2.2.1.1. Prior to FMT. Patient selection

2.2.1.1.1. Recurrent CDI

We recommend that FMT should be offered to patients with recurrent CDI who have had at least two recurrences, or those who have had one recurrence and have risk factors for further episodes, including severe and severe complicated CDI (Grades of Recommendation Assessment, Development and Evaluation (GRADE) of evidence: high; strength of recommendation: strong).

2.2.1.1.2. Refractory CDI

We recommend that FMT should be considered in cases of refractory CDI (GRADE of evidence: moderate; strength of recommendation: strong).

2.2.1.1.3. FMT as initial therapy for CDI

We recommend that FMT should not be administered as initial treatment for CDI (GRADE of evidence: low; strength of recommendation: strong).

2.2.1.1.4. Antimicrobial/antitoxin therapy prior to considering FMT for patients with CDI

1. We recommend that FMT for recurrent CDI should only be considered after recurrence of symptoms following resolution of an episode of CDI that was treated with appropriate antimicrobials for at least 10 days (GRADE of evidence: low; strength of recommendation: strong).

2. We recommend consideration of treatment with extended/pulsed vancomycin and/or fidaxomicin before considering FMT as treatment for recurrent CDI (GRADE of evidence: low; strength of recommendation: strong).

3. For those with severe or complicated CDI, which appears to be associated with reduced cure rates, we recommend that consideration should be given to offering patients treatment with medications which are associated with a reduced risk of recurrence (eg, fidaxomicin and bezlotoxumab), before offering FMT (GRADE of evidence: low; strength of recommendation: strong).

2.2.1.2. Post-FMT follow-up, outcomes and adverse events

2.2.1.2.1. Management of FMT failure

We recommend that FMT should be offered after initial FMT failure (GRADE of evidence: high; strength of recommendation: strong).

2.2.1.2.2. General approach to follow-up post-FMT

We recommend that all FMT recipients should routinely receive follow-up. Clinicians should follow-up FMT recipients for long enough to fully establish efficacy/adverse events, and for at least 8 weeks in total (GRADE of evidence: low; strength of recommendation: strong).

2.2.1.2.3. Management of the FMT recipient

1. We recommend that immediate management after endoscopic administration of FMT should be as per endoscopy unit protocol (GRADE of evidence: very low: strength of recommendation: strong).

2. We recommend that patients should be warned about the short term adverse events, in particular the possibility of self-limiting gastrointestinal (GI) symptoms. They should be advised that serious adverse events are rare (GRADE of evidence: very low; strength of recommendation: strong).

3. After enteral tube administration, we recommend that patients may have the tube removed and oral water given from 30 min post-administration (GRADE of evidence: very low; strength of recommendation: strong).

2.2.1.2.4. Definition of cure post-FMT for CDI

We recommend that 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 case basis (GRADE of evidence: very low; strength of recommendation: strong).

2.2.1.2.5. Definition of treatment failure post-FMT for CDI

We recommend that treatment failure/recurrence should be defined on a case by case basis. Routine testing for C. difficile toxin after FMT is not recommended, but it is appropriate to consider in the case of persistent CDI symptoms/suspected relapse (GRADE of evidence: low; strength of recommendation: strong).

2.2.2.1. General approach to comorbidities and FMT

1. We recommend that FMT should be avoided in those with anaphylactic food allergy (GRADE of evidence: very low; strength of recommendation: strong).

2. We suggest that FMT should be offered with caution to patients with CDI and decompensated chronic liver disease (GRADE of evidence: very low; strength of recommendation: weak).

2.2.2.2. Immunosuppression and FMT

1. We recommend that FMT should be offered with caution to immunosuppressed patients, in whom FMT appears efficacious without significant additional adverse effects (GRADE of evidence: moderate; strength of recommendation: strong).

2. We recommend that immunosuppressed FMT recipients at risk of severe infection if exposed to Epstein–Barr virus  (EBV)  or cytomegalovirus (CMV) should only receive FMT from donors negative for EBV and CMV (GRADE of evidence: very low; strength of recommendation: strong).

2.2.2.3. Other comorbidities and FMT

1. We recommend that FMT should be offered to those with recurrent CDI and inflammatory bowel disease (IBD), but patients should be counselled about a small but recognised risk of exacerbation of IBD (GRADE of evidence: moderate; strength of recommendation: strong).

2. We recommend that FMT should be considered for appropriate patients with recurrent CDI regardless of other comorbidities (GRADE of evidence: moderate; strength of recommendation: strong).

2.2.3.1. General approach to donor selection

We recommend that related or unrelated donors should both be considered acceptable. However, where possible, FMT is best sourced from a centralised stool bank, from a healthy unrelated donor (GRADE of evidence: low; strength of recommendation: strong).

2.2.3.2. Age and body mass index restrictions for potential donors

We suggest that people should only be considered as potential FMT donors if they are ≥18 and≤60 years old, and have a body mass index (BMI) of ≥18 and ≤30 kg/m² (GRADE of evidence: low; strength of recommendation: weak).

2.2.3.3. General approach to the donor screening assessment

It is mandatory to screen potential donors by questionnaire and personal interview, to establish risk factors for transmissible diseases and factors influencing the gut microbiota (box 1) (GRADE of evidence: low; strength of recommendation: strong).

2.2.3.4. Laboratory screening of potential donors

Blood and stool screening of donors is mandatory (boxes 2 and 3) (GRADE of evidence: low; strength of recommendation: strong).

2.2.3.5. Repeat donor checks, and donation pathway

1. In centres using frozen FMT, before FMT may be used clinically, we recommend that donors should have successfully completed a donor health questionnaire and laboratory screening assays both before and after the period of stool donation. This is the preferred means of donor screening (GRADE of evidence: low; strength of recommendation: strong).

2. In centres using fresh FMT, we recommend that a repeat health questionnaire should be assessed at the time of each stool donation. To ensure ongoing suitability for inclusion as a donor, the donor health questionnaire and laboratory screening should be repeated regularly (GRADE of evidence: low; strength of recommendation: strong).

2.2.4.1. General principles of FMT preparation

1. We recommend that stool collection should follow a standard protocol (GRADE  of evidence: low; strength of recommendation: strong).

2. We recommend that donor stool should be processed within 6 hours of defaecation (GRADE  of evidence: low; strength of recommendation: strong).

3. We recommend that both aerobically and anaerobically prepared FMT treatments should be considered suitable when preparing FMT for the treatment of recurrent CDI (GRADE  of evidence: moderate; strength of recommendation: strong).

4. We recommend that sterile 0.9% saline should be considered as an appropriate diluent for FMT production, and cryoprotectant such as glycerol should be added for frozen FMT (GRADE  of evidence: moderate: strength of recommendation: strong).

5. We recommend using ≥50 g of stool in each FMT preparation (GRADE  of evidence: moderate: strength of recommendation: strong).

6. We suggest that stool should be mixed 1:5 with diluent to make the initial faecal emulsion (GRADE  of evidence: low; strength of recommendation: weak).

7. We suggest that homogenisation and filtration of FMT should be undertaken in a closed disposable system (GRADE  of evidence: low; strength of recommendation: weak).

2.2.4.2. Fresh versus frozen FMT

We recommend that the use of banked frozen FMT material should be considered preferable to fresh preparations for CDI (GRADE  of evidence: high; strength of recommendation: strong).

2.2.4.3. Use of frozen FMT

1. We recommend that FMT material stored frozen at −80°C should be regarded as having a maximum shelf life of 6 months from preparation (GRADE  of evidence: low; strength of recommendation: strong).

2. We suggest consideration of thawing frozen FMT at ambient temperature, and using within 6 hours of thawing (GRADE  of evidence: low; strength of recommendation: weak).

3. We suggest not thawing FMT in warm water baths, due to the risks of cross contamination with Pseudomonas (and other contaminants) and reduced bacterial viability (GRADE  of evidence: very low; strength of recommendation: weak).

2.2.5.1. Use of specific medications in the period around FMT administration

2.2.5.1.1. General principles of FMT administration

1. We recommended that bowel lavage should be administered prior to FMT via the lower GI route, and that bowel lavage should be considered prior to FMT via the upper GI route; polyethylene glycol preparation is preferred (GRADE of evidence: low; strength of recommendation: strong).

2. For upper GI FMT administration, we suggest that a proton pump inhibitor should be considered, for example, the evening before and morning of delivery (GRADE of evidence: low; strength of recommendation: weak).

3. We suggest that a single dose of loperamide (or other antimotility drugs) should be considered following lower GI FMT delivery (GRADE of evidence: low; strength of recommendation: weak).

4. We suggest that prokinetics (such as metoclopramide) should be considered prior to FMT via the upper GI route (GRADE of evidence: low; strength of recommendation: weak).

5. We recommend that best practice for prevention of further transmission of CDI should be applied throughout when administering FMT to patients with CDI (nursing with enteric precautions, sporicidal treatment of endoscope, etc) (GRADE of evidence: high; strength of recommendation: strong).

2.2.5.1.2. Additional antibiotics pre-FMT

We recommend the administration of further antimicrobial treatment for CDI for at least 72 hours prior to FMT (GRADE of evidence: low; strength of recommendation: strong).

2.2.5.1.3. Washout period between antibiotic use and FMT

1. To minimise any deleterious effect of antimicrobials on the FMT material, we recommend that there should be a minimum washout period of 24 hours between the last dose of antibiotic and treatment with FMT (GRADE of evidence: low; strength of recommendation: strong).

2. We suggest considering consultation with infectious disease specialists or medical microbiologists for advice whenever FMT recipients also have an indication for long term antibiotics, or have an indication for non-CDI antibiotics within 8 weeks of FMT (GRADE of evidence: very low; strength of recommendation: weak).

2.2.5.2. Route of FMT delivery

2.2.5.2.1. Upper GI tract administration of FMT

1. We recommend that upper GI administration of FMT as treatment for recurrent or refractory CDI should be used where clinically appropriate (GRADE of evidence: high; strength of recommendation: strong).

2. Where upper GI administration is considered most appropriate, we recommend that FMT administration should be via nasogastric, nasoduodenal or nasojejunal tube, or alternatively via upper GI endoscopy. Administration via a permanent feeding tube is also appropriate (GRADE of evidence: high; strength of recommendation: strong).

3. We recommend that no more than 100 mL of FMT is administered to the upper GI tract (GRADE of evidence: low; strength of recommendation: strong).

4. We recommend that upper GI administration of FMT should be used with caution in those at risk of regurgitation and/or those with swallowing disorders (GRADE of evidence: low; strength of recommendation: strong).

2.2.5.2.2. Lower GI tract administration of FMT

1. We recommend that colonoscopic administration of FMT as treatment for recurrent or refractory CDI should be used where appropriate (GRADE of evidence: high; strength of recommendation: strong).

2. Where colonoscopic administration is used, we suggest considering preferential delivery to the caecum or terminal ileum, as this appears to give the highest efficacy rate (GRADE of evidence: low; strength of recommendation: weak).

3. We recommend that FMT via enema should be used as a lower GI option when delivery using colonoscopy or flexible sigmoidoscopy is not possible (GRADE of evidence: high; strength of recommendation: strong).

2.2.5.2.3. Capsulised FMT

Capsulised FMT holds promise as a treatment option for recurrent CDI and we recommend that this should be offered to patients as a potential treatment modality where available. Capsule preparations should follow a standard protocol. Further evidence regarding optimal dosing and formulation is required (GRADE of evidence: high; strength of recommendation: strong).

2.2.7.1. General considerations

1. The development of FMT centres should be encouraged (GRADE of evidence: very low; strength of recommendation: strong).

2. We suggest that FMT centres should work to raise awareness about FMT as a treatment option among clinicians caring for patients with CDI, and provide training to relevant healthcare professionals on the practicalities of delivering an FMT service (GRADE of evidence: very low; strength of recommendation: weak).

2.2.7.2. Legal aspects and clinical governance

In the UK, FMT must be manufactured in accordance with Medicines and Healthcare products Regulatory Agency (MHRA) guidance for human medicines regulation. When FMT is supplied on a named patient basis, within a single organisation, a pharmacy exemption may be used, subject to ensuring proper governance and traceability. All centres that are processing and distributing FMT should seek guidance from the MHRA and, where necessary, obtain appropriate licenses prior to establishing an FMT service. This is a legal requirement. In countries other than the UK, FMT should only be manufactured following appropriate approval from the national authority of that country (GRADE of evidence: very low; strength of recommendation: strong).

2.2.7.3. Multidisciplinary teams

We recommend that a multidisciplinary team should be formed to deliver FMT services (GRADE of evidence: very low; strength of recommendation: strong).

2.2.7.4. Infrastructure

We recommend utilisation of suitable laboratory facilities and infrastructure for FMT production (GRADE of evidence: very low; strength of recommendation: strong).

2.2.7.5. FMT manufacturing

We recommend ensuring the traceability of supply (GRADE of evidence: very low; strength of recommendation: strong).

2.2.7.6. FMT production quality control

We recommend monitoring, notification and investigation of all adverse events and reactions related to FMT (GRADE of evidence: very low; strength of recommendation: strong).

2.2.7.7. Donor screening governance

We recommend ensuring the clinical governance of donor screening (GRADE of evidence: very low; strength of recommendation: strong).

5.1.1.1. Recurrent CDI 

As already described, there is widespread consensus that FMT is an efficacious treatment for recurrent CDI. In defining recurrent CDI, some studies have relied on a minimum threshold of return of clinical symptoms (eg, at least three unformed bowel movements within 24 hours, for at least 2 consecutive days)12 18 following previous successful CDI treatment; most studies have also included a requirement for a positive microbiological test.12 14 18 35–45 Other studies explicitly state that a positive test was not required.46 Recommendations for CDI testing are beyond the scope of this guideline, and there are already well established evidence-based guidelines.47 These recommend testing with either a nucleic acid amplification test or glutamate dehydrogenase assay, followed by detection of free toxin (either by toxin A/B enzyme immunoassay or cytotoxin neutralisation assay), which allows differentiation of patients with active disease as well as those who are likely colonised.47 However, the working group discussed the importance of the accurate diagnosis of true recurrent CDI prior to consideration of FMT; in particular, they noted a study which observed that of 117 patients with presumed recurrent CDI referred for work-up for FMT, 25% (n=29/117) were determined to have a non-CDI diagnosis, with IBS (n=18) and IBD (n=3) being the most common alternative diagnoses, and younger patients more likely to be misdiagnosed.48

All of the reviewed studies have included patients with recurrent CDI but some studies offered FMT to patients at the first recurrence (second episode),12 15 16 18 35 37 42 43 46 49 whereas others offered FMT after the second recurrence (third episode).13 14 39 41 44 45 50 51 Some protocols offered FMT after three or more recurrences,52 while others did not define the point at which it was administered.40 53

The severity of infection has been used as a parameter to decide at which stage FMT is offered. Youngster et al offered FMT to patients with at least three episodes of mild to moderate CDI, or at least two episodes of severe CDI resulting in hospitalisation and associated with significant morbidity.17 Another study selected patients for FMT using four categories of severity, which also accounted for prior anti-CDI therapy and requirement for hospitalisation.54

None of the studies directly compared the efficacy of FMT according to the stage at which it was offered (ie, first recurrence vs ≥2 recurrences). A small number of studies55–57 included patients with severe CDI (defined as hypoalbuminaemia with increased peripheral white cell count and/or abdominal tenderness) or complicated CDI (defined as admission to intensive care, altered mental status, hypotension, fever, ileus, white blood cell count >30×10⁹/l, lactate >2.2 mmol/L or evidence of end organ damage). A single study described an apparent lower rate of treatment success when FMT was used to treat patients with recurrent CDI with disease caused by ribotype 027,43 but this is the case for all anti-CDI treatment modalities for this ribotype in comparison with others. The working group agreed that there was insufficient evidence to suggest that C. difficile ribotype should influence whether or not FMT is offered.

A lower primary cure rate was reported for complicated CDI (66%) compared with recurrent CDI (82%) and severe CDI (91%) in one study55; in a case series of 17 patients who all had severe and/or complicated CDI, a primary cure rate of 88% was described.57 A cohort of 328 patients was analysed to determine which factors were associated with failure of FMT.58 Higher early (1 month) failure rates were found in patients with severe (72%, n=19/25) or severe complicated (52.9%, n=9/17) CDI than for recurrent CDI (11.9%, n=34/286). This study also identified that patients who were treated with FMT as an inpatient were nearly four times more likely to fail as those who had FMT as an outpatient; however, the working group noted that the authors of this study themselves identified that inpatient status is likely a proxy of severity of CDI and/or comorbidities. A further similar study, including 64 patients treated with FMT as treatment for recurrent CDI, also identified severe CDI as the strongest independent risk factor for FMT failure on multivariate analysis.59

The working group discussed their experience of treating patients with CDI whose disease fitted an intermediate pattern to the typical descriptions given of recurrent or refractory CDI, for example, patients with CDI who have some (but incomplete) symptomatic improvement with anti-CDI antibiotics and worsening of disease when these are stopped. The experience of the working group was that such patients experienced excellent responses to FMT, and that these patients should be considered for FMT.

As FMT is currently an unlicensed medicine with poorly-studied long term sequelae, the working group considered that it should generally be reserved for patients who have had three or more episodes of infection. There are no studies directly comparing its effectiveness with some of the newer agents, such as fidaxomicin or bezlotoxumab, hence this recommendation is made on the basis of safety. However, the working group agreed that it may be reasonable in certain patient groups with ongoing risk factors for further recurrence to offer FMT after the second episode.

Recommendation

We recommend that FMT should be offered to patients with recurrent CDI who have had at least two recurrences, or those who have had one recurrence and have risk factors for further episodes, including severe and severe complicated CDI (GRADE of evidence: high; strength of recommendation: strong).

5.1.1.2. Refractory CDI

Two randomised trials allowed the recruitment of patients with refractory CDI. The first defined this as at least 3 weeks of ongoing severe symptoms despite standard antimicrobial therapy for CDI.17 The second required persistent or worsening diarrhoea and one of the following: ongoing abdominal pain, fever >38°C or white blood cell count >15×10⁹/l despite oral vancomycin at a dose of 500 mg four times daily for at least 5 days.16 Both studies included only small numbers of patients with refractory CDI (n=4/20 (20%) and n=15/219 (6.8%), respectively). There did not appear to be any significant difference in primary outcome measure (clinical cure) in patients with recurrent or refractory CDI, although neither study was designed to assess this difference. There are also a number of case series in which FMT was given to patients with refractory CDI; however, outcome measures were not reported for these groups individually in these studies.37 38 54 60

Overall, the working group concluded that 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, eg, ‘salvage therapy’). Consequently, the quality of evidence for the utility of FMT in refractory cases of CDI is lower than for recurrent CDI. Standardisation of definitions will allow more robust comparison between patient cohorts.

Recommendation

We recommend that FMT should be considered in cases of refractory CDI (GRADE of evidence: moderate; strength of recommendation: strong).

5.1.1.3. FMT as initial therapy for CDI

Experience of the use of FMT as initial therapy for CDI is very limited. In a case series of patients with CDI with ribotype 027, use of anti-CDI antibiotics together with nasogastric FMT within a week of diagnosis during an initial episode of CDI was associated with reduced mortality compared with using FMT only after the failure of three courses of antibiotics (mortality of 18.75% (n=3/16 patients) vs 64.4% (n=29/45 patients)).61 However, 37.5% (n=6/16) of the patients treated with FMT within a week of CDI diagnosis required further antibiotics and a second FMT within 1 month of the first FMT because of relapse.61 In a small pilot randomised trial, patients were randomised to either vancomycin or multi-donor FMT (administered either via upper or lower GI routes) as initial therapy for CDI; CDI resolution occurred in 88.9% (n=8/9) of patients with vancomycin, compared with 57.1% of patients (n=4/7) with one FMT, and 71.4% of patients (n=5/7) after two FMTs.62 Given the small size of these studies and equivocal results, the working group concluded that the reviewed studies did not support FMT as initial therapy for CDI.

Recommendation

We recommend that FMT should not be administered as initial treatment for CDI (GRADE of evidence: low; strength of recommendation: strong).

5.1.1.4. Antimicrobial/antitoxin therapy prior to considering FMT for patients with CDI

There are now at least two licensed agents (fidaxomicin and bezlotoxumab) which have been shown to significantly reduce the risk of recurrence compared with vancomycin.63 64 There is also some evidence that pulsed/tapered dosing of vancomycin and fidaxomicin (including pulsed fidaxomicin65) results in fewer recurrences than with standard dosing of these agents66 67 (although this finding has not been replicated in all studies68). Pre-planned subgroup analysis of patients with severe CDI in a randomised trial demonstrated a significantly lower recurrence rate when treated with fidaxomicin (13.0%, n=12/92) than when treated with vancomycin (26.6%, n=29/209)63; this finding was replicated in another RCT, with 8.3% (n=4/48) and 32.6% (n=14/43) experiencing a recurrence, respectively.69 In a further randomised trial, bezlotoxumab (together with standard of care antibiotics) was shown to reduce recurrence of severe CDI compared with standard of care antibiotics alone (10.9% (n=6/55) vs 20% (n=13/65), respectively).64

As discussed above, the working group noted that there are no 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, consideration should be given to using antimicrobial/antitoxin therapy associated with reduced CDI recurrence prior to considering the use of FMT.

Several studies specify that patients should be treated with anti-C. difficile antibiotics for a minimum period of 10 days before diagnosing recurrent CDI and offering FMT.12 15 16 18

Recommendations

1. We recommend that FMT for recurrent CDI should only be considered after recurrence of symptoms following resolution of an episode of CDI that was treated with appropriate antimicrobials for at least 10 days (GRADE of evidence: low; strength of recommendation: strong).

2. We recommend consideration of treatment with extended/pulsed vancomycin and/or fidaxomicin before considering FMT as treatment for recurrent CDI (GRADE of evidence: low; strength of recommendation: strong).

3. For those with severe or complicated CDI, which appears to be associated with reduced cure rates, we recommend that consideration should be given to offering patients treatment with medications which are associated with reduced risk of recurrence (eg, fidaxomicin and bezlotoxumab), before offering FMT (GRADE of evidence: low; strength of recommendation: strong).

5.1.2.1. Management of FMT failure

Where patients were deemed not to have responded to an initial FMT, many studies have offered repeat FMT and success rates have been excellent, even in patients with a modest response to a first FMT.14 15 17 18 35 43 46 51 54 70 71 The success of a second FMT appears to be high whether treatment failure represents non-response to the first FMT, or a late failure (ie, further relapse of CDI after an initial response); however, these terms have been defined variably between different studies (also see Section 5.1.2.5). Second FMTs have been offered as soon as 24–72 hours after an initial FMT for presumed non-response.37 72 73 For FMT failure in patients with pseudomembranous colitis, repeat FMT every 3 days until resolution of pseudomembranes has been a successful approach.18 Good outcomes in pseudomembranous disease have also been achieved through a protocol that routinely restarted 5 days of vancomycin if FMT failed, before offering another FMT.73 Other studies have demonstrated potential success in treating initial FMT failure with further antibiotics, including repeat FMT with vancomycin between procedures,42 or anti-CDI antibiotics alone.35 42 43 45 51 70 71 Patients unresponsive to two FMTs have been offered further FMT or antibiotic therapy,16 or even administration of intravenous immunoglobulin.35 While the working group collectively agreed that there was strong evidence to recommend repeat FMT after initial FMT failure, they were not able to recommend a specific protocol for administering repeat FMT and/or maximum number of FMTs, given the wide heterogeneity of approach described within the reviewed literature.

Recommendation

We recommend that FMT should be offered after initial FMT failure (GRADE of evidence: high; strength of recommendation: strong).

5.1.2.2. General approach to follow-up post-FMT

Follow-up post-FMT (in terms of duration, modality and regimen for follow-up) varies considerably between studies, and is largely dependent on study design. Follow-up regimens vary not only between studies but within them too, reflecting the retrospective nature of many early FMT studies in CDI, where follow-up mostly reflected pragmatic routine clinical care.

Modalities of follow-up have included outpatient review,14 43 58 71 74–76 telephone interview17 39 43 46 58 71 74 and case note/database review.35 39 40 42 43 45 46 49 51 54 70 71 74 Follow-up duration has varied from 60 days45 to 8 years,36 with very different durations used in each study. Once again, however, this variability in follow-up largely reflects the retrospective analysis of case series rather than being justified by any specific methodology. The working group decided by consensus that at least 8 weeks of follow-up was appropriate post-FMT to fully assess efficacy and potential adverse events; this figure was also influenced by discussions regarding the time point after FMT at which a decision could be made regarding cure/remission of CDI (see Section 5.1.2.4).

Recommendation

We recommend that all FMT recipients should routinely receive follow-up. Clinicians should follow-up FMT recipients for long enough to fully establish efficacy/adverse events, and for at least 8 weeks in total (GRADE of evidence: low; strength of recommendation: strong).

5.1.2.3. Management of the FMT recipient

Procedural adverse events during administration of FMT have predominantly occurred with colonoscopic administration of FMT. These have included mild nausea and vomiting attributed to sedation for the colonoscopy, minor mucosal tears during colonoscopy49 60 and microperforation following biopsy of an area of presumed ischaemic small bowel injury in a patient with chronically dilated small bowel (which resolved with conservative management46). One death occurred due to witnessed aspiration at the time of colonoscopy.60 Faecal regurgitation and vomiting with temporal association to upper GI FMT administration has also been described (discussed further in Section 5.5.2.2).77

The predominant short term adverse events post-FMT for CDI are mild: self-limiting GI symptoms have been the most frequently reported adverse events. These may be related to the route of administration and include belching,15 nausea,15 16 49 60 abdominal cramps/discomfort/bloating/ pain15 18 49 60 72 and diarrhoea.15 16 18 60 One patient with a history of autonomic dysfunction experienced dizziness with diarrhoea after FMT.15 These symptoms are typically short lived, resolving in hours to days.15 16 18 49 72 Minor subsequent adverse events have included a range of GI side effects, including self-limiting abdominal discomfort,14 17 57 76 nausea,14 49 70 flatulence,14 16 17 41 42 49 57 self-limiting irregular bowel movements,41 C. difficile toxin negative diarrhoea,52 55 constipation14 15 42 55 70 and constitutional symptoms/temperature disturbance.14 17

As such, immediately post-endoscopic administration of FMT, most FMT centres typically manage patients using standard protocols for an endoscopic procedure,41 49 without any specific adaptations (apart from to reiterate advice about the possibility of self-limiting GI side effects, and the use of departmental infection control protocols). There is often a relatively short period of post-procedural observation.15 18 Most studies allow patients to leave the administration site after the period of observation, although overnight observation was the protocol used for a cohort of very elderly patients with multiple comorbidities.51 Where enteral tube administration is used, post-procedure management has ranged between removal of the tube after 30 min (following nasoenteral administration of 500 mL of FMT15) to prompt post-procedure removal and oral water administration (after nasogastric administration of 90 mL of FMT72) with no direct adverse outcomes in either case. The working group felt that removal of the tube at 30 min, with administration of water at this point, was a pragmatic approach.

The definition of post-FMT serious adverse events has varied between studies, but has included significant morbidity necessitating hospital admission and death in the follow-up period. Many of these events are described as not directly caused by the FMT, including the scenario of post-FMT severe CDI recurrences72 and probable or certain CDI-related deaths16 60 70 occurring in the context of FMT failure, or deaths related to patient comorbidities.17 55 One patient was admitted to hospital with self-limiting abdominal pain post-FMT,60 and four patients with flares of IBD.60 Three patients underwent colectomy during the post-FMT follow-up period, with all related to ulcerative colitis and not believed to be due to CDI.60 Other reported serious adverse events include recurrent urinary tract infection,15 fever during haemodialysis15 and upper GI haemorrhage after nasogastric FMT (in a patient taking non-steroidal anti-inflammatory drugs51), none of which was thought to be strongly linked to FMT. There have also been a number of new onset autoimmune, inflammatory and metabolic conditions described post-FMT, although these have been described from single centres only, with these findings not replicated elsewhere. Such conditions include microscopic colitis, Sjögren’s syndrome, follicular lymphoma, peripheral neuropathy, immune thrombocytopenia and rheumatoid arthritis.53 55

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-up post-FMT to assess outcome and possible adverse events is essential.

The use of questionnaires to compare symptoms pre- and post-FMT is common. Specifically, data collected have included clinical response to symptom severity,55 stool frequency,15 17 46 55 57 72 stool consistency,14 15 72 abdominal pain or tenderness,55 57 rating of GI symptoms,72 general well being,55 72 days to improvement post-FMT,57 weight change,72 functional status55 and changes in medication/use of antibiotics.57 72 Additionally, certain patients have been given specific advice post-FMT to contact their clinical team if there is recurrence of diarrhoea or symptoms.14 35 41 43 Where patients underwent outpatient clinical evaluation, this was generally undertaken relatively early post-FMT.39 52 76 In one study, patients were additionally given instructions for cleaning and disinfection at home, with the aim of reducing the possibility of C. difficile reinfection,43 and counselling on the risk of recurrent CDI with future antibiotic courses.76

Recommendations

1. We recommend that immediate management after endoscopic administration of FMT should be as per the endoscopy unit protocol (GRADE of evidence: very low: strength of recommendation: strong).

2. We recommend that patients should be warned about short term adverse events, in particular the possibility of self-limiting GI symptoms. They should be advised that serious adverse events are rare (GRADE of evidence: very low; strength of recommendation: strong).

3. After enteral tube administration, we recommend that patients may have the tube removed and oral water given from 30 min post-administration (GRADE of evidence: very low; strength of recommendation: strong).

5.1.2.4. Definition of cure post-FMT for CDI

It is recognised that symptoms of CDI resolve relatively promptly after successful FMT, although this has been variably described (within hours in some studies,52 at an average of 4–5 days in others57 71). Treatment success post-FMT for CDI has no uniformly agreed definition, with the time point at which cure/remission is defined on clinical grounds varying between 3 and 5 days36 up to 6 months.42 A consensus document from the USA recommends ‘resolution of symptoms as a primary end point; absence within 8 weeks of FMT as a secondary end point’.78 The working group recommended that this definition should be made on a case by case basis; however, they agreed that an assessment for cure/remission of CDI within 8 weeks post-FMT was reasonable in most cases, and therefore that this was also a reasonable minimum length of time to undertake follow-up post-FMT (see Section 5.1.2.2).

Recommendation

We recommend that 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 case basis (GRADE of evidence: very low; strength of recommendation: strong).

5.1.2.5. Definition of treatment failure post-FMT for CDI

There is no uniformly agreed definition of treatment failure/recurrence post-FMT for CDI, with varied definitions used in studies. The use of C. difficile toxin as a marker of treatment success or failure is variable, with some studies opting not to test for C. difficile toxin unless symptoms consistent with CDI recurred.49 52–54 60 72 74 Some studies have routinely performed C. difficile toxin testing without specifying any action taken after a positive result,14 15 18 36 39 41 while others have tested for C. difficile PCR but relied on clinical criteria (even if PCR was positive) post-FMT for evaluating FMT efficacy.14 A recent prospective study from the USA identified that only 3% (3/129) of patients who were asymptomatic at 4 weeks post-FMT for recurrent CDI had positive C. difficile PCR, again emphasising that symptoms rather than laboratory assays are more useful contributors to establishing FMT success.79

Recommendation

We recommend that treatment failure/recurrence should be defined on a case by case basis. Routine testing for C. difficile toxin after FMT is not recommended, but it is appropriate to consider in the case of persistent CDI symptoms/suspected relapse (GRADE of evidence: low; strength of recommendation: strong).

5.5.1.1. General principles of FMT administration

Bowel purgatives have been proposed pre-FMT as a means of removing residual antibiotics that may affect engraftment of transplanted microorganisms, and as a means of removing any residual C. difficile toxin, spores and vegetative cells.110–114 Furthermore, bowel purgatives pre-colonoscopic FMT delivery facilitate safe endoscopy. Various bowel purgatives have been used in colonoscopic FMT studies, including polyethylene glycol (often 4 L),14 17 35 41 43 46 54–56 100 115–117 MoviPrep35 41 and macrogol.13 15 18 59 In those studies that used an upper GI route for FMT, polyethylene glycol54 55 84 and Klean-Prep15 61 were used. FMT without bowel preparation has also been used as treatment for recurrent CDI without any apparent reduction in efficacy, including in randomised studies.16

The rationale for the use of proton pump inhibitors (PPIs) prior to upper GI FMT is to minimise acidity which may impair engraftment of transplanted microorganisms; however, PPIs have been shown to alter the gut microbiota,118 119 and have also been associated with primary and recurrent CDI.120 121 Some studies advocate the use of PPIs prior to receiving FMT via the upper GI route,37 39 45 84 85 122 123 but there appears to be comparable efficacy data in studies where it has not been used. Certain studies have also given recipients PPIs prior to receiving colonoscopic FMT.17 87

The use of prokinetics (such as metoclopramide) has been described prior to FMT delivery via the upper GI tract route, but only in a very small number of studies.85 Given the potential risk of regurgitation/aspiration associated with upper GI administration of FMT, the working group felt that its use should be considered where appropriate.

A single dose/short course of loperamide has been used following FMT (predominantly for lower GI administration) in an attempt to prolong the exposure of the FMT to the mucosa, and to aid retention of the FMT within the GI tract.13 46 49 55 84 123 One study utilised diphenoxylate with atropine54 instead. However, no studies have compared FMT with and without antimotility drugs.

The working group also discussed infection control aspects as they apply to FMT administration. Specifically, they agreed that recipients should ideally be cared for in a single room with en suite bathroom facilities and, where appropriate, be placed at the end of an endoscopy list, to facilitate enhanced environmental decontamination and prevention of transmission of C. difficile spores. Protocols for decontamination of endoscopes should follow national guidance,124 125 using a sporicidal agent. Best practice for prevention of transmission of healthcare associated infections, as described in national guidelines,126 should also be applied throughout.

Recommendations

1. We recommend that bowel lavage should be administered prior to FMT via the lower GI route, and bowel lavage should be considered prior to FMT via the upper GI route; polyethylene glycol preparation is preferred (GRADE of evidence: low; strength of recommendation: strong).

2. For upper GI FMT administration, we suggest that a PPI should be considered, for example, the evening before and morning of delivery (GRADE of evidence: low; strength of recommendation: weak).

3. We suggest that a single dose of loperamide (or other antimotility drugs) should be considered following lower GI FMT delivery (GRADE of evidence: low; strength of recommendation: weak).

4. We suggest that prokinetics (such as metoclopramide) should be considered prior to FMT via the upper GI route (GRADE of evidence: low; strength of recommendation: weak).

5. We recommend that best practice for prevention of further transmission of CDI should be applied throughout when administering FMT to patients with CDI (nursing with enteric precautions, sporicidal treatment of endoscope, etc) (GRADE of evidence: high; strength of recommendation: strong).

5.5.1.2. Additional antibiotics pre-FMT

Many studies have given further courses of conventional antimicrobial C. difficile treatment prior to FMT. Regimens have included vancomycin alone,12 14 18 35 39 55 59 86 117 metronidazole or vancomycin,40 41 43 122 or alternatively vancomycin, fidaxomicin or metronidazole,56 with one study using a range of regimens which included rifaximin.123 The length of treatment was also variable, ranging from 24 hours54 up to 4 days prior to receiving FMT39 45; however, comparative studies have not been undertaken.

Recommendation

We recommend the administration of further antimicrobial treatment for CDI for at least 72 hours prior to FMT (GRADE of evidence: low; strength of recommendation: strong).

5.5.1.3. Washout period between antibiotic use and FMT

Nearly all studies specified a washout period after completing anti-CDI antibiotics and before administration of FMT. However, this time period appeared to be arbitrarily selected and varied from as little as 4 hours46 or 12 hours51, up to 72 hours.36 The majority of studies specified either 24 hours15 37 39 40 45 54 127 or 48 hours41 42 49 60, however some allowed a range from 1 to 3 days.16 44 52 53 55 One study appeared to allow co-administration of vancomycin with bowel preparation, without a washout period.18

The working group discussed the challenging scenario of providing FMT to patients with recurrent CDI, but who also had a strong indication for long term non-anti-CDI antibiotics (eg, splenectomy, osteomyelitis or infective endocarditis), or patients who develop an indication for antibiotics for a reason other than CDI shortly after receiving FMT. The concern in this instance is that the use of antibiotics may limit engraftment of microbial communities derived from the FMT, and therefore reduce its effectiveness. The working group discussed a recent retrospective study demonstrating that exposure to non-anti-CDI antimicrobials within 8 weeks of FMT is associated with an approximate threefold risk of FMT failure (n=8/29 failures with antibiotic exposure vs 36/320 failures without antibiotic exposure).128 Similarly, the experience of the large pan-Netherlands stool bank129 was that ~50% of their failures of FMT in the treatment of recurrent CDI occurred in patients who had received antibiotics within 1 month of their FMT. For patients requiring long term antibiotics, the working group’s expert opinion was that such patients should still be eligible 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 of indication of antibiotics. Both in this scenario, and the scenario in which antibiotics are required shortly after receiving FMT, the working party agreed that infectious diseases specialists/medical microbiologists should be involved in making decisions regarding the choice of agents used.

Recommendations

1. To minimise any deleterious effect of antimicrobials on the FMT material, we recommend that there should be a minimum washout period of 24 hours between the last dose of antibiotic and treatment with FMT (GRADE of evidence: low; strength of recommendation: strong).

2. We suggest considering consultation with infectious disease specialists or medical microbiologists for advice whenever FMT recipients also have an indication for long term antibiotics, or have an indication for non-CDI antibiotics within 8 weeks of FMT (GRADE of evidence: very low; strength of recommendation: weak).

5.5.2.1. Introduction

FMT can be delivered via the lower GI route (retention enema, colonoscopy), upper GI route (endoscopically, or via nasogastric tube, nasoduodenal tube or nasojejenal tube), or via capsules (containing either frozen FMT or lyophilised faecal material). Systematic reviews with meta-analysis suggest that FMT for recurrent CDI via colonoscopy may have slightly higher efficacy compared with upper GI administration127 130–132 with similar safety profiles, but also note the trend towards using larger amounts of stool or ‘higher concentration’ FMT in lower GI administration. One systematic review (reviewing principally case series, and including only one randomised study) compared remission rates for CDI using FMT delivered to different areas of the GI tract, and reported that for FMT infused into the stomach, duodenum/jejunum, caecum/ascending colon and rectum, the rates of cure rate were 81%, 86%, 93% and 84%, respectively.131

In the only randomised study that directly compared upper and lower GI administration, there was no significant difference in overall cure rate (P=0.53).17

5.5.2.2. Upper GI tract administration of FMT

FMT has been shown to be safe and efficacious in the treatment of C. difficile when administered via nasogastric tube,37 39 45 61 83 123 nasoduodenal tube,15 84 85 enteroscopy122 123 or via the infusion channel on a gastroscope.40 45 In a randomised trial, nasoduodenal donor FMT has been shown to be more efficacious than vancomycin in treating recurrent CDI.15 Furthermore, it has been shown that FMT can also be safely and effectively delivered via a percutaneous endoscopic gastrostomy tube.45 83 The working group noted that upper GI administration of FMT may be particularly suitable for certain patient groups, such as those in whom there are contraindications or who would find it difficult to tolerate lower GI endoscopy, and/or patients unlikely to be unable to retain enemas.

Typically, smaller volumes of faecal suspension are administered to the upper GI tract compared with lower GI administration, with quoted volumes ranging from 25 mL39 up to 150 mL84 or 250 mL.37 85 Up to 500 mL of suspension has been given safely and effectively via the upper GI route.15 77 However, the working group expressed concerns regarding the risk of regurgitation and aspiration if large volumes of FMT are administered to the upper GI tract, and also discussed cases in which this has been described with adverse outcomes.80 This included a reported death from aspiration, after 100–150 mL of FMT was delivered by enteroscope into the distal duodenum under general anaesthetic as attempted treatment for recurrent CDI.133 A further report described a case of fatal aspiration pneumonitis likely related to a 500 mL FMT via nasoduodenal tube; this patient had a swallowing disorder following oropharyngeal radiation after surgical removal of a maxillary carcinoma 2 years previously.77 Based on their expert opinion, the working group recommended that upper GI FMT should be used with caution in those at risk of regurgitation (eg, known large hiatus hernia, severe gastro-oesophageal reflux disease, etc) and/or with swallowing disorders (although administration via a gastrostomy tube would be acceptable). They also recommended that no more than 100 mL of FMT should be administered to the upper GI tract to minimise these risks.

Recommendations

1. We recommend that upper GI administration of FMT as treatment for recurrent or refractory CDI should be used where clinically appropriate (GRADE of evidence: high; strength of recommendation: strong).

2. Where upper GI administration is considered most appropriate, we recommend that FMT administration should be via nasogastric, nasoduodenal or nasojejunal tube, or alternatively via upper GI endoscopy. Administration via a permanent feeding tube is also appropriate (GRADE of evidence: high; strength of recommendation: strong).

3. We recommend that no more than 100 mL of FMT is administered to the upper GI tract (GRADE of evidence: low; strength of recommendation: strong).

4. We recommend that upper GI administration of FMT should be used with caution in those at risk of regurgitation and/or those with swallowing disorders (GRADE of evidence: low; strength of recommendation: strong).

5.5.2.3. Lower GI tract administration of FMT

FMT via enema

Successful treatment of C. difficile with FMT enema has been demonstrated16 38 42 53 55 83 86 but enema appears to have a lower efficacy than other routes of FMT administration. Specifically, in a randomised study primarily comparing the efficacy of fresh and frozen FMT in the treatment of recurrent CDI, only 52.8% of patients in the ‘frozen’ arm and 50.5% of patients in the ‘fresh’ arm of the study (n=57/108 and 56/111, respectively) experienced resolution of symptoms after a single enema, by modified intention to treat analysis.16 However, resolution rates in both arms only reached >80% after at least three enemas.16 A recent randomised study demonstrated similar rates of recurrence of CDI in patients with recurrent CDI treated with either a single FMT enema or a 6 week vancomycin taper (n=9/16 patients with recurrence vs 5/12, respectively).12 Notwithstanding this, enemas do have specific advantages, such as being a treatment option where full colonoscopy is contraindicated. It is also possible to give multiple infusions relatively easily and outside a hospital setting.

FMT via colonoscopy

Randomised study evidence has demonstrated that colonoscopic FMT has higher efficacy in treating recurrent CDI than vancomycin.18 Efficacy is similar whether FMT is fresh or frozen, but modestly reduced when using a lyophilised FMT product.13 Colonoscopic delivery of donor FMT into the ileum or caecum was associated with a 91% cure rate for recurrent CDI.14 Observational studies highlighted similar success, describing cure rates of 88% (n=14/16)74 and 91%46 (n=21/23) in response to infusion of donor FMT into the caecum or terminal ileum. A further advantage of using colonoscopy to administer FMT has been to allow assessment for the presence of pseudomembranes; in certain reviewed studies, the presence or absence of pseudomembranes has influenced the FMT regimen used.18 73 However, the working group noted that many patients with CDI are frail and elderly, and as such it will not always be safe or feasible to undertake colonoscopy in this particular group of patients. Flexible sigmoidoscopy appears to be an feasible option where full colonoscopy cannot be performed (eg, unable to tolerate colonoscopy, severity of colitis).56 60

The amount of faecal suspension via enema has varied between 150 and 500 mL.16 38 42 55 86 The amount of faecal suspension delivered via colonoscopy has been similarly variable, with some studies suggesting as little as 100 mL can be used with success rates of 94%43: 250–400 mL had a success rate of 100%36 whereas infusions of up to 500–700 mL were associated with cure rates of 92%.46 However, the working group noted that it is difficult to compare ‘concentration’ of FMT in different studies as different protocols used varied starting amounts of faecal material. Currently, there are no randomised studies that compare concentration/volume of colonoscopic or enema FMT. As such, no recommendation was made to this regard.

Recommendations

1. We recommend that colonoscopic administration of FMT as treatment for recurrent or refractory CDI should be used where appropriate (GRADE of evidence: high; strength of recommendation: strong).

2. Where colonoscopic administration is used, we suggest considering preferential delivery to the caecum or terminal ileum, as this appears to give the highest efficacy rate (GRADE of evidence: low; strength of recommendation: weak).

3. We recommend that FMT via enema should be used as a lower GI option when delivery using colonoscopy or flexible sigmoidoscopy is not possible (GRADE of evidence: high; strength of recommendation: strong).

5.5.2.4. Capsulised FMT

Capsulised FMT aims to remove some of the concerns regarding conventional FMT, such as the invasive means of administration and palatability. The largest case series describing the use of capsules as treatment for recurrent CDI72 89 noted clinical resolution at 8 weeks off antibiotics for CDI in 82% of cases (n=147/180) after one course of capsules, and 91% (n=164/180) after two courses. The capsules contained frozen FMT prepared in a diluent of saline with 10% glycerol; 15 capsules were administered each day for two consecutive days (equating to a mean 48 g of original crude stool). Other smaller case series have demonstrated comparable results,87 123 134 including when lyophilised stool is used instead of frozen whole FMT.134

The working group reviewed two randomised studies which have examined the efficacy of capsulised FMT in treating recurrent CDI. In one study, published in abstract form,94 a ‘high dose’ regimen of frozen FMT capsules (30 capsules each day for 2 days) was compared with ‘low dose’ (30 capsules in 1 day). CDI resolution was comparably high in both arms with one treatment course (77% (n=7/9) in the ‘high dose’ arm vs 70% (n=7/10) in the ‘low dose arm’). Four of five initial non-responders entered remission after a second capsule course with the ‘high dose’ regimen.94 In a recent large randomised trial, patients with recurrent CDI were randomised to receive thawed frozen FMT either via colonoscopy or via capsules (one treatment of 40 capsules).11 On per protocol analysis, remission at 12 weeks after a single treatment occurred in 96% in both arms (n=51/53 by capsule, n=50/52 by colonoscopy).

The working group discussed certain unresolved issues regarding capsules. Specifically, capsules are often large, and swallowing 30 capsules in a single day may be a significant undertaking for patients with CDI, such as the frail elderly with an existing high pill burden. They also noted that follow-up data post-capsule administration is relatively short compared with other modalities of FMT.

Recommendation

Capsulised FMT holds promise as a treatment option for recurrent CDI and we recommend that this should be offered to patients as a potential treatment modality where available. Capsule preparations should follow a standard protocol. Further evidence regarding optimal dosing and formulation is required (GRADE of evidence: high; strength of recommendation: strong).

5.6.2.1. Efficacy

All four RCTs, with a total of 277 subjects, included patients with mild to moderate ulcerative colitis (Mayo score 3–11 and endoscopic subscore of at least 1). Participants were aged between 27 and 56 years and largely included patients on stable immunosuppressive therapy (only one study excluded patients using biologic treatments and methotrexate within the preceding 2 months).136 Three studies included patients on oral corticosteroids at the time of FMT, however only two required a mandatory wean of these to meet eligibility. Studies generally included patients with all disease distributions found in ulcerative colitis. Time to evaluation of response to FMT in these studies varied between 7 and 12 weeks. Two studies used autologous FMT as placebo.136 139 Three of the four studies demonstrated that patients receiving donor FMT were significantly more likely to achieve clinical and endoscopic remission compared with placebo.137–139 The pooled rate of combined clinical and endoscopic remission was 27.9% for donor FMT and 9.5% for placebo. A pooled risk ratio for failure of FMT to achieve these combined outcomes was 0.8 (95% CI 0.7 to 0.9). Deep remission (histological) was only reported in one RCT: 18.4% of patients receiving FMT achieved this outcome compared with 2.7% of those receiving placebo.137

5.6.2.2. Characteristics of FMT preparation and delivery

The four RCTs varied in their FMT preparation and delivery methodology. Two RCTs delivered frozen FMT, one fresh FMT and one used a combination. Three RCTs with a positive outcome delivered the FMT via the lower GI route; these studies used a high intensity protocol ranging from a total of three infusions in 1 week to 40 FMTs over an 8 week period.137–139 The other RCT (that failed to show efficacy of FMT for ulcerative colitis) had adopted a low intensity protocol of two nasoduodenal infusions given 3 weeks apart.136 Interestingly, the only RCT that prepared stool in anaerobic conditions demonstrated the highest rate of steroid free clinical remission and steroid free clinical response with donor FMT.139 A further interesting observation in one study was a trend towards higher rates of remission with one particular donor.137

5.6.2.3. Adverse events

Short lived GI symptoms, such as abdominal bloating, cramps, diarrhoea and fever, were reported in patients receiving FMT for ulcerative colitis. There were no significant differences in serious adverse events between patients receiving FMT compared with placebo (10 vs 7, respectively). Most of the serious adverse events were a consequence of worsening colitis: one patient who received FMT required a colectomy.136 In addition, one patient developed concurrent CDI.137 No deaths were reported in any of the studies.