Recurrent Clostridium Difficile Infection Research Articles

Long-term beneficial effect of faecal microbiota transplantation on colonisation of multidrug-resistant bacteria and resistome abundance in patients with recurrent Clostridioides difficile infection

BackgroundMultidrug-resistant (MDR) bacteria are a growing global threat, especially in healthcare facilities. Faecal microbiota transplantation (FMT) is an effective prevention strategy for recurrences of Clostridioides difficile infections and can also be useful for other microbiota-related diseases.MethodsWe study the effect of FMT in patients with multiple recurrent C. difficile infections on colonisation with MDR bacteria and antibiotic resistance genes (ARG) on the short (3 weeks) and long term (1–3 years), combining culture methods and faecal metagenomics.ResultsBased on MDR culture (n = 87 patients), we notice a decrease of 11.5% in the colonisation rate of MDR bacteria after FMT (20/87 before FMT = 23%, 10/87 3 weeks after FMT). Metagenomic sequencing of patient stool samples (n = 63) shows a reduction in relative abundances of ARGs in faeces, while the number of different resistance genes in patients remained higher compared to stools of their corresponding healthy donors (n = 11). Furthermore, plasmid predictions in metagenomic data indicate that patients harboured increased levels of resistance plasmids, which appear unaffected by FMT. In the long term (n = 22 patients), the recipients’ resistomes are still donor-like, suggesting the effect of FMT may last for years.ConclusionsTaken together, we hypothesise that FMT restores the gut microbiota to a composition that is closer to the composition of healthy donors, and potential pathogens are either lost or decreased to very low abundances. This process, however, does not end in the days following FMT. It may take months for the gut microbiome to re-establish a balanced state. Even though a reservoir of resistance genes remains, a notable part of which on plasmids, FMT decreases the total load of resistance genes.

Protective effects of fecal microbiota transplantation against ischemic stroke and other neurological disorders: an update.

The bidirectional communication between the gut and brain or gut-brain axis is regulated by several gut microbes and microbial derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides. The Gut microbiota (GM) produce neuroactives, specifically neurotransmitters that modulates local and central neuronal brain functions. An imbalance between intestinal commensals and pathobionts leads to a disruption in the gut microbiota or dysbiosis, which affects intestinal barrier integrity and gut-immune and neuroimmune systems. Currently, fecal microbiota transplantation (FMT) is recommended for the treatment of recurrent Clostridioides difficile infection. FMT elicits its action by ameliorating inflammatory responses through the restoration of microbial composition and functionality. Thus, FMT may be a potential therapeutic option in suppressing neuroinflammation in post-stroke conditions and other neurological disorders involving the neuroimmune axis. Specifically, FMT protects against ischemic injury by decreasing IL-17, IFN-γ, Bax, and increasing Bcl-2 expression. Interestingly, FMT improves cognitive function by lowering amyloid-β accumulation and upregulating synaptic marker (PSD-95, synapsin-1) expression in Alzheimer's disease. In Parkinson's disease, FMT was shown to inhibit the expression of TLR4 and NF-κB. In this review article, we have summarized the potential sources and methods of administration of FMT and its impact on neuroimmune and cognitive functions. We also provide a comprehensive update on the beneficial effects of FMT in various neurological disorders by undertaking a detailed interrogation of the preclinical and clinical published literature.

A21 EFFECTS OF LYOPHILIZED FECAL FILTRATE COMPARED TO LYOPHILIZED DONOR STOOL IN THE TREATMENT OF RECURRENT CLOSTRIDIOIDES DIFFICILE INFECTION: A MULTI-CENTER RANDOMIZED TRIAL

Abstract Background Fecal microbiota transplantation (FMT) is the most effective therapy in the treatment of recurrent Clostridioides difficile infection (rCDI), and can be offered in fresh, frozen or lyophilized formulation with similar efficacy. Microbial engraftment is thought to be one of the mechanisms mediating its efficacy. However, the importance of microbes has been questioned by two small preliminary clinical studies that showed sterile fecal filtrate could prevent C. difficile recurrence. Aims To establish whether lyophilized sterile fecal filtrate (LSFF) is noninferior to lyophilized FMT (LFMT) in efficacy Methods In this double-blind, non-inferiority study conducted in 4 academic centers in Alberta and British Columbia, we randomized rCDI patients with ≥ 3 CDI episodes to either LSFF or LFMT at a 1:1 ratio between 2019 and 2023.The non inferiority margin was 10%. Each treatment dose consisted of 15 oral capsules. Participants who failed the assigned treatments were offered open-label LFMT. An interim analysis was planned after reaching 50% of recruitment target (124/248 participants). Primary outcome was the proportion of participants without CDI recurrence 8 weeks following assigned treatment. Secondary outcomes included 1) the proportion of participants without CDI recurrence 24 weeks following assigned treatment, 2) serious adverse events (mortality, hospitalization and infections related to treatments), and 3) minor adverse events (nausea, vomiting, abdominal pain and fever). Exploratory outcomes included changes in quality of life, stool microbial composition analyses, as well as patient preferences. Results 137 participants were randomized (mean [SD] age, 61.2 [18.6] years; 89 women [65.4%]; mean CDI episodes 3.8) to LFMT group (66 participants) and LSFF (71 participants) group. In per-protocol analysis, prevention of rCDI 8 weeks after assigned treatment was achieved in 63.8% of participants in LSFF group and 86.9% in LFMT group (difference, -23.1%), resulting in trial termination. Serious adverse events were infrequent: 4 hospitalizations deemed not related and 1 hospitalization possibly related, and 1 death from COVID deemed not related to assigned treatment. Minor adverse events were self-limited and infrequent: nausea (6), vomiting (2), abdominal discomfort (15) and fever (2). Conclusions Among adults with rCDI, LSFF was inferior to LFMT by oral capsules in preventing recurrent infection over 8 weeks. The result emphasizes the importance of microbes in mediating FMT efficacy. Preserving microbial viability in future development of microbial therapeutics is paramount. Funding Agencies CIHR

A20 FECAL MICROBIOTA TRANSPLANTATION FORMULATIONS DO NOT AFFECT BACTERIAL VIABILITY OR TREATMENT OUTCOMES IN RECURRENT C. DIFFICILE INFECTION

Abstract Background Fecal microbiota transplantation (FMT) is the most effective therapy for recurrent Clostridioides difficile infections (rCDI) with multiple RCTs showing efficacy of 80-90%. Frozen FMT is a commonly used formulation but requires storage at -80°C, creating barriers to storage and transportation. More recently, lyophilized FMT (LFMT) has shown promise as an alternative formulation, but little data exists as to how bacterial viability may be affected compared to fresh or frozen FMT by different storage temperatures and duration, and real-world outcome data is sparse. As such, this study aims to evaluate the viability and efficacy of LFMT compared to fresh and frozen FMT. Aims To 1) compare bacterial viability in 3 FMT formulations: fresh, frozen and lyophilization, at varying storage temperatures and duration, and 2) correlate different formulations with treatment outcomes. Methods We compared bacterial viability using flow cytometry to determine the proportion of live vs dead bacteria on fresh, frozen and lyophilized donor stool samples stored at different temperatures (-80°C for frozen, -80°C and +4°C for LFMT) and duration (up to 12 months). We then retrospectively examined treatment success rates in rCDI patients who received fresh, frozen or LFMT at the University of Alberta since inception of the FMT program in 2012. Success is defined as no recurrence of CDI 8 weeks after receiving a single FMT treatment. Results Compared to fresh FMT (20% live cells), the proportions of live cells in frozen formulation stored at -80°C and lyophilized formulations stored at -80°C and 4°C did not diminish over time for up to 12 months as shown in Figure 1. Between 2013-2022, outcome data was available in 503 rCDI patients with baseline characteristics and treatment outcomes shown in Table 1. A logistic regression analysis comparing LFMT to frozen FMT resulted in an odds ratio of 0.14, indicating that success rate of LFMT is 14% higher than frozen FMT. Conclusions Our study showed that LFMT stored at either -80°C or 4°C over 12 months did not result in diminished bacterial viability compared with frozen FMT. Furthermore, treatment success rate following LFMT in rCDI patients was not lower than with frozen FMT. This finding has implication for stool banks and FMT programs as LFMT can be stored and shipped at 4°C, facilitating use in outpatient settings. Table 1. Baseline characteristics and success rates of rCDI patients who received fresh, frozen or LFMT. Figure 1. Proportions of live cells in frozen FMT stored at -80°C, LFMT stored at -80°C and 4°C, at 1, 3, 6, 9 and 12 months. Funding Agencies None

The Strain and the Clinical Outcome of Clostridioides difficile Infection: A Meta-analysis.

The association between bacterial strains and clinical outcomes in Clostridioides difficile infection (CDI) has yielded conflicting results across studies. We conducted a systematic review and meta-analyses to assess the impact of these strains. Five electronic databases were used to identify studies reporting CDI severity, complications, recurrence, or mortality according to strain type from inception to June 2022. Random effect meta-analyses were conducted to assess outcome proportions and risk ratios (RRs). A total of 93 studies were included: 44 reported recurrences, 50 reported severity or complications, and 55 reported deaths. Pooled proportions of complications were statistically comparable between NAP1/BI/R027 and R001, R078, and R106. Pooled attributable mortality was 4.8% with a gradation in patients infected with R014/20 (1.7%), R001 (3.8%), R078 (5.3%), and R027 (10.2%). Higher 30-day all-cause mortality was observed in patients infected with R001, R002, R027, and R106 (range, 20%-25%).NAP1/BI/R027 was associated with several unfavorable outcomes: recurrence 30 days after the end of treatment (pooled RR, 1.98; 95% CI, 1.02-3.84); admission to intensive care, colectomy, or CDI-associated death (1.88; 1.09-3.25); and 30-day attributable mortality (1.96; 1.23-3.13). The association between harboring the binary toxin gene and 30-day all-cause mortality did not reach significance (RR, 1.6 [0.9-2.9]; 7 studies). Numerous studies were excluded due to discrepancies in the definition of the outcomes and the lack of reporting of important covariates. NAP1/BI/R027, the most frequently reported and assessed strain, was associated with unfavorable outcomes. However, there were not sufficient data to reach significant conclusions on other strains.

Current perspectives on fecal microbiota transplantation in inflammatory bowel disease.

Fecal microbiota transplantation (FMT) has emerged as a promising therapeutic modality within the domain of inflammatory bowel disease (IBD). While FMT has secured approval and demonstrated efficacy in addressing recurrent and refractory Clostridioides difficile infection, its application in IBD remains an area of active exploration and research. The current status of FMT in IBD reflects a nuanced landscape, with ongoing investigations delving into its effectiveness, safety and optimal implementation. Early-stage clinical trials and observational studies have provided insights into the potential of FMT to modulate the dysbiotic gut microbiota associated with IBD, aiming to mitigate inflammation and promote mucosal healing. However, considerable complexities persist, including variations in donor selection, treatment protocols and outcome assessments. Challenges in standardizing FMT protocols for IBD treatment are compounded by the dynamic nature of the gut microbiome and the heterogeneity of IBD itself. Despite these challenges, enthusiasm for FMT in IBD emanates from its capacity to address gut microbial dysbiosis, signifying a paradigm shift towards more comprehensive approaches in IBD management. As ongoing research progresses, an enhanced understanding of FMT's role in IBD therapy is anticipated. This article synthesizes the current status of FMT in IBD, elucidating the attendant challenges and aspiring towards the refinement of its application for improved patient outcomes.

A Systematic Literature Review on Risk Factors for and Timing of Clostridioides difficile Infection in the United States.

Clostridioides difficile infection (CDI) is a major public health threat. Up to 40% of patients with CDI experience recurrent CDI (rCDI), which is associated with increased morbidity. This study aimed to define an at-risk population by obtaining a detailed understanding of the different factors leading to CDI, rCDI, and CDI-related morbidity and of time to CDI. We conducted a systematic literature review (SLR) of MEDLINE (using PubMed) and EMBASE for relevant articles published between January1, 2016, and November11, 2022, covering the US population. Of the 1324 articles identified, 151 met prespecified inclusion criteria. Advanced patient age was a likely risk factor for primary CDI within a general population, with significant risk estimates identified in nine of 10 studies. Older age was less important in specific populations with comorbidities usually diagnosed at earlier age, such as bowel disease and cancer. In terms of comorbidities, the established factors of infection, kidney disease, liver disease, cardiovascular disease, and bowel disease along with several new factors (including anemia, fluid and electrolyte disorders, and coagulation disorders) were likely risk factors for primary CDI. Data on diabetes, cancer, and obesity were mixed. Other primary CDI risk factors were antibiotics, proton pump inhibitors, female sex, prior hospitalization, and the length of stay in hospital. Similar factors were identified for rCDI, but evidence was limited. Older age was a likely risk factor for mortality. Timing of primary CDI varied depending on the population: 2-3weeks in patients receiving stem cell transplants, within 3weeks for patients undergoing surgery, and generally more than 3weeks following solid organ transplant. This SLR uses recent evidence to define the most important factors associated with CDI, confirming those that are well established and highlighting new ones that could help to identify patient populations at high risk.

Microbiota-Based Live Biotherapeutic Products for Clostridioides Difficile Infection- The Devil is in the Details.

Clostridioides difficile infection (CDI) remains a significant contributor to healthcare costs and morbidity due to high rates of recurrence. Currently, available antibiotic treatment strategies further disrupt the fecal microbiome and do not address the alterations in commensal flora (dysbiosis) that set the stage for CDI. Advances in microbiome-based research have resulted in the development of new agents, classified as live biotherapeutic products (LBPs), for preventing recurrent CDI (rCDI) by restoring eubiosis. Prior to the LBPs, fecal microbiota transplantation (FMT) was available for this purpose; however, lack of large-scale availability and safety concerns have remained barriers to its widespread use. The LBPs are an exciting development, but questions remain. Some are derived directly from human stool while other developmental products contain a defined microbial consortium manufactured ex vivo, and they may be composed of either living bacteria or their spores, making it difficult to compare members of this heterogenous drug class to one another. None have been studied head-to head or against FMT in preventing rCDI. As a class, they have considerable variability in their biologic composition, biopharmaceutic science, route of administration, stages of development, and clinical trial data. This review will start by explaining the role of dysbiosis in CDI, then give the details of the biopharmaceutical components for the LBPs which are approved or in development including how they differ from FMT and from one another. We then discuss the clinical trials of the LBPs currently approved for rCDI and end with the future clinical directions of LBPs beyond C. difficile.

Clostridioides difficile Infection: Diagnosis and Treatment Challenges.

Clostridioides difficile is the most important cause of healthcare-associated diarrhea in the United States. The high incidence and recurrence rates of C. difficile infection (CDI), associated with high morbidity and mortality, pose a public health challenge. Although antibiotics targeting C. difficile bacteria are the first treatment choice, antibiotics also disrupt the indigenous gut flora and, therefore, create an environment that is favorable for recurrent CDI. The challenge of treating CDI is further exacerbated by the rise of antibiotic-resistant strains of C. difficile, placing it among the top five most urgent antibiotic resistance threats in the USA. The evolution of antibiotic resistance in C. difficile involves the acquisition of new resistance mechanisms, which can be shared among various bacterial species and different C. difficile strains within clinical and community settings. This review provides a summary of commonly used diagnostic tests and antibiotic treatment strategies for CDI. In addition, it discusses antibiotic treatment and its resistance mechanisms. This review aims to enhance our current understanding and pinpoint knowledge gaps in antimicrobial resistance mechanisms in C. difficile, with an emphasis on CDI therapies.

P1045 Comparative Efficacy of Fecal Microbiota Transplantation for Clostridioides Difficile Infection in Patients with and without Inflammatory Bowel Disease: A Retrospective Cohort Study

Abstract Background Clostridioides difficile infection (CDI) significantly exacerbates and worsens the prognosis of inflammatory bowel disease (IBD). While fecal microbiota transplantation (FMT) is recognized as a safe and efficacious therapy for patients battling recurrent or refractory CDI, but comparative studies focusing on the success rates in IBD and non-IBD patients remain scarce. Our study aims to shed light on this gap in knowledge. Methods In this retrospective cohort study conducted at Chang Gung Memorial Hospital between April 2019 and February 2023, patients undergoing FMT via colonoscopy for recurrent or refractory CDI were enrolled. Participants were categorized into IBD and non-IBD groups based on their underlying conditions. We compared baseline characteristics and clinical outcomes at one-month and one-year follow-up intervals. CDI diagnosis was confirmed through positive CD toxin A/B genes and associated clinical symptoms. Donor specimens were sourced from Chang Gung Microbiota Therapy Center's fecal bank. Results Our study included 88 patients who received FMT, comprising 30 in the IBD group and 58 in the non-IBD group. The indications were recurrent CDI in 31 patients, refractory CDI in 54, and both conditions in 3 patients. Among the IBD subgroup, 20 patients had ulcerative colitis, and 10 had Crohn's disease. In the baseline comparison, the IBD group was significantly younger (mean±SD, 45.23±16.45 years vs. 61.90±24.40 years, P = 0.001) and had fewer comorbidities such as hypertension (10.0% vs. 55.2%, P < 0.001), diabetes mellitus (6.7% vs. 31.0%, P = 0.014), and cancer (3.3% vs. 31.0%, P = 0.012) than the non-IBD group. Additionally, the IBD group had less prior Fidaxomin use (6.9% vs. 26.3%, P = 0.021) and fewer HMG-CoA reductase inhibitor users (0.0% vs. 15.5%, P = 0.025). Post-FMT, IBD severity indices showed significant improvement at one month. The mean partial Mayo score in the IBD group decreased by 2.9 points, the endoscopic Mayo subscore decreased by 0.7 points, and the Crohn’s Disease Activity Index decreased by 79.98 points. At this time, the IBD group showed a similar percentage of negative CDI toxin A/B tests (83.3% vs. 63.8%, P = 0.174) but had lower clinical remission rates (79.5% vs. 96.5%, P = 0.006) compared to the non-IBD group. However, at the one-year follow-up, the eradication rate (94.4% vs. 73.9%, P = 0.112) and clinical remission rate (84.2% vs. 90.3%, P = 0.661) were comparable between both groups. No safety issues or adverse effects were reported in any of the patients. Conclusion FMT demonstrates safety and efficacy in treating recurrent or refractory CDI in both IBD and non-IBD patients, also aiding in mitigating IBD-associated inflammation.

The combined effect of systemic antibiotics and proton pump inhibitors on Clostridioides difficile infection and recurrence.

Antibiotics and proton pump inhibitors (PPI) are recognized risk factors for acquisition and recurrence of Clostridioides difficile infection (CDI), yet combined effects remain unclear. To assess the short- and long-term effects of antibiotics and PPIs on CDI risk and recurrence. Population-based study including all 43 152 patients diagnosed with CDI in Sweden (2006-2019), and 355 172 matched population controls without CDI. The impact of antibiotics and PPIs on CDI risk and recurrence was explored for recent (0-30 days) and preceding (31-180 days) use prior to their first CDI diagnosis, using multivariable conditional logistic regression presented as odds ratios (ORs) and 95% confidence interval, adjusted for demographics, comorbidities and other drugs. Compared to controls, the combined effect of recent PPIs and antibiotics [ORAB+PPI = 17.51 (17.48-17.53)] on CDI risk was stronger than the individual effects [ORAB = 15.37 (14.83-15.93); ORPPI = 2.65 (2.54-2.76)]. Results were less pronounced for exposure during the preceding months. Dose-response analyses showed increasing exposure correlated with CDI risk [recent use: ORAB = 6.32 (6.15-6.49); ORPPI = 1.65 (1.62-1.68) per prescription increase].Compared to individuals without recurrence (rCDI), recent [ORAB = 1.30 (1.23-1.38)] and preceding [ORAB = 1.23 (1.16-1.31); ORPPI = 1.12 (1.03-1.21)] use also affected the risk of recurrence yet without significant interaction between both. Recent macrolides/lincosamides/streptogramins; other antibacterials including nitroimidazole derivates; non-penicillin beta lactams and quinolones showed the strongest association with CDI risk and recurrence, particularly for recent use. PPI use, both recent and preceding, further increased the CDI risk associated with almost all antibiotic classes. Recent and less recent use of PPIs and systemic antibiotics was associated with an increased risk of CDI, particularly in combination.

Gut Microbiota-Gut Metabolites and Clostridioides difficile Infection: Approaching Sustainable Solutions for Therapy.

Clostridioides difficile (C. difficile) infection (CDI) is the most common hospital-acquired infection. With the combination of a high rate of antibiotic resistance and recurrence, it has proven to be a debilitating public health threat. Current treatments for CDI include antibiotics and fecal microbiota transplantation, which contribute to recurrent CDIs and potential risks. Therefore, there is an ongoing need to develop new preventative treatment strategies for CDI. Notably, gut microbiota dysbiosis is the primary risk factor for CDI and provides a promising target for developing novel CDI therapy approaches. Along with gut microbiota dysbiosis, a reduction in important gut metabolites like secondary bile acids and short-chain fatty acids (SCFAs) were also seen in patients suffering from CDI. In this review study, we investigated the roles and mechanisms of gut microbiota and gut microbiota-derived gut metabolites, especially secondary bile acids and SCFAs in CDI pathogenesis. Moreover, specific signatures of gut microbiota and gut metabolites, as well as different factors that can modulate the gut microbiota, were also discussed, indicating that gut microbiota modulators like probiotics and prebiotics can be a potential therapeutic strategy for CDI as they can help restore gut microbiota and produce gut metabolites necessary for a healthy gut. The understanding of the associations between gut microbiota-gut metabolites and CDI will allow for developing precise and sustainable approaches, distinct from antibiotics and fecal transplant, for mitigating CDI and other gut microbiota dysbiosis-related diseases.

Durability and outcomes of fecal microbiota transplantation for recurrent Clostridioides difficile infection in patients with moderate to severe inflammatory bowel disease.

Durability and outcomes of fecal microbiota transplantation for recurrent Clostridioides difficile infection in patients with moderate to severe inflammatory bowel disease.

Systematic review of the orally administered microbiome therapeutic, fecal microbiota spores, live-brpk, to prevent recurrence of Clostridioides difficile infection in adults.

Clostridioides difficile infection (CDI) has been linked to over 200,000 cases of illness in hospitalized patients and over 20,000 deaths annually. Up to 25% of patients with an initial CDI episode will experience recurrent CDI (rCDI), which most commonly occurs in the first 8 weeks following antibiotic therapy. In patients with first or multiple rCDI, infection, the microbiome is similarly disrupted, which highlights the challenges of using antibiotics alone while underscoring the need for microbiome restoration regardless of the number of recurrences. In this systematic review, we describe the role of the gastrointestinal microbiome in CDI, and systematically review fecal microbiota spores, live-brpk (VOWST™; VOS for Vowst Oral Spores) for prevention of recurrence in rCDI. The PubMed database was searched using "recurrent Clostridioides difficile infection" AND (SER-109 OR VOS) and limited to clinical trials. The search yielded 7 results: 3 articles describing 3 clinical trials (two Phase 3 trials (ECOSPOR III and ECOSPOR IV) and one Phase 2 trial (ECOSPOR)), 1 describing follow-up of ECOSPOR III, 1 describing a post hoc analysis of comorbidities in ECOSPOR III, and 2 describing health-related quality of life in ECOSPOR III. Compared with placebo, VOS following standard-of-care antibiotics for CDI significantly reduced risk of recurrence at 8 weeks (relative risk, 0.32 (95% CI: 0.18-0.58); p < 0.001; number needed to treat: 4) with a tolerable safety profile; rCDI rates remained low through 24 weeks. The disrupted microbiome, secondary to/exacerbated by antibiotic treatment, was rapidly (i.e., Week 1) restored with VOS. Compared with placebo, VOS demonstrated greater improvements in health-related quality of life. Clinical care of patients with rCDI now includes Food and Drug Administration-approved therapeutics to address microbiome restoration. Clinical trial evidence supports use of VOS following antibiotics and importance of microbiome restoration in rCDI.

Clostridioides difficile Biofilm.

Clostridioides difficile infection (CDI), previously Clostridium difficile infection, is a symptomatic infection of the large intestine caused by the spore-forming anaerobic, gram-positive bacterium Clostridioides difficile. CDI is an important healthcare-associated disease worldwide, characterized by high levels of recurrence, morbidity, and mortality. CDI is observed at a higher rate in immunocompromised patients after antimicrobial therapy, with antibiotics disrupting the commensal microbiota and promoting C. difficile colonization of the gastrointestinal tract.A rise in clinical isolates resistant to multiple antibiotics and the reduced susceptibility to the most commonly used antibiotic molecules have made the treatment of CDI more complicated, allowing the persistence of C. difficile in the intestinal environment.Gut colonization and biofilm formation have been suggested to contribute to the pathogenesis and persistence of C. difficile. In fact, biofilm growth is considered as a serious threat because of the related antimicrobial tolerance that makes antibiotic therapy often ineffective. This is the reason why the involvement of C. difficile biofilm in the pathogenesis and recurrence of CDI is attracting more and more interest, and the mechanisms underlying biofilm formation of C. difficile as well as the role of biofilm in CDI are increasingly being studied by researchers in the field.Findings on C. difficile biofilm, possible implications in CDI pathogenesis and treatment, efficacy of currently available antibiotics in treating biofilm-forming C. difficile strains, and some antimicrobial alternatives under investigation will be discussed here.

Efficacy and Health-Related Quality of Life Impact of Fecal Microbiota, Live-jslm: A Post Hoc Analysis of PUNCH CD3 Patients at First Recurrence of Clostridioides difficile Infection.

Clostridioides difficile infection (CDI) causes symptoms of varying severity and negatively impacts patients' health-related quality of life (HRQL). Despite antibiotic treatment, recurrence of CDI (rCDI) is common and imposes clinical and economic burdens on patients. Fecal microbiota, live-jslm (REBYOTA [RBL]) is newly approved in the USA for prevention of rCDI following antibiotic treatments. We analyzed efficacy and HRQL impact of RBL vs. placebo in patients at first rCDI using data from the phase3 randomized, double-blind placebo-controlled clinical trial, PUNCH CD3. This post hoc analysis included patients at first rCDI fromPUNCH CD3. Treatment success (i.e., absence of diarrhea within 8weeks post-treatment) was analyzed adjusting for baseline patient characteristics. HRQL was measured using the Clostridioides difficile Quality of Life Survey (Cdiff32); absolute scores and change from baseline in total and domain (physical, mental, and social) scores were summarized and compared between arms. Analyses were conducted for the trial's blinded phase only. Among 86 eligible patients (32.8% of the overall trial population, RBL 53 [61.6%], placebo 33 [38.4%]), RBL-treated patients had significantly lower odds of recurrence (i.e., greater probability of treatment success) at week8 vs. placebo (odds ratio 0.35 [95% confidence interval 0.13, 0.98]). Probability of treatment success at week8 was 81% for RBL and 60% for placebo, representing 21% absolute and 35% relative increases for RBL (crude proportions 79.2% vs. 60.6%; relative risk 0.53, p = 0.06). Additionally, RBL was associated with significantly higher Cdiff32 total (change score difference 13.5 [standard deviation 5.7], p < 0.05) and mental domain (16.2 [6.0], p < 0.01) scores vs. placebo from baseline to week8. Compared to placebo, RBL demonstrated a significantly higher treatment success in preventing further rCDI and enhanced HRQL among patients at first recurrence, establishing RBL as an effective treatment to prevent further recurrences in these patients. ClinicalTrials.gov Identifier NCT03244644.

Comparative effectiveness of treatments for recurrent Clostridioides difficile infection: a network meta-analysis of randomized controlled trials.

Clostridioides difficile infection (CDI) is the most common cause of healthcare-associated infectious diarrhea. A major clinical challenge is recurrent CDI (rCDI) without effective standard drug-based therapy. Additionally, a comprehensive comparison of various therapy effectiveness in rCDI patients is still under investigation. A Bayesian network meta-analysis (NMA) of randomized control trials up to March 2024 was performed to investigate the efficacy of rCDI interventions. Seventeen trials were included, comprising 4,148 CDI patients with ten interventions, including fecal microbiota transplantation (FMT) by lower gastrointestinal (LGI), FMT by upper gastrointestinal (UGI), Autologous FMT (AFMT), vancomycin + FMT, vancomycin, placebo, fidaxomicin, Vowst (SER109), Rebyota (RBX2660), and monoclonal antibody. NMA showed that FMT by LGI had the highest efficacy in treating rCDIs with an odds ratio (95% confidence interval) of 32.33 (4.03, 248.69) compared with placebo. FMT by UGI also showed high efficacy, whereas the efficacy comparison between FMT by LGI and UGI was not statistically significant (ORs) (95% CI), 1.72 (0.65, 5.21). The rankogram and surface under the cumulative ranking curve (SUCRA) also showed FMT by LGI ranked at the top and FMT by UGI ranked second in the curative effect. NMA demonstrates FMT's significant efficacy in rCDI management, regardless of administration route (lower or upper gastrointestinal). Despite its significant benefits, FMT's safety is a concern due to the lack of standardized FDAcompliant manufacturing and oversight. Microbiota-based therapies also exhibit potential. However, limited research mandates further clinical exploration. Antibiotics, in contrast, display comparatively reduced efficacy in rCDI, potentially linked to disruptions in native gut microflora balance. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=368435, Identifier CRD42022368435.

European Practice for CDI Treatment.

Clostridioides difficile infection (CDI) remains a significant cause of morbidity and mortality worldwide. Historically, two antibiotics (metronidazole and vancomycin) and a recent third (fidaxomicin) have been used for CDI treatment; convincing data are now available showing that metronidazole is the least efficacious agent. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) management guidance for CDI were updated in 2021. This guidance document outlines the treatment options for a variety of CDI clinical scenarios and for non-antimicrobial management (e.g., faecal microbiota transplantation, FMT). One of the main changes is that metronidazole is no longer recommended as first-line CDI treatment. Rather, fidaxomicin is preferred on the basis of reduced recurrence rates with vancomycin as an acceptable alternative. Recommended options for recurrent CDI now include bezlotoxumab as well as FMT.A 2017 survey of 20 European countries highlighted variation internationally in CDI management strategies. A variety of restrictions were in place in 65% countries prior to use of new anti-CDI treatments, including committee/infection specialist approval or economic review/restrictions. This survey was repeated in November 2022 to assess the current landscape of CDI management practices in Europe. Of 64 respondents from 17 countries, national CDI guidelines existed in 14 countries, and 11 have already/plan to incorporate the ESCMID 2021 CDI guidance, though implementation has not been surveyed in 6. Vancomycin is the most commonly used first-line agent for the treatment of CDI (n=42, 66%), followed by fidaxomicin (n=30, 47%). Six (9%) respondents use metronidazole as first-line agent for CDI treatment, whereas 22 (34%) only in selected low-risk patient groups. Fidaxomicin is more likely to be used in high-risk patient groups. Availability of anti-CDI therapy influenced prescribing in six respondents (9%). Approval pre-prescription was required before vancomycin (n=3, 5%), fidaxomicin (n=10, 6%), bezlotoxumab (n=11, 17%) and FMT (n=10, 6%). Implementation of CDI guidelines is rarely audited.Novel anti-CDI agents are being evaluated; it is not yet clear what will be the roles of these agents. The treatment of recurrent CDI is particularly troublesome, and several different live biotherapeutics are being developed, in addition to FMT.

Retrospective subgroup analysis of fecal microbiota, live-jslm (REBYOTA®) administered by colonoscopy under enforcement discretion for the prevention of recurrent Clostridioides difficile infection.

Fecal microbiota, live-jslm (RBL; REBYOTA®), is the first Food and Drug Administration (FDA)-approved, single-dose, rectally administered, microbiota-based live biotherapeutic product for preventing Clostridioides difficile infection (CDI) recurrence. Alternative routes of administration are of clinical interest. Evaluate the safety and efficacy of RBL administration via colonoscopy. Retrospective analysis of electronic medical records of participants administered RBL via colonoscopy under FDA enforcement discretion. The number of participants with treatment and/or procedure-emergent adverse events (TEAEs) was evaluated. Treatment success and sustained clinical response, defined as the absence of CDI recurrence within 8 weeks and 6 months, respectively, were evaluated. TEAEs were experienced by 75% (6/8) of participants; most were mild to moderate in severity, and none due to RBL or its administration. Most participants had treatment success (80%; 8/10); 75% (6/8) had sustained clinical response. Real-world safety and efficacy of RBL administered via colonoscopy were consistent with clinical trials of rectally administered RBL.

Real-world effectiveness of fidaxomicin in patients at high risk of Clostridioides difficile recurrence.

Compare the real-world impact of fidaxomicin (FDX) and vancomycin (VAN) on Clostridioides difficile infection (CDI) recurrence in a high-risk patient population. A retrospective, matched-cohort study evaluating hospitalized patients with CDI from January 1, 2016, to November 1, 2022, within a tertiary academic medical center. Adult patients with at least 1 prior CDI case who received either FDX or VAN for non-fulminant CDI while admitted, and had at least 1 additional risk factor for recurrence. Risk factors included age >70, solid organ or bone marrow transplant recipients, broad-spectrum antibiotic use within 30 days, or receipt of chemotherapy/immune-modulating agents within 30days of admission. FDX and VAN patients were matched according to risk factors. A total of 415 patient admissions were identified. After the exclusion of 92 patients for fulminant CDI, diarrhea from another cause, or use of VAN taper therapy, and 15 unmatched patients, 308 patient admissions were included (68 FDX and 240 VAN patients). There were no significant differences in 4-week recurrence (26% vs 23%; OR 1.1; P = .51), 90-day CDI readmission (29% vs 23%; P = .65), or 90-day all-cause readmission (54% vs 53%; P = .91). There was a significant 17% decrease in 90-day mortality associated with the use of FDX (OR .3; P = .04). In a real-world high-risk patient population, the use of FDX compared to oral VAN did not result in decreased CDI recurrence within 4 weeks or fewer hospital readmissions within 90 days. Further research is needed to better assess the value of FDX in this patient population.