify the specific FMT batch number. Further tothis, it is also recommended that treatment directories alsorecord clinical outcome, such as that developed in the USA[155] and Germany [156] to standardise and improve futureclinical practice.

Evidence:Working group consensus opinion (quality of evidence: 4).Good practice point:Ensure traceability of supply (strong).

FMT production quality controlSafety and clinical governance is a central responsibility for

FMT centres, particularly in light of the absence of phase IIIlicensing trials for FMT, which would normally be required for anovel medicinal product. Reporting and investigating adverseevents and reactions contributes to knowledge of the FMTsafety profile, while also identifying previously unknown safetyissues. Governance structures and processesmust be in place tomonitor, notify and investigate all FMT-related adverse eventsor reactions locally, and FMT users are encouraged to use theMHRA Yellow Card Scheme for formal notification. FMT supplyshould be suspended if serious adverse events or reactionsoccur which are directly attributable to FMT, and there shouldbe a clear documented pathway to achieve this. To facilitate a‘look-back exercise’ if required, it is advisable to store docu-mentation and reference samples, both product-based anddonor/patient-based. Specifically, retention of productiondocumentation should be for at least five years after the use ofthe batch; retention of reference FMT samples (and stoolsamples from donors and recipients) should be for at least oneyear after the last use. Retention of excipient samples should befor at least one year after expiry of the excipient.

Evidence:Working group consensus opinion and legal requirement

(quality of evidence: 4).Good practice point:Monitor, notify and investigate all adverse events and re-

actions related to FMT (strong).

Donor screening governanceThe testing requirements for donor screening have been

discussed previously; however, it is worth noting here thepertinent clinical governance issues which should beaddressed. Donor anonymity should be maintained at all times.

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S26

The laboratory undertaking testing of donor samples should becompetent for such activity, demonstrable by accreditationwith the United Kingdom Accreditation Service (UKAS). Theresults of donor testing should remain confidential. Thereshould be appropriate standard operating procedures to ensurethat the outcome of donor screening is built into a robust FMTbatch release process. To ensure unbiased autonomy duringdonor screening, it is suggested that a clinician independent tothe FMT production team is responsible for ratifying FMT do-nors prior to donation. Finally, the duration of donor follow-upshould be considered and extend beyond the period of activedonation to capture acute and chronic health changes.

Evidence:Working group consensus opinion (quality of evidence: 4).Good practice point:Ensure the clinical governance of donor screening (strong).

Conclusions

FMT has become an accepted, efficacious treatment forrecurrent and/or refractory CDI. In developing this guideline,the evidence for the technique has been reviewed in thecontext of other available treatments. Specific guidance forbest practice for an FMT service is provided.

Further research

� As described within this guideline, many aspects of theterminology of CDI are used variably between studies, andend-points in FMT trials are inconsistent. The workinggroup noted the need to standardise this terminology toallow more robust comparisons between studies.

� Given the relative novelty of FMT as a procedure, anypotential long-term adverse events associated with itsuse are poorly-defined. The establishment of formal FMTregistries should be considered. While this would pri-marily act as an important tool for defining the safety andefficacy of FMT, it would also be a valuable database forresearchers within the field. Standardisation of other keydocumentation related to FMT administration (e.g.establishment of a proforma for assessing eligibility forFMT and/or follow-up after FMT) would also be advanta-geous for the same reasons.

� The working group noted the lack of consistency in defi-nitions related to the severity of CDI disease and toresponse or failure to FMT. This limited interpretation ofthe published studies. As such, the working group thoughtthat standardisation of these definitions would allowmore accurate delineation of the factors influencing theefficacy of FMT for CDI. The working group also noted thatonly one reviewed study had reported the relationshipbetween C difficile ribotype and FMT outcome, and thatrecording of this information should be encouraged betterto evaluate its influence.

� Further well-designed clinical trials (in particular, RCTs)are required to identify the optimal means of adminis-tration of FMT as treatment for recurrent and/or re-fractory CDI.

� The working group noted that even capsulised FMT maybe associated with potential drawbacks. They also notedthat there are many patients with recurrent CDI for whom

FMT (or any form of ‘bacteriotherapy’) may be inappro-priate, including those with very marked immunosup-pression, and/or multi-organ disease. Despite high levelsof efficacy, there is a small but appreciable FMT failurerate and it is not currently understood whether this is dueto underlying donor or recipient factors. Therefore, aresearch priority should be in basic and translationalstudies better to define the mechanisms underlying theefficacy of FMT in CDI. This includes comparing thestructure and function of the microbiota of donors topatients pre-FMT and post-FMT, via techniques includingnext-generation microbial sequencing, metabolicprofiling, and immunological assays. This would allow therefinement of FMT from its current state to a more tar-geted therapy, removing the concerns associated withFMT.

� The working group identified a need for further well-designed RCTs to investigate the potential role of FMTfor non-CDI indications.

Appendices. Supplementary data

Supplementary data related to this article can be found athttps://doi.org/10.1016/j.jhin.2018.07.037.

References

[1] Lawson PA, Citron DM, Tyrrell KL, Finegold SM. Reclassificationof clostridium difficile as clostridioides difficile (hall and o’toole1935) prevot 1938. Anaerobe 2016;40:95e9. https://doi.org/10.1016/j.anaerobe.2016.06.008.

[2] National Institute for Health and Care Excellence (NICE). Faecalmicrobiota transplant for recurrent clostridium difficile infectionj guidance and guidelines j nice. NICE; 2014. https://www.nice.org.uk/guidance/ipg485. [last accessed 2 October 2017].

[3] Public Health England. Updated guidance on the managementand treatment of clostridium difficile infection. Public HealEngl 2013:1e29. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/321891/clostridium_difficile_management_and_treatment.pdf. [last accessed 20 March 2017].

[4] Debast SB, Bauer MP, Kuijper EJ. European society of clinicalmicrobiology and infectious diseases: update of the treatmentguidance document for clostridium difficile infection. ClinMicrobiol Infect 2014;20:1e26. https://doi.org/10.1111/1469-0691.12418.

[5] Mcdonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC,Coffin SE, et al. Clinical practice guidelines for clostridiumdifficile infection in adults and children: 2017 update by theInfectious Diseases Society Of America (IDSA) and Society ForHealthcare Epidemiology of America (SHEA). Clin Infect Dis2018;31:431e55. https://doi.org/10.1093/cid/cix1085.

[6] Cammarota G, Ianiro G, Tilg H, Rajili�c-Stojanovi�c M, Kump P,Satokari R, et al. European consensus conference on faecalmicrobiota transplantation in clinical practice. Gut2017;66:569e80. https://doi.org/10.1136/gutjnl-2016-313017.

[7] Konig J, Siebenhaar A, Hogenauer C, Arkkila P, Nieuwdorp M,Noren T, et al. Consensus report: faecal microbiota transfer -clinical applications and procedures. Aliment Pharmacol Ther2017;45:222e39. https://doi.org/10.1111/apt.13868.

[8] Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC,Franzos MA, et al. Treating clostridium difficile infection withfecal microbiota transplantation. Clin Gastroenterol Hepatol2011;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] Kump PK, Krause R, Steininger C, Grochenig HP, Moschen A,Madl C, et al. Empfehlungen zur anwendung der fakalenmikrobiotatransplantation “stuhltransplantation”: konsen-sus der osterreichischen gesellschaft fur gastroenterologieund hepatologie (oggh) in zusammenarbeit mit der oster-reichischen gesellschaft fur infektiologie und.Z Gastroenterol 2014;52:1485e92. https://doi.org/10.1055/s-0034-1385562.

[10] Sokol H, Galperine T, Kapel N, Bourlioux P, Seksik P, Barbut F,et al. Faecal microbiota transplantation in recurrent clostridiumdifficile infection: recommendations from the french group offaecal microbiota transplantation. Dig Liver Dis 2016;48:242e7.https://doi.org/10.1016/j.dld.2015.08.017.

[11] Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effectof oral capsulee vs colonoscopy-delivered fecal microbiotatransplantation on recurrent clostridium difficile infection.Jama 2017;318:1985. https://doi.org/10.1001/jama.2017.17077.

[12] Hota SS, Sales V, Tomlinson G, Salpeter MJ, Mcgeer A, Coburn B,et al. Oral vancomycin followed by fecal transplantation versustapering oral vancomycin treatment for recurrent clostridiumdifficile infection: an open-label, randomized controlled trial.Clin Infect Dis 2017;64:265e71. https://doi.org/10.1093/cid/ciw731.

[13] Jiang ZD, Ajami NJ, Petrosino JF, Jun G, Hanis CL, Shah M, et al.Randomised clinical trial: faecal microbiota transplantation forrecurrent clostridum difficile infection e fresh, or frozen, orlyophilised microbiota from a small pool of healthy donorsdelivered by colonoscopy. Aliment Pharmacol Ther2017;45:899e908. https://doi.org/10.1111/apt.13969.

[14] Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M,et al. Effect of fecal microbiota transplantation on recurrence inmultiply recurrent clostridium difficile infection. Ann Intern Med2016;165:609e16. https://doi.org/10.7326/m16-0271.

[15] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, DeVos WM, et al. Duodenal infusion of donor feces for recurrentclostridium difficile. N Engl J Med 2013;368:407e15. https://doi.org/10.1056/nejmoa1205037.

[16] Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A,et al. Frozen vs fresh fecal microbiota transplantation andclinical resolution of diarrhea in patients with recurrent clos-tridium difficile infection a randomized clinical trial. JAMA - JAm Med Assoc 2016;315:142e9. https://doi.org/10.1001/jama.2015.18098.

[17] Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB,et al. Fecal microbiota transplant for relapsing clostridiumdifficile infection using a frozen inoculum from unrelated do-nors: a randomized, open-label, controlled pilot study. ClinInfect Dis 2014;58:1515e22. https://doi.org/10.1093/cid/ciu135.

[18] Cammarota G, Masucci L, Ianiro G, Bibbo S, Dinoi G,Costamagna G, et al. Randomised clinical trial: faecal micro-biota transplantation by colonoscopy vs. vancomycin for thetreatment of recurrent clostridium difficile infection. AlimentPharmacol Ther 2015;41:835e43. https://doi.org/10.1111/apt.13144.

[19] Medicines and Healthcare Products Regulatory Agency. FaecalMicrobiota Transplantation (FMT) mhra’s position n.d. http://www.bsg.org.uk/images/stories/docs/clinical/guidance/fmt_mhra_position_june2015.pdf [last accessed October 3 2017].

[20] Thomas A. HTA policy on the regulation of faecal microbiotatransplant hta-pol-030. 2015. p. 2e3. http://www.bsg.org.uk/images/stories/docs/clinical/guidance/hta_pol_030_policy_regulation_of_fmt.pdf. [last accessed 3 October 2017].

[21] Khoruts A, Sadowsky MJ. Understanding the mechanisms offaecal microbiota transplantation. Nat Rev Gastroenterol Hep-atol 2016;13:508e16. https://doi.org/10.1038/nrgastro.2016.98.

[22] Petrof EO, Gloor GB, Vanner SJ, Weese SJ, Carter D,Daigneault MC, et al. Stool substitute transplant therapy for theeradication of clostridium difficile infection: “repoopulating”the gut. Microbiome 2013;1:3. https://doi.org/10.1186/2049-2618-1-3.

[23] Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R,Grasis JA, et al. Efficacy of sterile fecal filtrate transfer fortreating patients with clostridium difficile infection. Gastroen-terology 2017;152. https://doi.org/10.1053/j.gastro.2016.11.010. 799e811.e7.

[24] Khanna S, Pardi DS, Kelly CR, Kraft CS, Dhere T, Henn MR, et al.A novel microbiome therapeutic increases gut microbial di-versity and prevents recurrent clostridium difficile infection.J Infect Dis 2016;214:173e81. https://doi.org/10.1093/infdis/jiv766.

[25] Martin J, Wilcox M. New and emerging therapies for clostridiumdifficile infection. Curr Opin Infect Dis 2016;29:546e54. https://doi.org/10.1097/qco.0000000000000320.

[26] Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB.Patient attitudes toward the use of fecal microbiota trans-plantation in the treatment of recurrent clostridium difficileinfection. Clin Infect Dis 2012;55:1652e8. https://doi.org/10.1093/cid/cis809.

[27] Kahn SA, VachonA, RodriquezD,Goeppinger SR, SurmaB,Marks J,et al. Patient perceptions of fecal microbiota transplantation forulcerative colitis. Inflamm Bowel Dis 2013;19:1506e13. https://doi.org/10.1097/mib.0b013e318281f520.

[28] Quraishi MN, Segal J, Mullish B, Mccune Vl, Hawkey P, Colville A,et al. National survey of practice of faecal microbiota trans-plantation for clostridium difficile infection in the UK. J HospInfect 2017;95:444e5. https://doi.org/10.1016/j.jhin.2016.10.023.

[29] Porter RJ, Fogg C. Faecal microbiota transplantation for clos-tridium difficile infection in the United Kingdom. Clin MicrobiolInfect 2015;21:578e82. https://doi.org/10.1016/j.cmi.2015.01.020.

[30] Ding NS, Mullish BH, Mclaughlin J, Hart A, Marchesi Jr . Meetingupdate: faecal microbiota transplantation - bench, bedside,courtroom? Frontline Gastroenterol 2018;9:45e8. https://doi.org/10.1136/flgastro-2016-100752.

[31] Prior AR, Kevans D, Mcdowell L, Cudmore S, Fitzpatrick F.Treatment of clostridium difficile infection: a national survey ofclinician recommendations and the use of faecal microbiotatransplantation. J Hosp Infect 2017;95:438e41. https://doi.org/10.1016/j.jhin.2016.10.004.

[32] Richardson WS, Wilson MC, Nishikwa J, Haywood RSA. The well-built clinical question: a key to evidence-based decisions. 1995Acp J Club 1995;123:a12e3.

[33] SIGN. Sign 50. 2015. http://www.sign.ac.uk/assets/sign50_2015.pdf. [last accessed 18 October 2017].

[34] Higgins JPT, Green S. Cochrane handbook for systematic reviewsof interventions j cochrane training. 2011. http://handbook-5-1.cochrane.org. [last accessed 18 October 2017].

[35] Varier RU, Biltaji E, Smith KJ, Roberts MS, Kyle Jensen M,Lafleur J, et al. Cost-effectiveness analysis of fecal microbiotatransplantation for recurrent clostridium difficile infection.Infect Control Hosp Epidemiol 2015;36:438e44. https://doi.org/10.1017/ice.2014.80.

[36] Konijeti GG, Sauk J, Shrime MG, Gupta M, Ananthakrishnan AN.Cost-effectiveness of competing strategies for management ofrecurrent clostridium difficile infection: a decision analysis. ClinInfect Dis 2014;58:1507e14. https://doi.org/10.1093/cid/ciu128.

[37] Baro E, Galperine T, Denies F, Lannoy D, Lenne X, Odou P, et al.Cost-effectiveness analysis of five competing strategies for themanagement of multiple recurrent community-onset clostridiumdifficile infection in france. Plos One 2017;12:e0170258.https://doi.org/10.1371/journal.pone.0170258.

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S28

[38] Lapointe-Shaw L, Tran KL, Coyte PC, Hancock-Howard RL,Powis J, Poutanen SM, et al. Cost-effectiveness analysis of sixstrategies to treat recurrent clostridium difficile infection. PlosOne 2016;11:e0149521. https://doi.org/10.1371/journal.pone.0149521.

[39] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y,Alonso-Coello P, et al. Grade: an emerging consensus on ratingquality of evidence and strength of recommendations. Bmj2008;336:924e6. https://doi.org/10.1136/bmj.39489.470347.ad.

[40] Satokari R, Mattila E, Kainulainen V, Arkkila PET. Simple faecalpreparation and efficacy of frozen inoculum in faecal microbiotatransplantation for recurrent clostridium difficile infection - anobservational cohort study. Aliment Pharmacol Ther2015;41:46e53. https://doi.org/10.1111/apt.13009.

[41] Yoon SS, Brandt LJ. Treatment of refractory/recurrent c.difficile-associated disease by donated stool transplanted viacolonoscopy. J Clin Gastroenterol 2010;44:562e6. https://doi.org/10.1097/mcg.0b013e3181dac035.

[42] Zainah H, Hassan M, Shiekh-Sroujieh L, Hassan S, Alangaden G,Ramesh M. Intestinal microbiota transplantation, a simple andeffective treatment for severe and refractory clostridium diffi-cile infection. Dig Dis Sci 2014;60:181e5. https://doi.org/10.1007/s10620-014-3296-y.

[43] Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplant viaretention enema for refractory or recurrent clostridium difficileinfection. Arch Intern Med 2012;172:191e3. https://doi.org/10.1001/archinte.172.2.191.

[44] Aas J, Gessert CE, Bakken JS. Recurrent clostridium difficilecolitis: case series involving 18 patients treated with donor stooladministered via a nasogastric tube. Clin Infect Dis2003;36:580e5. https://doi.org/10.1086/367657.

[45] Garborg K, Waagsbø B, Stallemo A, Matre J, Sundøy A. Results offaecal donor instillation therapy for recurrent clostridiumdifficile-associated diarrhoea. Scand J Infect Dis 2010;42:857e61.https://doi.org/10.3109/00365548.2010.499541.

[46] Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Stan-dardized frozen preparation for transplantation of fecal micro-biota for recurrent clostridium difficile infection. Am JGastroenterol 2012;107:761e7. https://doi.org/10.1038/ajg.2011.482.

[47] Lee CH, Belanger JE, Kassam Z, Smieja M, Higgins D,Broukhanski G, et al. The outcome and long-term follow-up of 94patients with recurrent and refractory clostridium difficileinfection using single to multiple fecal microbiota trans-plantation via retention enema. Eur J Clin Microbiol Infect Dis2014;33:1425e8. https://doi.org/10.1007/s10096-014-2088-9.

[48] Mattila E, Uusitalo-Seppala R, Wuorela M, Lehtola L, Nurmi H,Ristikankare M, et al. Fecal transplantation, through colonos-copy, is effective therapy for recurrent clostridium difficileinfection. Gastroenterology 2012;142:490e6. https://doi.org/10.1053/j.gastro.2011.11.037.

[49] Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution forrecurrent clostridium difficile infection: results and methodol-ogy. J Clin Gastroenterol 2010;44:567e70. https://doi.org/10.1097/mcg.0b013e3181dadb10.

[50] Rubin TA, Gessert CE, Aas J, Bakken JS. Fecal microbiometransplantation for recurrent clostridium difficile infection:report on a case series. Anaerobe 2013;19:22e6. https://doi.org/10.1016/j.anaerobe.2012.11.004.

[51] Patel NC, Griesbach CL, Dibaise JK, Orenstein R. Fecal micro-biota transplant for recurrent clostridium difficile infection:mayo clinic in arizona experience. Mayo Clin Proc2013;88:799e805. https://doi.org/10.1016/j.mayocp.2013.04.022.

[52] Crobach MJT, Planche T, Eckert C, Barbut F, Terveer EM,Dekkers OM, et al. European society of clinical microbiology andinfectious diseases: update of the diagnostic guidance document

for clostridium difficile infection. Clin Microbiol Infect2016;22(suppl 4):s63e81. https://doi.org/10.1016/j.cmi.2016.03.010.

[53] Jackson M, Olefson S, Machan JT, kelly CR. A high rate ofalternative diagnoses in patients referred for presumed clos-tridium difficile infection. J Clin Gastroenterol 2016;50:742e6.https://doi.org/10.1097/mcg.0000000000000447.

[54] Ray A, Smith R, Breaux J. Fecal microbiota transplantation for clos-tridium difficile infection: the ochsner experience. Ochsner J2014;14:538e44. https://doi.org/10.1097/mog.0000000000000023.

[55] Kao D, Roach B, Hotte N, Silva M, Madsen K, Beck PLT.A prospective, dual center, randomized trial comparing colo-noscopy versus capsule delivered Fecal Microbiota Trans-plantation (FMT) in the management of Recurrent ClostridiumDifficile Infection (RCDI). Can J Gastroenterol Hepatol2016;2016:1e204. https://doi.org/10.1155/2016/4792898.

[56] Macconnachie AA, Fox R, Kennedy DR, Seaton RA. Faecaltransplant for recurrent clostridium difficile-associated diar-rhoea: a UK case series. Qjm 2009;102:781e4. https://doi.org/10.1093/qjmed/hcp118.

[57] Kelly CR, de Leon L, Jasutkar N. Fecal microbiota trans-plantation for relapsing clostridium difficile infection in 26 pa-tients. J Clin Gastroenterol 2012;46:145e9. https://doi.org/10.1097/mcg.0b013e318234570b.

[58] Brandt LJ, Aroniadis OC, Mellow M, Kanatzar A, Kelly C, Park T,et al. Long-term follow-up of colonoscopic fecal microbiotatransplant for recurrent clostridium difficile infection. Am JGastroenterol 2012;107:1079e87. https://doi.org/10.1038/ajg.2012.60.

[59] Pathak R, Enuh HA, Patel A, Wickremesinghe P. Treatment ofrelapsing clostridium difficile infection using fecal microbiotatransplantation. Clin Exp Gastroenterol 2013;7:1e6. https://doi.org/10.2147/ceg.s53410.

[60] Agrawal M, Aroniadis OC, Brandt LJ, Kelly C, Freeman S,Surawicz C, et al. The long-term efficacy and safety of fecalmicrobiota transplant for recurrent, severe, and complicatedclostridium difficile infection in 146 elderly individuals. J ClinGastroenterol 2016;50:403e7. https://doi.org/10.1097/mcg.0000000000000410.

[61] FischerM,KaoD,KellyC,KuchipudiA,Jafri S-M,BlumenkehlM,etal.Fecal microbiota transplantation is safe and efficacious for recur-rent or refractory clostridium difficile infection in patients with in-flammatory bowel disease. Inflamm Bowel Dis 2016;22:2402e9.https://doi.org/10.1097/mib.0000000000000908.

[62] Aroniadis OC, Brandt LJ, Greenberg A, Borody T, Kelly CR,Mellow M, et al. Long-term follow-up study of fecal microbiotatransplantation for severe and/or complicated clostridiumdifficile infection: a multicenter experience. J Clin Gastro-enterol 2016;50:398e402. https://doi.org/10.1097/mcg.0000000000000374.

[63] Fischer M, Kao D, Mehta SR, Martin T, Dimitry J, Keshteli AH,et al. Predictors of early failure after fecal microbiota trans-plantation for the therapy of clostridium difficile infection: amulticenter study. Am J Gastroenterol 2016;111:1024e31.https://doi.org/10.1038/ajg.2016.180.

[64] Ianiro G, Valerio L, Masucci L, Pecere S, Bibbo S, Quaranta G,et al. Predictors of failure after single faecal microbiota trans-plantation in patients with recurrent clostridium difficile infec-tion: results from a 3-year, single-centre cohort study. ClinMicrobiol Infect 2017;23:337.e1e3. https://doi.org/10.1016/j.cmi.2016.12.025.

[65] Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A,et al. Fecal microbiota transplant for treatment of clostridiumdifficile infection in immunocompromised patients. Am J Gas-troenterol 2014;109:1065e71. https://doi.org/10.1038/ajg.2014.133.

[66] Lagier J-C, Delord M, Million M, Parola P, Stein A, Brouqui P,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 thenasogastric route: a preliminary report. Eur J Clin MicrobiolInfect Dis 2015;34:1597e601. https://doi.org/10.1007/s10096-015-2394-x.

[67] Camacho-Ortiz A, Gutierrez-Delgado EM, Garcia-Mazcorro JF,Mendoza-Olazaran S, Martınez-Melendez A, Palau-Davila L, et al.Randomized clinical trial to evaluate the effect of fecal micro-biota transplant for initial clostridium difficile infection in in-testinal microbiome. Plos One 2017;12:e0189768. https://doi.org/10.1371/journal.pone.0189768.

[68] Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y,et al. Fidaxomicin versus vancomycin for clostridium difficileinfection. N Engl J Med 2011;364:422e31. https://doi.org/10.1056/nejmoa0910812.

[69] Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T,et al. Bezlotoxumab for prevention of recurrent clostridiumdifficile infection. N Engl J Med 2017;376:305e17. https://doi.org/10.1056/nejmoa1602615.

[70] Guery B, Menichetti F, Anttila VJ, Adomakoh N, Aguado JM,Bisnauthsing K, et al. Extended-pulsed fidaxomicin versus van-comycin for clostridium difficile infection in patients 60 yearsand older (extend): a randomised, controlled, open-label, phase3b/4 trial. Lancet Infect Dis 2017;18:296e307. https://doi.org/10.1016/s1473-3099(17)30751-x.

[71] Mcfarland LV, Elmer GW, Surawicz CM. Breaking the cycle:treatment strategies for 163 cases of recurrent clostridiumdifficile disease. Am J Gastroenterol 2002;97:1769e75. https://doi.org/10.1111/j.1572-0241.2002.05839.x.

[72] Sirbu BD, Soriano MM, Manzo C, Lum J, Gerding DN, Johnson S.Vancomycin taper and pulse regimen with careful follow-up forpatients with recurrent clostridium difficile infection. ClinInfect Dis 2017;65:1396e9. https://doi.org/10.1093/cid/cix529.

[73] Gentry CA, Giancola SE, Thind S, Kurdgelashvili G, Skrepnek GH,Williams RJ. A propensity-matched analysis between standardversus tapered oral vancomycin courses for the management ofrecurrent clostridium difficile infection. Open Forum Infect Dis2017;4:ofx235. https://doi.org/10.1093/ofid/ofx235.

[74] Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS,Weiss K, et al. Fidaxomicin versus vancomycin for infection withclostridium difficile in europe, canada, and the usa: a double-blind, non-inferiority, randomised controlled trial. LancetInfect Dis 2012;12:281e9. https://doi.org/10.1016/s1473-3099(11)70374-7.

[75] Tauxe WM, Haydek JP, Rebolledo PA, Neish E, Newman Kl,Ward A, et al. Fecal microbiota transplant for clostridium diffi-cile infection in older adults. Therap Adv Gastroenterol2016;9:273e81. https://doi.org/10.1177/1756283x15622600.

[76] Khan MA, Sofi AA, Ahmad U, Alaradi O, Khan AR, Hammad T,et al. Efficacy and safety of, and patient satisfaction with,colonoscopic-administered fecal microbiota transplantation inrelapsing and refractory community- and hospital-acquiredclostridium difficile infection. Can J Gastroenterol Hepatol2014;28:434e8.

[77] Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J,Hohmann EL. Oral, capsulized, frozen fecal microbiota trans-plantation for relapsing clostridium difficile infection. Jama - JAm Med Assoc 2014;312:1772e8. https://doi.org/10.1001/jama.2014.13875.

[78] Fischer M, Sipe BW, Rogers NA, Cook GK, Robb BW,Vuppalanchi R, et al. Faecal microbiota transplantation plusselected use of vancomycin for severe-complicated clostridiumdifficile infection: description of a protocol with high successrate. Aliment Pharmacol Ther 2015;42:470e6. https://doi.org/10.1111/apt.13290.

[79] Costello SP, Conlon MA, Vuaran MS, Roberts-Thomson IC,Andrews JM. Faecal microbiota transplant for recurrent clos-tridium difficile infection using long-term frozen stool is

effective: clinical efficacy and bacterial viability data. AlimentPharmacol Ther 2015;42:1011e8. https://doi.org/10.1111/apt.13366.

[80] Allegretti Jr , Korzenik Jr , Hamilton MJ. Fecal microbiotatransplantation via colonoscopy for recurrent C. difficile infec-tion. J Vis Exp 2014:52154. https://doi.org/10.3791/52154.

[81] van Beurden YH, de Groot PF, van Nood E, Nieuwdorp M,Keller JJ, Goorhuis A. Complications, effectiveness, and longterm follow-up of fecal microbiota transfer by nasoduodenaltube for treatment of recurrent clostridium difficile infection.United Eur Gastroenterol J 2017;5:868e79. https://doi.org/10.1177/2050640616678099.

[82] Allegretti Jr , Allegretti AS, Phelps E, Xu H, Kassam Z, Fischer M.Asymptomatic clostridium difficile carriage rate post-fecalmicrobiota transplant is low: a prospective clinical and stoolassessment. Clin Microbiol Infect 2018;24:780.e1e3. https://doi.org/10.1016/j.cmi.2017.10.022.

[83] Baxter M, Colville A. Adverse events in faecal microbiotatransplant: a review of the literature. J Hosp Infect2016;92:117e27. https://doi.org/10.1016/j.jhin.2015.10.024.

[84] Hefazi M, Patnaik MM, Hogan WJ, Litzow MR, Pardi DS, Khanna S.Safety and efficacy of fecal microbiota transplant for recurrentclostridium difficile infection in patients with cancer treatedwith cytotoxic chemotherapy: a single-institution retrospectivecase series. Mayo Clin Proc 2017;92:1617e24. https://doi.org/10.1016/j.mayocp.2017.08.016.

[85] Qazi T, Amaratunga T, Barnes EL, Fischer M, Kassam Z,Allegretti Jr . The risk of inflammatory bowel disease flares afterfecal microbiota transplantation: systematic review and meta-analysis. Gut Microbes 2017;8:574e88. https://doi.org/10.1080/19490976.2017.1353848.

[86] Mattila E, Uusitalo-Seppala R, Wuorela M, Lehtola L, Nurmi H,Ristikankare M, et al. Fecal transplantation, through colonos-copy, is effective therapy for recurrent clostridium difficileinfection. Gastroenterology 2012;142:490e6. https://doi.org/10.1053/j.gastro.2011.11.037.

[87] Meighani A, Hart BR, Mittal C, Miller N, John A, RameshM. Predictorsof fecal transplant failure. Eur J Gastroenterol Hepatol2016;28:826e30.https://doi.org/10.1097/meg.0000000000000614.

[88] Alrabaa S, Jariwala R, Zeitler K, Montero J. Fecal microbiotatransplantation outcomes in immunocompetent and immu-nocompromised patients: a single-center experience.Transpl Infect Dis 2017;19:e12726. https://doi.org/10.1111/tid.12726.

[89] Cohen NA, Livovsky DM, Yaakobovitch S, Ben Yehoyada M, BenAmi R, Adler A, et al. A retrospective comparison of fecal mi-crobial transplantation methods for recurrent clostridium diffi-cile infection. Isr Med Assoc J 2016;18:594e9.

[90] Orenstein R, Dubberke E, Hardi R, Ray A, Mullane K, Pardi DS,et al. Safety and durability of rbx2660 (microbiota suspension)for recurrent clostridium difficile infection: results of the punchcd study. Clin Infect Dis 2016;62:596e602. https://doi.org/10.1093/cid/civ938.

[91] Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, Honig G.Effectiveness of fecal-derived microbiota transfer using orallyadministered capsules for recurrent clostridium difficile infec-tion. Bmc Infect Dis 2015;15:191. https://doi.org/10.1186/s12879-015-0930-z.

[92] Kao D, Roach B, Beck P, Hotte N, Madsen K, Louie T. A dualcenter, randomized trial comparing colonoscopy and oralcapsule delivered fecal microbiota transplantation in thetreatment of recurrent clostridium difficile infection: pre-liminary results. Am J Gastroenterol 2015;110:s553. https://doi.org/10.1038/ajg.2015.294.

[93] Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H,Levin J, et al. Oral, frozen fecal microbiota transplant (fmt)capsules for recurrent clostridium difficile infection. Bmc Med2016;14:134. https://doi.org/10.1186/s12916-016-0680-9.

B.H. Mullish et al. / Journal of Hospital Infection 100 (2018) S1eS31S30

[94] Anand R, Song Y, Garg S, Girotra M, Sinha A, Sivaraman A, et al.Effect of aging on the composition of fecal microbiota in donorsfor fmt and its impact on clinical outcomes. Dig Dis Sci2017;62:1002e8. https://doi.org/10.1007/s10620-017-4449-6.

[95] Alang N, Kelly CR. Weight gain after fecal microbiota trans-plantation. Open Forum Infect Dis 2015;2:ofv004. https://doi.org/10.1093/ofid/ofv004.

[96] Fischer M, Kao D, Kassam Z, Smith J, Louie T, Sipe B, et al. Stooldonor body mass index does not affect recipient weight after asingle fecal microbiota transplantation for clostridium difficileinfection. Clin Gastroenterol Hepatol 2017. https://doi.org/10.1016/j.cgh.2017.12.007.

[97] Marchesi Jr , Adams DH, Fava F, Hermes GDA, Hirschfield GM,Hold G, et al. The gut microbiota and host health: a new clinicalfrontier. Gut 2016;65:330e9. https://doi.org/10.1136/gutjnl-2015-309990.

[98] Allegretti Jr , Fischer M, Papa E, Elliott RJ, Klank J, Mendolia G,et al. su1738 fecal microbiota transplantation delivered via oralcapsules achieves microbial engraftment similar to traditionaldelivery modalities: safety, efficacy and engraftment resultsfrom a multi-center cluster randomized dose-finding study.Gastroenterology 2016;150:s540. https://doi.org/10.1016/s0016-5085(16)31855-8.

[99] Langdon A, Crook N, Dantas G. The effects of antibiotics on themicrobiome throughout development and alternative ap-proaches for therapeutic modulation. Genome Med 2016;8:39.https://doi.org/10.1186/s13073-016-0294-z.

[100] Lange K, Buerger M, Stallmach A, Bruns T. Effects of antibioticson gut microbiota. Dig Dis 2016;34:260e8. https://doi.org/10.1159/000443360.

[101] Becattini S, Taur Y, Pamer EG. Antibiotic-induced changes in theintestinalmicrobiotaanddisease.TrendsMolMed2016;22:458e78.https://doi.org/10.1016/j.molmed.2016.04.003.

[102] Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators ofgut microbiota: between good and evil. Gut 2016;65:1906e15.https://doi.org/10.1136/gutjnl-2016-312297.

[103] Allegretti Jr , Korzenik Jr , Hamilton MJ. Tu1361 intestinalmicrobiome restoration for recurrent clostridium difficileinfection in patients with concurrent inflammatory bowel dis-ease. Gastroenterology 2015;148:s869. https://doi.org/10.1016/s0016-5085(15)32948-6.

[104] Dubberke ER, Olsen MA. Burden of clostridium difficile on thehealthcare system. Clin Infect Dis 2012;55:s88e92. https://doi.org/10.1093/cid/cis335.

[105] National Health Service. Population screening programmes: NHSbowel cancer screening (BCSP) Programme - gov.uk n.d.https://www.gov.uk/topic/population-screening-programmes/bowel [Accessed June 10 2018].

[106] TSO. Guidelines for the blood transfusion services in the UnitedKingdom. 7th edition 2005 TSO accredited agents web access n.d.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/228828/0117033715.pdf.[last accessed 12 July 2018].

[107] Emanuelsson F, Claesson BEB, Ljungstrom L, Tvede M, Ung K-A.Faecal microbiota transplantation and bacteriotherapy forrecurrent clostridium difficile infection: a retrospective evalu-ation of 31 patients. Scand J Infect Dis 2014;46:89e97. https://doi.org/10.3109/00365548.2013.858181.

[108] Endtz HP, van Den Braak N, van Belkum A, Kluytmans JA,Koeleman JG, Spanjaard L, et al. Fecal carriage of vancomycin-resistant enterococci in hospitalized patients and those living inthe community in the netherlands. J Clin Microbiol1997;35:3026e31.

[109] Willems RJL, Top J, van Santen M, Robinson DA, Coque TM,Baquero F, et al. Global spread of vancomycin-resistantenterococcus faecium from distinct nosocomial genetic com-plex. Emerg Infect Dis 2005;11:821e8. https://doi.org/10.3201/eid1106.041204.

[110] Gough E, Shaikh H, Manges AR. Systematic review of intestinalmicrobiota transplantation (fecal bacteriotherapy) for recurrentclostridium difficile infection. Clin Infect Dis 2011;53:994e1002.https://doi.org/10.1093/cid/cir632.

[111] Casewell MW, Slater NGP, Cooper JE. Operating theatre water-baths as a cause of pseudomonas septicaemia. J Hosp Infect1981;2:237e40. https://doi.org/10.1016/0195-6701(81)90043-8.

[112] Muyldermans G, de Smet F, Pierard D, Steenssens L, Stevens D,Bougatef A, et al. Neonatal infections with pseudomonas aeru-ginosa associated with a water-bath used to thaw fresh frozenplasma. J Hosp Infect 1998;39:309e14.

[113] Sleight SC, Wigginton NS, Lenski RE. Increased susceptibility torepeated freeze-thaw cycles in escherichia coli following long-term evolution in a benign environment. Bmc Evol Biol2006;6:104. https://doi.org/10.1186/1471-2148-6-104.

[114] O’brien CL, Allison GE, Grimpen F, Pavli P. Impact of colonoscopybowel preparation on intestinal microbiota. Plos One2013;8:e62815. https://doi.org/10.1371/journal.pone.0062815.

[115] Mai V, Stine OC. Bowel preparation for colonoscopy: relevant forthe gut’s microbiota? Gut 2015;64:1504e5. https://doi.org/10.1136/gutjnl-2014-308937.

[116] Jalanka J, Salonen A, Salojarvi J, Ritari J, Immonen O,Marciani L, et al. Effects of bowel cleansing on the intestinalmicrobiota. Gut 2015;64:1562e8. https://doi.org/10.1136/gutjnl-2014-307240.

[117] Mai V, Greenwald B, Glenn Morris J, Raufman J-P, Stine OC.Effect of bowel preparation and colonoscopy on post-procedureintestinal microbiota composition. Gut 2006;55:1822e3.https://doi.org/10.1136/gut.2006.108266.

[118] Harrell L, Wang Y, Antonopoulos D, Young V, Lichtenstein L,Huang Y, et al. Standard colonic lavage alters the natural state ofmucosal-associated microbiota in the human colon. Plos One2012;7:e32545. https://doi.org/10.1371/journal.pone.0032545.

[119] Chin SM, Sauk J, Mahabamunuge J, Kaplan JL, Hohmann EL,Khalili H. Fecal microbiota transplantation for recurrent clos-tridium difficile infection in patients with inflammatory boweldisease: a single-center experience. Clin Gastroenterol Hepatol2017;15:597e9. https://doi.org/10.1016/j.cgh.2016.11.028.

[120] Wang S, Xu M, Wang W, Cao X, Piao M, Khan S, et al. Systematicreview: adverse events of fecal microbiota transplantation. PlosOne 2016;11:e0161174. https://doi.org/10.1371/journal.pone.0161174.

[121] Khoruts A, Rank KM, Newman KM, Viskocil K, Vaughn BP,Hamilton MJ, et al. Inflammatory bowel disease affects theoutcome of fecal microbiota transplantation for recurrentclostridium difficile infection. Clin Gastroenterol Hepatol2016;14:1433e8. https://doi.org/10.1016/j.cgh.2016.02.018.

[122] De Jager CPC, Wever PC, Gemen EFA, van Oijen MGH, vanGageldonk-Lafeber AB, Siersema PD, et al. Proton pump inhib-itor therapy predisposes to community-acquired streptococcuspneumoniae pneumonia. Aliment Pharmacol Ther2012;36:941e9. https://doi.org/10.1111/apt.12069.

[123] Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al.Proton pump inhibitors affect the gut microbiome. Gut2016;65:740e8. https://doi.org/10.1136/gutjnl-2015-310376.

[124] Mcdonald EG, Milligan J, Frenette C, Lee TC. Continuous protonpump inhibitor therapy and the associated risk of recurrentclostridium difficile infection. Jama Intern Med 2015;175:784.https://doi.org/10.1001/jamainternmed.2015.42.

[125] Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridiumdifficile-associated diarrhea and proton pump inhibitor therapy:a meta-analysis. Am J Gastroenterol 2012;107:1001e10.https://doi.org/10.1038/ajg.2012.179.

[126] Girotra M, Garg S, Anand R, Song Y, Dutta SK. Fecal microbiotatransplantation for recurrent clostridium difficile infection inthe elderly: long-term outcomes and microbiota changes. Dig DisSci 2016;61:3007e15. https://doi.org/10.1007/s10620-016-4229-8.

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,et al. Fecal microbiota transplant in patients with recurrentclostridium difficile infection. Dtsch Arztebl Int 2016;113:583e9.https://doi.org/10.3238/arztebl.2016.0583.

[128] Department of Health (UK). Management and decontamination offlexibleendoscopes (htm01-06) - gov.ukn.d. https://www.gov.uk/government/publications/management-and-decontamination-of-flexible-endoscopes [Accessed December 19 2017].

[129] British Society of Gastroenterology. Guidance on decontamina-tion of equipment for gastrointestinal endoscopy. 2017.edition n.d. https://www.bsg.org.uk/resource/guidance-on-decontamination-of-equipment-for-gastrointestinal-endoscopy-2017-edition.html. [last accessed 19 December 2017].

[130] Loveday HP, Wilson JA, Pratt RJ, Golsorkhi M, Tingle A, Bak A,et al. Epic3: national evidence-based guidelines for preventinghealthcare-associated infections in nhs hospitals in england.J Hosp Infect 2014;86:s1e70. https://doi.org/10.1016/s0195-6701(13)60012-2.

[131] Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota trans-plantation for clostridium difficile infection: systematic reviewand meta-analysis. Am J Gastroenterol 2013;108:500e8.https://doi.org/10.1038/ajg.2013.59.

[132] Allegretti Jr , Kao D, Sitko J, Fischer M, Kassam Z. Early anti-biotic use post-fecal microbiota transplantation increases therisk of treatment failure. Clin Infect Dis 2017;66:134e5. https://doi.org/10.1093/cid/cix684.

[133] Terveer EM, van Beurden YH, Goorhuis A, Seegers JFML,Bauer MP, van Nood E, et al. How to: establish and run a stoolbank. Clin Microbiol Infect 2017;23:924e30. https://doi.org/10.1016/j.cmi.2017.05.015.

[134] Quraishi MN, Widlak M, Bhala N, Moore D, Price M, Sharma N,et al. Systematic review with meta-analysis: the efficacy offaecal microbiota transplantation for the treatment of recurrentand refractory clostridium difficile infection. Aliment PharmacolTher 2017;46:479e93. https://doi.org/10.1111/apt.14201.

[135] Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota trans-plantation for the treatment of clostridium difficile infection: asystematic review. J Clin Gastroenterol 2014;48:693e702.https://doi.org/10.1097/mcg.0000000000000046.

[136] Drekonja D, Reich J, Gezahegn S, Greer N, Shaukat A,Macdonald R, et al. Fecal microbiota transplantation for clos-tridium difficile infection a systematic review. Ann Intern Med2015;162:630e8. https://doi.org/10.7326/m14-2693.

[137] Baxter M, Ahmad T, Colville A, Sheridan R. Fatal aspirationpneumonia as a complication of fecal microbiota transplant.Clin Infect Dis 2015;61:136e7. https://doi.org/10.1093/cid/civ247.

[138] Hecker MT, Obrenovich ME, Cadnum JL, Jencson AL, Jain AK,Ho E, et al. Fecal microbiota transplantation by freeze-driedoral capsules for recurrent clostridium difficile infection. OpenForum Infect Dis 2016;3:ofw091. https://doi.org/10.1093/ofid/ofw091.

[139] Ni J, Wu GD, Albenberg L, Tomov VT. Gut microbiota and ibd:causation or correlation? Nat Rev Gastroenterol Hepatol2017;14:573e84. https://doi.org/10.1038/nrgastro.2017.88.

[140] Rossen NG, Fuentes S, van Der Spek MJ, Tijssen JG,Hartman JHA, Duflou A, et al. Findings from a randomizedcontrolled trial of fecal transplantation for patients with ul-cerative colitis. Gastroenterology 2015;149. https://doi.org/10.1053/j.gastro.2015.03.045. 110e118.e4.

[141] Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M,Onischi C, et al. Fecal microbiota transplantation inducesremission in patients with active ulcerative colitis in a ran-domized controlled trial. Gastroenterology 2015;149. https://doi.org/10.1053/j.gastro.2015.04.001. 102e109.e6.

[142] Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van DenBogaerdeJ,SamuelD,etal.Multidonor intensive faecalmicrobiota

transplantation for activeulcerativecolitis: a randomisedplacebo-controlled trial. Lancet (London, England) 2017;389:1218e28.https://doi.org/10.1016/s0140-6736(17)30182-4.

[143] Costello SP, Waters O, Bryant RV, Katsikeros R, Makanyanga J,Schoeman M, et al. Short duration, low intensity, pooled fecalmicrobiota transplantation induces remission in patients withmild-moderately active ulcerative colitis: a randomisedcontrolled trial. Gastroenterology 2017;152:s198e9. https://doi.org/10.1016/s0016-5085(17)30969-1.

[144] Johnsen PH, Hilpusch F, Cavanagh JP, Leikanger IS, Kolstad C,Valle PC, et al. Faecal microbiota transplantation versus pla-cebo for moderate-to-severe irritable bowel syndrome: adouble-blind, randomised, placebo-controlled, parallel-group,single-centre trial. Lancet Gastroenterol Hepatol 2018;3:17e24.https://doi.org/10.1016/s2468-1253(17)30338-2.

[145] Tian H, Ge X, Nie Y, Yang L, Ding C, Mcfarland LV, et al. Fecalmicrobiota transplantation in patients with slow-transit con-stipation: a randomized, clinical trial. Plos One 2017;12,e0171308. https://doi.org/10.1371/journal.pone.0171308.

[146] Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, et al. Fecalmicrobiota transplant from a rational stool donor improves he-patic encephalopathy: a randomized clinical trial. Hepatology2017;66:1727e38. https://doi.org/10.1002/hep.29306.

[147] Vrieze A, van Nood E, Holleman F, Salojarvi J, Kootte RS,Bartelsman JFWM, et al. Transfer of intestinal microbiota fromlean donors increases insulin sensitivity in individuals withmetabolic syndrome. Gastroenterology 2012;143. https://doi.org/10.1053/j.gastro.2012.06.031. 913e916.e7.

[148] Kootte RS, Levin E, Salojarvi J, Smits LP, Hartstra AV,Udayappan SD, et al. Improvement of insulin sensitivity afterlean donor feces in metabolic syndrome is driven by baselineintestinal microbiota composition. Cell Metab 2017;26. https://doi.org/10.1016/j.cmet.2017.09.008. 611e619.e6.

[149] OpenBiome. Home d openbiome n.d. http://www.openbiome.org/home/[Accessed October 19 2017].

[150] Medicines and Healthcare Products Regulatory Agency.Apply for manufacturer or wholesaler of medicines licences -gov.uk n.d. https://www.gov.uk/guidance/apply-for-manufacturer-or-wholesaler-of-medicines-licences#apply-for-a-manufacturerimporter-licence [Accessed February 15 2018].

[151] Medicines and Healthcare Products Regulatory Agency. Supplyunlicensed medicinal products (specials) - gov.uk n.d. https://www.gov.uk/government/publications/supply-unlicensed-medicinal-products-specials [Accessed February 15 2018].

[152] Edelstein CA, Kassam Z, Daw J, Smith MB, Kelly CR. The regulationof fecal microbiota for transplantation: an international perspec-tiveforpolicyandpublichealth.ClinResRegulAff2015;32:99e107.https://doi.org/10.3109/10601333.2015.1046602.

[153] HTA. Human tissue authority guide to quality and safety assur-ance for human tissues and cells for patient treatment. 2010.https://www.hta.gov.uk/sites/default/files/annex_-_guide_to_quality_and_safety_assurance_for_tissues_and_cells_for_patient_treatment.pdf. [last accessed 9 October 2017].

[154] Medicines and Healthcare Products Regulatory Agency. Rulesand guidance for pharmaceutical manufacturers and distribu-tors 2017 n.d. https://www.pharmpress.com/product.asp?productid¼mc_orange&affiliateid¼ [Accessed October 9 2017].

[155] Kelly CR, Kim AM, Laine L, Wu GD. The aga’s fecal microbiotatransplantation national registry: an important step towardunderstanding risks and benefits of microbiota therapeutics.Gastroenterology 2017;152:681e4. https://doi.org/10.1053/j.gastro.2017.01.028.

[156] Vehreschild M. MicroTrans - A multicenter registry of fecalmicrobiota transplantation (MicroTrans) n.d. https://clinicaltrials.gov/ct2/show/NCT02681068 [Accessed October 92017].