Real-world Effectiveness of Fecal Microbiota Transplantation for First or Second Clostridioides difficile Infection.

BACKGROUND & AIMS: Clostridioides difficile infection (CDI) is associated with high mortality. Fecal microbiota transplantation (FMT) is an established treatment for recurrent CDI, but its use for first or second CDI remains experimental. We aimed to investigate the effectiveness of FMT for first or second CDI in a real-world clinical setting. METHODS: This multi-site Danish cohort study included patients with first or second CDI treated with FMT from June 2019 to February 2023. The primary outcome was cure of C. difficile-associated diarrhea (CDAD) 8 weeks after the last FMT treatment. Secondary outcomes included CDAD cure 1 and 8 weeks after the first FMT treatment and 90-day mortality following positive C. difficile test. RESULTS: We included 467 patients, with 187 (40%) having their first CDI. The median patient age was 73 years (interquartile range [IQR], 58-82 years). Notably, 167 (36%) had antibiotic-refractory CDI, 262 (56%) had severe CDI, and 89 (19%) suffered from fulminant CDI. Following the first FMT treatment, cure of CDAD was achieved in 353 patients (76%; 95% confidence interval [CI], 71%-79%) at week 1. At week 8, 255 patients (55%; 95% CI, 50%-59%) maintained sustained effect. In patients without initial effect, repeated FMT treatments led to an overall cure of CDAD in 367 patients (79%; 95% CI, 75%-82%). The 90-day mortality was 10% (95% CI, 8%-14%). CONCLUSION: Repeated FMT treatments demonstrate high effectiveness in managing patients with first or second CDI. Forwarding FMT in CDI treatment guidelines could improve patient survival. CLINICALTRIALS: gov, Number: NCT03712722.

Frailty level at discharge predicts mortality in older patients with Clostridioides difficile more accurately than age or disease severity.

PURPOSE: Clostridioides difficile infection (CDI) has a high mortality among older patients. Identification of older patients with CDI in increased mortality risk is important to target treatment and thereby reduce mortality. The aim of this study was to investigate mortality rates and compare frailty levels at discharge, measured by the record-based Multidimensional Prognostic Index (MPI), with age and severity of CDI as mortality predictors in patients with CDI diagnosed during hospitalisation. METHODS: This was a population-based cohort study from Central Denmark Region, Denmark, including all patients ≥ 60 years with a positive CD toxin test without prior infection and diagnosed from 1 January to 31 December 2018. Frailty level, estimated from the electronic medical record, was defined as low, moderate, or severe frailty. CDI severity was graded according to international guidelines. Primary outcome was 90-day mortality. RESULTS: We included 457 patients with median age 77 years (interquartile range 69-84) and females (49%). Overall, 90-day mortality was 28%, and this was associated with age (hazard ratio (HR): 2.71 (95% confidence interval 1.64-4.47)), CDI severity (HR 4.58 (3.04-6.88)) and frailty (HR 10.15 (4.06-25.36)). Frailty was a better predictor of 90-day mortality than both age (p < 0.001) and CDI severity (p = 0.04) with a receiver operating characteristic curve area of 77%. CONCLUSION: The 90-day mortality among older patients with CDI in a Danish region is 28%. Frailty measured by record-based MPI at discharge outperforms age and disease severity markers in predicting mortality in older patients with CDI.

Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Clostridioides difficile infection is an urgent antibiotic-associated health threat with few treatment options. Microbiota restoration with faecal microbiota transplantation is an effective treatment option for patients with multiple recurring episodes of C difficile. We compared the efficacy and safety of faecal microbiota transplantation compared with placebo after vancomycin for first or second C difficile infection. METHODS: We did a randomised, double-blind, placebo-controlled trial (EarlyFMT) at a university hospital in Aarhus, Denmark. Eligible patients were aged 18 years or older with first or second C difficile infection (defined as ≥3 watery stools [Bristol stool chart score 6-7] per day and a positive C difficile PCR test). Patients were randomly assigned (1:1) to faecal microbiota transplantation or placebo administered on day 1 and between day 3 and 7, after they had received 125 mg oral vancomycin four times daily for 10 days. Randomisation was done by investigators using a computer-generated randomisation list provided by independent staff. Patients and investigators were masked to the treatment group. The primary endpoint was resolution of C difficile-associated diarrhoea (CDAD) 8 weeks after treatment. We followed up patients for 8 weeks or until recurrence. We planned to enrol 84 patients with a prespecified interim analysis after 42 patients. The primary outcome and safety outcomes were analysed in the intention-to-treat population, which included all randomly assigned patients. The trial is registered with ClinicalTrials.gov, NCT04885946. FINDINGS: Between June 21, 2021, and April 1, 2022, we consecutively screened 86 patients, of whom 42 were randomly assigned to faecal microbiota transplantation (n=21) or placebo (n=21). The trial was stopped after the interim analysis done on April 7, 2022 for ethical reasons because a significantly lower rate of resolution was identified in the placebo group compared with the faecal microbiota transplantation group (Haybittle-Peto boundary limit p<0·001). 19 (90%; 95% CI 70-99) of 21 patients in the faecal microbiota transplantation group and seven (33%, 95% CI 15-57) of 21 patients in the placebo group had resolution of CDAD at week 8 (p=0·0003). The absolute risk reduction was 57% (95% CI 33-81). Overall, 204 adverse events occurred, with one or more adverse events being reported in 20 of 21 patients in the faecal microbiota transplantation group and all 21 patients in the placebo group. Diarrhoea (n=23 in the faecal microbiota transplantation group; n=14 in the placebo group) and abdominal pain (n=14 in the faecal microbiota transplantation group; n=11 in the placebo group) were the most common adverse events. Three serious adverse events possibly related to study treatment occurred (n=1 in the faecal microbiota transplantation group; n=2 in the placebo group), but no deaths or colectomies during the 8-week follow-up. INTERPRETATION: In patients with first or second C difficile infection, first-line faecal microbiota transplantation is highly effective and superior to the standard of care vancomycin alone in achieving sustained resolution from C difficile. FUNDING: Innovation Fund Denmark.

Involving frail older patients in identifying outcome measures for transitional care-a feasibility study.

BACKGROUND: During care transitions, the older (75+) patient's agenda can easily be missed. To counteract this, involving patients in shared clinical decision making has proven to be of great value. Likewise, involving patients and other stakeholders as researchers is gaining ground. Patient and public involvement (PPI) in research entails many benefits, for example, by bringing further insight from those with lived experiences of being ill. There are various challenges associated with involving some older patients, for example frailty, cognitive impairment and other chronic illnesses. To the best of our knowledge, there are only a few examples of initiatives involving older patients beyond research participation. The feasibility of involving frail older patients during an ongoing care transition from hospital to primary health care remains unknown. To investigate the feasibility of including older frail patients, their relatives and health care professionals (HCPs) as co-researchers, we established a study with increasingly demanding levels of patient involvement to identify relevant outcome measures for future transitional care research. METHODS: The study was a pragmatic, qualitative feasibility study. The involved individuals were frail older patients, their relatives and HCPs. Patients and their relatives were interviewed, while the interviewer made reflective notes. A thematic analysis was made. Relatives and HCPs discussed the themes to identify relevant outcome measures and potentially co-create new patient-reported outcome measures (PROMs) for use in future transitional care studies. The feasibility was evaluated according to six involvement steps. The level of involvement was evaluated using the five-levelled Health Canada Public Involvement Continuum (HCPIC). RESULTS: In total, eight patients, five relatives and three HCPs were involved in the study. Patients were involved in discussing care transitions (HCPIC level 3), while some relatives were engaged (HCPIC level 4) in forming PROMs. The partnership level of involvement (HCPIC level 5) was not reached. The thematic analysis and the subsequent theme discussion successfully formed PROMs. The key PROMs were related to care, transparency and the relatives' roles in the transitional care process. CONCLUSIONS: When applying a pragmatic involvement approach, frail older patients can be successfully involved in identifying relevant transitional care outcome measures; however, involving these patients as fellow researchers seems infeasible. To maintain involvement, supportive relatives are essential. Useful experiences for future research involvement of this vulnerable group were reported, arguing that patient participation has the potential to become inherent in future geriatric research.

The purpose of the study was to involve patients in identifying relevant outcome measures for future transitional care research. Involving patients in research is not new. What makes this project special is that it seeks to involve old, frail patients aged 75 plus.The project used open-form interviews that were not constrained in time and were not audio recorded; this was done to obtain confidence from the patients and their relatives. Each patient was interviewed twice: shortly before the patients left the hospital and shortly after discharge. The purpose was to discuss the patient's experiences during the discharge period. The first interview took place in the hospital, whereas the interviewer visited the patients in their residence for the second interview. An expert panel was then formed involving the patients' relatives and the professional health care workers. The expert panel discussed themes based on the data expressed by the patients during the interviews. In addition, an attempt was made to establish long-term cooperation between the patients, their relatives and the researchers. The health condition and vulnerable state of the patients made it difficult to continue their involvement throughout the research process. In fact, only the relatives and professionals were able to take part in the expert panel. Despite these challenges, the outcome of the project was positive. In conclusion, it makes sense to involve frail patients in transitional care research despite the challenges these patients face in their old age. In future research, frail older patients, relatives and other stakeholders can be involved.

Faecal microbiota transplantation as a home therapy to frail older people.

BACKGROUND: Clostridioides (Clostridium) difficile infection (CDI) is a leading cause of antibiotics-associated diarrhoea. Faecal microbiota transplantation (FMT) is effective for recurrent CDI and may be provided as a home treatment to frail, older people. METHODS: We present four consecutive patients with recurrent CDI, treated at home using nasojejunal tube-delivered or encapsulated donor faeces. The primary outcome was combined clinical resolution and a negative CD toxin test 8 weeks post-treatment. RESULTS: All four patients had severe CDI and all improved clinically following one FMT. Sustained resolution following one FMT was observed in one patient. Two patients had recurrence and received a second FMT using capsules; both achieved resolution. One patient who had recurrence declined from further FMT due to fear of relapse and was established on long-term vancomycin. No adverse events related to FMT were observed. CONCLUSION: Frail older people may benefit from FMT. Home treatment is a viable option and may be considered both for clinical cure and for palliation.