The effect of non-pooled multi-donor faecal microbiota transplantation for inducing clinical remission in patients with chronic pouchitis: Results from a multicentre randomised double-blinded placebo-controlled trial (MicroPouch).

BACKGROUND AND AIMS: To investigate if treatment with non-pooled multi-donor faecal microbiota transplantation (FMT) for four weeks was superior to placebo to induce clinical remission in patients with chronic pouchitis. METHODS: The study was a randomised double-blinded placebo-controlled study with a 4-week intervention period and 12-month follow-up. Eligible patients with chronic pouchitis were recruited from five Danish hospitals. Participants were randomised to non-pooled multi-donor FMT derived from four faecal donors, or placebo. Treatment was delivered daily by enema for two weeks followed by every second day for two weeks. Disease severity was accessed at inclusion and 30-day follow-up, using the Pouchitis Disease Activity Index (PDAI); PDAI <7 was considered equivalent to clinical remission. Faecal samples from participants and donors were analysed by shotgun metagenomic sequencing. RESULTS: Inclusion was stopped after inclusion of 30 participants who were randomised 1:1 for treatment with FMT or placebo. There was no difference in participants achieving clinical remission between the two groups at 30-day follow-up, relative risk 1.0 (95%CI(0.55;1.81)). Treatment with FMT resulted in a clinically relevant increase in adverse events compared to placebo, incidence rate ratio 1.67 (95%CI(1.10;2.52)); no serious adverse events within either group. Faecal microbiota transplantation statistically significantly increased the similarity of participant faecal microbiome to the faecal donor microbiome at 30-days follow-up (p=0.01), which was not seen after placebo. CONCLUSIONS: Non-pooled multi-donor FMT was comparable to placebo in inducing clinical remission in patients with chronic pouchitis but showed a clinically relevant increase in adverse events compared to placebo.

Multi-strain probiotics during pregnancy in women with obesity influence infant gut microbiome development: results from a randomized, double-blind placebo-controlled study.

Probiotics have been described to influence host health and prevent the risk of obesity by gut microbiome (GM) modulation. In a randomized double-blinded placebo-controlled feasibility study, we investigated whether Vivomixx® multi-strain probiotics administered to 50 women with obesity during pregnancy altered the GM composition and perinatal health outcomes of their infants up to 9 months after birth. The mothers and infants were followed up with four visits after birth: at 3 d, and at 3, 6, and 9 months after delivery. The infants were monitored by anthropometric measurements, fecal sample analysis, and questionnaires regarding health and diet.The study setup after birth was feasible, and the women and infants were willing to participate in additional study visits and collection of fecal samples during the 9-month follow-up. In total, 47 newborns were included for microbiome analysis.Maternal prenatal Vivomixx® administration did not alter infant GM diversity nor differential abundance, and the probiotic strains were not vertically transferred. However, the infant GM exhibited a decreased prevalence of the obesity-associated genera, Collinsella, in the probiotic group and of the metabolic health-associated Akkermansia in the placebo group, indicating that indirect community-scale effects of Vivomixx® on the GM of the mothers could be transferred to the infant.Moreover, 3 d after birth, the GM of the infant was influenced by mode of delivery and antibiotics administered during birth. Vaginally delivered infants had increased diversity and relative abundance of the metabolic health-associated Bifidobacterium and Bacteroides while having a decreased relative abundance of Enterococcus compared with infants delivered by cesarean section. Maternal antibiotic administration during birth resulted in a decreased relative abundance of Bifidobacteriumin the GM of the infants. In conclusion, this study observed potential effects on obesity-associated infant GM after maternal probiotic supplementation.

Lacticaseibacillus rhamnosus GG Versus Placebo for Eradication of Vancomycin-Resistant Enterococcus faecium in Intestinal Carriers: A Systematic Review and Meta-Analysis.

The aim of this review was to assess the efficacy and safety of Lacticaseibacillus rhamnosus GG (LGG) (previously known as Lactobacillus rhamnosus GG) for the eradication of vancomycin-resistant Enterococcus faecium (VREfm) in colonized carriers. We searched Cochrane Central, EMBASE, and the PubMed Library from inception to 21 August 2023, for randomized controlled trials (RCTs) investigating the effectiveness of LGG for the eradication of gastrointestinal carriage of VREfm. An initial screening was performed followed by a full-text evaluation of the papers. Out of 4076 articles in the original screening, six RCTs (167 participants) were included in the review. All were placebo-controlled RCTs. The meta-analysis was inconclusive with regard to the effect of LGG for clearing VREfm colonization. The overall quality of the evidence was low due to inconsistency and the small number of patients in the trials. We found insufficient evidence to support the use of LGG for the eradication of VREfm in colonized carriers. There is a need for larger RCTs with a standardized formulation and dosage of LGG in future trials.

No effect of multi-strain probiotic supplementation on metabolic and inflammatory markers and newborn body composition in pregnant women with obesity: Results from a randomized, double-blind placebo-controlled study.

BACKGROUND AND AIMS: Modulation of the gut microbiome composition with probiotics may have beneficial metabolic effects in pregnant women with obesity. The aim was to investigate the effect of probiotic supplementation during pregnancy on metabolic and inflammatory markers and the body composition of the offspring. METHODS AND RESULTS: A randomized double-blind trial in 50 pregnant women (pre-pregnancy BMI ≥30 and < 35 kg/m2) comparing multi-strain probiotics (Vivomixx®; 450 billion CFU/d) versus placebo from 14 to 20 weeks of gestation until delivery was carried out. Participants were followed with two predelivery visits at gestational week 27-30 and 36-37 and with one postdelivery visit. All visits included fasting blood samples (C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin, C-peptide, glucose, glucagon, and glucagon-like peptide-1 (GLP-1)). At delivery, umbilical cord blood samples were collected (GLP-1 and glucagon). At the postdelivery visit, a dual-energy X-ray absorptiometry (DXA) scan of the newborn was performed. Forty-nine of 50 participants completed the study until delivery, and 36 mother-offspring dyads underwent postdelivery examinations including a DXA scan. There were no significant differences in changes in measured biomarkers between the probiotic versus the placebo group. No differences were found in newborn body composition or GLP-1 and glucagon. GLP-1 measured in umbilical blood samples was positively correlated to fat percent in offspring from the probiotic group. CONCLUSION: In this study of pregnant women with obesity and their newborns, there was no effect of probiotic supplementation in mothers or babies on metabolic or inflammatory biomarkers or on body composition of offspring. This study was registered at clinicaltrials.gov as NCT02508844.

Antibiotic-free vaginal microbiota transplant with donor engraftment, dysbiosis resolution and live birth after recurrent pregnancy loss: a proof of concept case study.

Background: Vaginal dysbiosis covers imbalances in the vaginal microbiota, defined by altered composition of bacteria, viruses, and fungi and is associated with euploid pregnancy losses, premature birth, infertility, or bacterial vaginosis. A large proportion of women who have vaginal dysbiosis do not experience any symptoms. Antibiotics are the traditional treatment, recently combined with local probiotics in some cases. Vaginal Microbiota Transplantation (VMT) with eubiotic vaginal bacterial microbiota after antibiotic eradication of pathogens has successfully been performed in a case study with five patients, but no VMT has been performed without the use of antibiotics. Methods: This is a proof of concept case study. The patient was found to have vaginal dysbiosis at the RPL clinic at Copenhagen University Hospital Hvidovre, Denmark on the 23rd of June 2021. She was offered and accepted to receive experimental treatment in the form of a VMT as a compassionate use case. VMT is the transfer of cervicovaginal secretions (CVS) from a healthy donor with a Lactobacillus-dominant vaginal microbiome to a recipient with a dysbiotic vaginal microbiome. CVS is a mixture of e.g., mucus, bacteria, metabolites present in the vaginal canal. Potential donors were thoroughly screened for the absence of STIs, and the most suitable donor sample for the specific patient in this study was determined via an in vitro microbiome competition assay. Findings: A 30-year-old patient with one livebirth and a complicated pregnancy history of two stillbirths and 1 s trimester pregnancy loss in gestational weeks 27 (2019), 17 (2020) and 23 (2020) respectively with complaints of vaginal irritation and discharge that had aggravated in all her pregnancies. Her vaginal microbiome composition showed a 90% dominance of Gardnerella spp. After one VMT there was a complete shift in microbiome composition to 81.2% L. crispatus and 9% L. jensenii with a concurrent resolvement of vaginal symptoms. Single nucleotide polymorphism-analysis confirmed her microbiome to be of donor origin and it remain stable now 1.5 years after the VMT. Five months after the VMT she became pregnant and has successfully delivered a healthy baby at term. Interpretation: Here we report a successful VMT with confirmed donor strain engraftment followed by a successful pregnancy and delivery after a series of late pregnancy losses/stillbirths. Findings suggest that VMT is a potential treatment for severe vaginal dysbiosis. Further, larger studies are required. Funding: The study was partially funded (i.e., analysis costs) by Freya Biosciences Aps, Fruebjergvej, 2100 Copenhagen, Denmark.

Fecal microbiota transplantation for the treatment of irritable bowel syndrome: A systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is the most prevalent gastrointestinal disorder in developed countries and reduces patients' quality of life, hinders their ability to work, and increases health care costs. A growing number of trials have demonstrated an aberrant gut microbiota composition in IBS, also known as 'gut dysbiosis'. Fecal microbiota transplantation (FMT) has been suggested as a treatment for IBS. AIM: To assess the efficacy and safety of FMT for the treatment of IBS. METHODS: We searched Cochrane Central, MEDLINE, EMBASE and Web of Science up to 24 October 2022 for randomised controlled trials (RCTs) investigating the effectiveness of FMT compared to placebo (including autologous FMT) in treating IBS. The primary outcome was the number of patients with improvements of symptoms measured using a validated, global IBS symptoms score. Secondary outcomes were changes in quality-of-life scores, non-serious and serious adverse events. Risk ratios (RR) and corresponding 95%CI were calculated for dichotomous outcomes, as were the mean differences (MD) and 95%CI for continuous outcomes. The Cochrane risk of bias tool was used to assess the quality of the trials. GRADE criteria were used to assess the overall quality of the evidence. RESULTS: Eight RCTs (484 participants) were included in the review. FMT resulted in no significant benefit in IBS symptoms three months after treatment compared to placebo (RR 1.19, 95%CI: 0.68-2.10). Adverse events were reported in 97 participants in the FMT group and in 45 participants in the placebo group (RR 1.17, 95%CI: 0.63-2.15). One serious adverse event occurred in the FMT group and two in the placebo group (RR 0.42, 95%CI: 0.07-2.60). Endoscopic FMT delivery resulted in a significant improvement in symptoms, while capsules did not. FMT did not improve the quality of life of IBS patients but, instead, appeared to reduce it, albeit non significantly (MD -6.30, 95%CI: -13.39-0.79). The overall quality of the evidence was low due to moderate-high inconsistency, the small number of patients in the studies, and imprecision. CONCLUSION: We found insufficient evidence to support or refute the use of FMT for IBS. Larger trials are needed.

The Clinical Efficacy, Safety, and Tolerability of Vancomycin for the Treatment of Recurrent Clostridioides difficile Infection - A Systematic Review.

Introduction: The aim of this systematic review of randomized clinical trials (RCTs) was to examine the efficacy, safety, and tolerability of vancomycin for treatment of recurrent Clostridioides difficile infection (rCDI). Methods: The PubMed database was searched from inception to August 23, 2022. An initial screening was performed followed by a full-text evaluation of the papers. Inclusion criteria were RCTs investigating vancomycin for treatment of rCDI. Results: A total of six studies and 269 patients were included in the review. Three studies used a fixed dose regimen of vancomycin, one study used pulse regimen, one study used a taper-and-pulse regimen, and one study used a taper-and-pulse regimen for the participants with two or more recurrences. The resolution of infection varied from 19% to 58.3% in five of six studies reporting this as an outcome. Four out of six studies reported new episodes of rCDI as an intervention outcome, in those studies 50-63% of participants experienced rCDI. Regarding the safety and tolerability of vancomycin treatment for rCDI, one study described several adverse events regarding gastrointestinal discomfort along with fatigue and skin rash. There were no records of serious adverse events in the included studies. Conclusion: While oral vancomycin is mostly safe and well tolerated in the RCTs reviewed here, the efficacy for treating rCDI varies greatly from 19-58.3%, and 50-63% of participants experienced new episodes of rCDI.

The Efficacy of Faecal Microbiota Transplant and Rectal Bacteriotherapy in Patients with Recurrent Clostridioides difficile Infection: A Retrospective Cohort Study.

The most effective treatment for recurrent Clostridioides difficile infection (CDI) is faecal microbiota transplantation (FMT); however, the optimal route of administration is thus far unknown. This retrospective cohort study of 343 patients sought to evaluate the efficacy of treatment with FMT capsules, FMT enema, and rectal bacteriotherapy (RBT) during a five-year period. The primary endpoint was clinical resolution from CDI after eight weeks, and secondary endpoints were time to recurrence and death during the follow-up period. The proportion of patients with clinical resolution was 79.9% in the FMT capsule group, 53.3% in the FMT enema group, and 61.8% in the RBT group, corresponding to an adjusted odds ratio of 3.79 (CI: 1.82 to 8.26) in the FMT capsule group compared with FMT enema, and 2.92 (CI: 1.49 to 6.03) compared with RBT. The hazards ratio for recurrence within the first 12 months of follow-up was 0.24 (CI: 0.06 to 0.89) in the FMT capsule group compared with FMT enema, and 0.26 (CI: 0.08 to 0.91) compared with RBT. There was no difference in mortality. In conclusion, FMT capsules were more effective than both FMT enema and RBT as treatment of recurrent CDI and reduced the risk of further recurrences.

Synbiotic Intervention with Lactobacilli, Bifidobacteria, and Inulin in Healthy Volunteers Increases the Abundance of Bifidobacteria but Does Not Alter Microbial Diversity.

Synbiotics combine probiotics and prebiotics and are being investigated for potential health benefits. In this single-group-design trial, we analyzed changes in the gut microbiome, stool quality, and gastrointestinal well-being in 15 healthy volunteers after a synbiotic intervention comprising Lacticaseibacillus rhamnosus (LGG), Lactobacillus acidophilus (LA-5), Lacticaseibacillus paracasei subsp. paracasei (L. CASEI 431), and Bifidobacterium animalis subsp. lactis BB-12 and 20 g of chicory-derived inulin powder consumed daily for 4 weeks. Fecal samples were collected at baseline and at completion of the intervention, and all participants completed a fecal diary based on the Bristol Stool Scale and recorded their gastrointestinal well-being. No adverse effects were observed after consumption of the synbiotic product, and stool consistency and frequency remained almost unchanged during the trial. Microbiome analysis of the fecal samples was achieved using shotgun sequencing followed by taxonomic profiling. No changes in alpha and beta diversity were seen after the intervention. Greater relative abundances of Bifidobacteriaceae were observed in 12 subjects, with indigenous bifidobacteria species constituting the main increase. All four probiotic organisms increased in abundance, and L. rhamnosus, B. animalis, and L. acidophilus were differentially abundant, compared to baseline. Comparison of the fecal strains to the B. animalis subsp. lactis BB-12 reference genome and the sequenced symbiotic product revealed only a few single-nucleotide polymorphisms differentiating the probiotic B. animalis subsp. lactis BB-12 from the fecal strains identified, indicating that this probiotic strain was detectable after the intervention. IMPORTANCE The effects of probiotics/synbiotics are seldom investigated in healthy volunteers; therefore, this study is important, especially considering the safety aspects of multiple probiotics together with prebiotic fiber in consumption by humans. The study explores at the potential of a synbiotic intervention with lactobacilli, bifidobacteria, and inulin in healthy volunteers and tracks the ingested probiotic strain B. animalis subsp. lactis.

No Effect of Lactobacillus rhamnosus GG on Eradication of Colonization by Vancomycin-Resistant Enterococcus faecium or Microbiome Diversity in Hospitalized Adult Patients.

The purpose of this trial was to evaluate the efficacy of a 4-week supplementation of Lactobacillus rhamnosus GG (LGG) in eliminating the gastrointestinal carrier state of vancomycin-resistant Enterococcus faecium (VREfm) in hospitalized adults. The primary outcome of the study was the number of patients with cleared VREfm colonization after the 4-week intervention. Secondary outcomes were clearance of VREfm colonization at weeks 8, 16, and 24, number of VREfm infections (isolated from nonintestinal foci), and changes in fecal microbiome diversity after the intervention. The trial was a multicenter, randomized, double-blind, placebo-controlled trial in hospitalized adult VREfm carriers. Patients were enrolled and randomized to receive 60 billion CFU of LGG daily or placebo for 4 weeks. For a subgroup of patients, rectal swabs for VREfm were collected also at 8, 16, and 24 weeks and analyzed using shotgun metagenomics. Patients ingesting a minimum of 50% of the probiotic during the 4-week intervention were included in subsequent outcome analyses (48 of 81 patients). Twelve of 21 patients in the LGG group (57%) compared to 15 of 27 patients in the placebo group (56%) cleared their VREfm carriage. Eighteen patients completed the entire 24-week intervention with the same minimum compliancy. Of these, almost 90% in both groups cleared their VREfm carriage. We found a statistically significant difference between VREfm clearers and nonclearers regarding metronidazole and vancomycin usage as well as length of hospitalization after inclusion. The microbiome analyses revealed no significant difference in alpha diversity between the LGG and the placebo group. Beta diversity differed between the groups and the different time points. This study did not show an effect of LGG in eradication of VREfm after a 4-week intervention. IMPORTANCE Whereas other studies exploring the effect of L. rhamnosus in clearing VREfm from the intestine included children and adults, with a wider age range, our study consisted of a geriatric patient cohort. The natural clearance of VREfm in this study was almost 60% after 4 weeks, thus much higher than described previously. Also, this study characterizes the microbiome of VREfm patients in detail. This article showed no effect of the probiotic L. rhamnosus in clearing VREfm from the intestine of patients.

Substantial Intestinal Microbiota Differences Between Patients With Ulcerative Colitis From Ghana and Denmark.

Background: Ulcerative colitis (UC) is a relapsing nontransmural inflammatory disease that is restricted to the colon and is characterized by flare-ups of bloody diarrhea. In this study, we aimed to investigate intestinal bacterial diversity in healthy controls and patients with UC with and without active disease, from Ghana and Denmark. Methods: The study included 18 UC patients (9 with active and 9 with inactive disease) and 18 healthy controls from Ghana. In addition 16 UC patients from Denmark (8 UC with active and 8 UC with inactive disease) and 19 healthy controls from Denmark. Microbiota diversity analysis relied on sequencing of ribosomal small subunit genes. Purified genomic DNA was submitted to PCR using a primer set targeting prokaryotes and eukaryotes. The purified DNA was sequenced on the Illumina MiSeq system in a 2 × 250 bp set up (Illumina, San Diego, CA, USA). Blinded analysis of the taxonomy table was performed using BioNumerics-7.5 (Applied Maths NV, Sint-Martens-Latem, Belgium). Results: When analyzing the taxonomy data for prokaryotes, cluster and principal component analysis shows Danish healthy controls clustered together, but separate from healthy controls from Ghana, which also clustered together. The Shannon diversity index (SDI) for prokaryotes shows significant differences between Danish healthy controls and patients in comparison with the corresponding groups from Ghana (p = 0.0056). Significant increased abundance of Escherichia coli was detected in healthy controls from Ghana in comparison with healthy controls from Denmark. The SDI of the prokaryotes ranges between 0 and 3.1 in the Ghana study groups, while in the Danish study groups it ranges between 1.4 and 3.2, the difference is however not significant (p = 0.138). Our data show a significant increased abundance of eukaryotes species in the healthy control group from Ghana and Denmark in comparison with patient groups from Ghana and Denmark. Conclusion: Overall, healthy controls and patients with UC from Denmark have increased diversity of prokaryotes. Healthy controls from Denmark and Ghana have increased abundance of eukaryotes in comparison with UC patient groups from Denmark and Ghana.

The use of core genome multilocus sequence typing to determine the duration of vancomycin-resistant Enterococcus faecium outbreaks.

The prevalence of vancomycin-resistant Enterococcus faecium has increased rapidly, and in Denmark, we are facing an endemic outbreak situation in hospitals. The aim of this study was to use whole-genome sequencing (WGS) and core genome multilocus sequencing typing (cgMLST) to determine the duration of VREfm outbreaks and thereby evaluate the effect of our infection control strategies. We included all VREfm isolates from six hospitals in the Capital Region of Denmark that were sequenced between 2012 and 2020. Ward data were collected from our laboratory information system. A ward outbreak was defined as two patient samples from the same ward within a period of 30 days belonging to the same cgMLST cluster. cgMLST complex types were determined using Ridom SeqSphere v7.2.3, where a maximum of 20 allelic differences between isolates defines a cluster. We included 1690 patient isolates between 2012 and 2020. Our collection consisted of 45 unique clusters and 227 ward outbreaks. The median duration of outbreaks was 20 days. We reported a median outbreak duration of VREfm outbreaks based on WGS data to be 20 days, and thus concluded that our infection control precautions are adequate.

Bacteraemia caused by Lactobacillus rhamnosus given as a probiotic in a patient with a central venous catheter: a WGS case report.

INTRODUCTION: Lactobacilli, especially Lactobacillus (L.) rhamnosus, are common and well-documented components of commercial probiotics [1]. Whole genome sequencing (WGS) is often used to compare bacterial genomes and their relatedness. In outbreak situations, it is used to investigate the transmission of pathogenic bacteria. WGS has also been used to determine safety in probiotics, by looking at potential virulence factors and resistance genes. CASE PRESENTATION: This case report describes a 56-year old multi-traumatised, immunocompetent woman who was given L. rhamnosus GG as a probiotic, and later developed a blood stream infection with L. rhamnosus GG.The patient was fed by a nasogastric tube, and she also had a central venous catheter for parenteral feeding. When the patient developed diarrhoea after long-term hospitalisation, she was given L. rhamnosus GG, as a probiotic, which was standard care on the ward where she was hospitalised. In this case report we describe the use of WGS to demonstrate that a patient fed with L. rhamnosus GG as a probiotic, developed a blood stream infection with the same strain. CONCLUSION: In this case WGS was applied to show the relatedness of a probiotic and a pathogenic strain of L. rhamnosus GG. This case emphasises the need for caution when administering probiotics to patients with indwelling catheters. The patient was immunocompetent and she cleared the infection without the need for antibiotics.

Long-Term Safety Following Faecal Microbiota Transplantation as a Treatment for Recurrent Clostridioides difficile Infection Compared with Patients Treated with a Fixed Bacterial Mixture: Results from a Retrospective Cohort Study.

Faecal microbiota transplantation (FMT) is the recommended treatment for recurrent C. difficile infection (rCDI) following a second recurrence. FMT is considered safe in the short term when procedures for the screening of donors and transferred material are followed. However, the long-term safety profile of FMT treatment is largely unknown. In a retrospective cohort study, we assessed the long-term safety of patients treated for rCDI with FMT or a fixed bacterial mixture, rectal bacteriotherapy (RBT). The overall survival, risk of hospital admission, onset of certain pre-specified diseases (cancer, diabetes mellitus, hypertension and inflammatory bowel disease) and risk of being diagnosed with a multidrug-resistant organism were assessed by undertaking a review of the treated patients' medical records for up to five years following treatment. A total of 280 patients were treated for rCDI with FMT (n = 145) or RBT (n = 135) between 2016 and 2020. In the five years following treatment, there were no differences in survival (adjusted hazard ratio (aHR) 1.03; 95% CI 0.68-1.56), p = 0.89), risk of hospital admission ((aHR 0.92; 95% CI 0.72-1.18), p = 0.5) or onset of any of the analysed diseases. In conclusion, FMT was not associated with increased mortality, risk of hospital admission or onset of disease following treatment when compared with RBT.

Successful treatment of Clostridioidesdifficile infection with single-donorfaecal microbiota transplantation capsules.

INTRODUCTION: Treatment of recurrent Clostridioides difficile infection with faecal microbiota transplantation (FMT) is highly effective and is the recommended treatment following a second recurrence. The cure rates of capsule treatment are high (82%-88%). Whether using multi-donor or single-donor FMT capsules affects cure rates remains incompletely understood. METHODS: A retrospective case series of patients with recurrent, refractory or fulminant C. difficile infection treated for three days with single-donor FMT capsules from October to December 2020 was conducted. The aim of the study was to investigate the clinical efficacy (cure rate) of the treatment and to compare cure rates with previously reported cure rates of treatment with multi-donor FMT capsules produced at the same stool bank. Clinical cure was defined as absence of diarrhoea or diarrhoea with a C. difficile negative stool sample eight weeks after treatment. RESULTS: Clinical cure was observed in 15 of the 18 (83.3%) patients following three days of FMT capsule treatment. Cure rates were comparable (p = 1.0) to previously reported cure rates (88.9%) of multi-donor FMT capsule treatment of recurrent C. difficile infection. CONCLUSIONS: Three days of single-donor FMT capsule treatment was effective and safe in the treatment of recurrent, refractory and fulminant C. difficile infection with cure rates comparable to those of multi-donor FMT capsule treatment. FUNDING: This work was supported by the Danish Innovation Fund under Grant 7076-00129B, MICROHEALTH. The funders had no role in the study design, data collection or analysis, the decision to publish, or in the preparation of the manuscript. The FMT capsules from the Aleris-Hamlet FMT Stool Bank were supplied to the Copenhagen University Hospital - Hvidovre Hospital free of charge. TRIAL REGISTRATION: not relevant.

Substantial Decrease in Vancomycin-Resistant Enterococcus faecium Outbreak Duration and Number of Patients During the Danish COVID-19 Lockdown: A Prospective Observational Study.

Vancomycin-resistant Enterococcus faecium (VREfm) is a globally significant nosocomial pathogen with a rapidly increasing prevalence. The objectives were to investigate VREfm outbreak duration and study the additional impact that infection control bundle strategies (ICBSs) set up to curb coronavirus disease 2019 (COVID-19) spreading had on VREfm outbreaks. Outbreak data set were collected prospectively from April 2, 2014 to August 13, 2020 at Copenhagen University Hospital Bispebjerg, Denmark. All VREfm samples had polymerase chain reaction performed for vanA/vanB genes before whole genome sequencing using the Illumina MiSeq platform. The relatedness of isolates was studied by core genome multilocus sequence typing (cgMLST) using Ridom SeqSphere. Eighty-one outbreaks had a median outbreak duration of 32.5 days (range 5-204 days) and 1,161 VREfm isolates were sequenced. The same cgMLST cluster types reappeared after outbreaks were terminated. When comparing the first 5 months of the COVID-19 pandemic with the corresponding period in 2019, we found a 10-fold decrease in VREfm outbreak patients and median outbreak duration decreased from 56 to 7 days (88%). Several COVID-19 ICBSs were implemented from March 13 through summer 2020. VREfm outbreaks lasted up to 204 days, but our findings suggest that outbreaks might last longer since the same cgMLST persisted in the same wards for years implying an endemic situation with recurrent outbreaks caused by hospital reservoirs or readmittance of unknown VREfm carriers. The sharp decline in VREfm outbreaks during the COVID-19 pandemic was most likely due to the ICBSs, resulting in a decrease in VREfm transmission.

Sentinel surveillance and epidemiology of Clostridioides difficile in Denmark, 2016 to 2019.

BackgroundSince 2008, Danish national surveillance of Clostridioides difficile has focused on binary toxin-positive strains in order to monitor epidemic types such as PCR ribotype (RT) 027 and 078. Additional surveillance is needed to provide a more unbiased representation of all strains from the clinical reservoir.AimSetting up a new sentinel surveillance scheme for an improved understanding of type distribution relative to time, geography and epidemiology, here presenting data from 2016 to 2019.MethodsFor 2─4 weeks in spring and autumn each year between 2016 and 2019, all 10 Danish Departments of Clinical Microbiology collected faecal samples containing toxigenic C. difficile. Isolates were typed at the national reference laboratory at Statens Serum Institut. The typing method in 2016-17 used tandem-repeat-sequence typing, while the typing method in 2018-19 was whole genome sequencing.ResultsDuring the study period, the sentinel surveillance scheme included ca 14-15% of all Danish cases of C. difficile infections. Binary toxin-negative strains accounted for 75% and 16 of the 20 most prevalent types. The most common sequence types (ST) were ST2/13 (RT014/020) (19.5%), ST1 (RT027) (10.8%), ST11 (RT078) (6.7%), ST8 (RT002) (6.6%) and ST6 (RT005/117) (5.1%). The data also highlighted geographical differences, mostly related to ST1 and temporal decline of ST1 (p = 0.0008) and the increase of ST103 (p = 0.002), ST17 (p = 0.004) and ST37 (p = 0.003), the latter three binary toxin-negative.ConclusionSentinel surveillance allowed nationwide monitoring of geographical differences and temporal changes in C. difficile infections in Denmark, including emerging types, regardless of binary toxin status.

The Use and Efficacy of Biological Therapies for Inflammatory Bowel Disease in a Danish Tertiary Centre 2010-2020.

Background: Patients with inflammatory bowel disease (IBD) who receive biologicals frequently experience lack or loss of response. Our aim was to describe the use and efficacy of biological therapy in a tertiary IBD center. Methods: We included all bio-naive IBD patients who initiated biological therapy between 2010 and 2020 at our centre. Their medical records were reviewed. Results: The population consisted of 327 Crohn's disease (CD) patients, 291 ulcerative colitis (UC) patients, and 3 patients with IBD unclassified (IBDU). The median follow-up was 3 years (interquartile range = 2-5) after initiating therapy. The annual number of patients initiating biological therapy rose from 29 (2010) to 85 (2019). Most patients (457, 73.6%) received 1 biological drug; 164 (26.4%) patients received 2 or more biologicals. Primary lack of response was observed in 36.4% (106/291) and 17.4% (57/327) of UC and CD patients; loss of response was observed in 27.1% (79/291) and 31.5% (103/327) of UC and CD patients, respectively. The 5-year surgery rates were 26.6% and 20.4% in UC and CD patients, respectively. Multivariate Cox regression showed that treatment with thiopurine reduced the likelihood of needing to switch biological therapy, requiring surgery or corticosteroids in UC patients (HR: 0.745, 95% CI: 0.559-0.993), but not in CD patients (HR: 0.996, 95% CI: 0.736-1.349). Conclusions: The annual number of IBD patients initiated on biological therapy increased considerably between 2010 and 2020. One-quarter of these patients required surgery after 5 years. Our findings suggest a beneficial effect of concurrent thiopurines for UC patients receiving biologicals, but this was not found for CD patients. This effect in UC patients was not observed when we included patients initiating thiopurines up to 6 months after the introduction of biological therapy.

Systematic review with meta-analysis: encapsulated faecal microbiota transplantation - evidence for clinical efficacy.

BACKGROUND: Faecal microbiota transplantation (FMT) is an effective treatment of recurrent Clostridioides difficile infection (rCDI) and is being applied experimentally in other diseases. Encapsulated administration may be equivalent in efficacy to delivery through other routes. METHODS: A systematic review was undertaken of studies using encapsulated FMT up to 26 October 2020. Data on indication, clinical outcomes, safety, treatment protocol and capsule preparation were collected and reported. Pooled rates of clinical efficacy in rCDI were calculated using random-effects meta-analysis. The impact of single variables on clinical efficacy was evaluated using univariate meta-regression. RESULTS: A total of 35 studies reporting the treatment of 960 patients with encapsulated FMT for eight different indications met the inclusion criteria. Most studies (n = 18, 51%) and patients (n = 755, 79%) were from studies on rCDI. Cure rates after single and multiple courses of treatments with encapsulated FMT in rCDI were 85% (95% CI: 82%-88%) and 93% (95% CI: 88%-96%) respectively. The treatment outcome was not significantly affected by dose, number of delivered capsules, anaerobic/aerobic processing, single/multi-donor treatment, lyophilisation, or any other single factor in the production or delivery of encapsulated FMT. Promising but non-comparable results from the treatment of ulcerative colitis and multidrug-resistant organisms were reported. CONCLUSIONS: Encapsulated FMT is an effective and safe treatment of rCDI, with cure rates comparable to FMT delivered through other routes. The treatment is effective despite variations in donor screening, preparation and treatment protocol. For other indications, the role of FMT capsules is still not sufficiently examined, although some studies show promising results. PLAIN LANGUAGE SUMMARY: Transfer of faecal material through capsules in the treatment of various diseases. Evidence for clinical efficacy The bacteria and other microorganisms of the gut is different in patient with various diseases in comparison with healthy subjects.Therefore, ways to change the microorganisms of the gut in a beneficial direction has been the subject of various research projects within recent years.Faecal microbiota transplantation often referred as FMT is a method of transferring microorganisms from healthy donors to patients with various diseases and is seen as one way to change the microbial community of the gut in a beneficial direction.Faecal microbiota transplantation can be performed in different ways such as through endoscopy, enemas or capsules. The transfer through capsules is preferred by the patients and has advantages since it can be administered long-term and can be delivered to the patients in their home. In this paper, we evaluated all accessible research reporting treatment with encapsulated faecal microbiota transplantation in the treatment of various diseases. We report the following major findings:-Treatment with capsules is safe when guidelines for screening donors and testing faecal material is followed.-The treatment is highly effective in the treatment of recurrent C. difficile infection, a disease with high mortality often caused by repeated antibiotic treatments. The treatment was effective in 596 of 723 patients following one course of capsule treatment.-Faecal microbiota transplantation delivered through capsules is as effective as treatment delivered through other routes in the treatment of C. difficile infection.-The treatment is effective in the treatment of C. difficile infection across studies and countries, despite great differences in the ways the capsules were prepared and delivered.-Increasing the amount of faecal material used in the production did not affect the efficacy of the treatment.-There are promising results in the treatment of other diseases such as liver disease, inflammatory bowel disease and the treatment of multi-drug resistant bacteria.