Machine Learning-based Prediction Models for C difficile Infection: A Systematic Review.

BACKGROUND: Despite research efforts, predicting Clostridioides difficile incidence and its outcomes remains challenging. This systematic review aimed to evaluate the performance of machine-learning (ML) models in predicting CDI incidence and complications using clinical data from electronic health records. METHODS: We conducted a comprehensive search of databases (OVID, Embase, MEDLINE ALL, Web of Science, and Scopus) from inception up to September 2023. Studies employing ML techniques for predicting CDI or its complications were included. The primary outcome was the type and performance of ML models assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Twelve retrospective studies that evaluated CDI incidence and/or outcomes were included. The most common used ML models were random forest and Gradient Boosting. The AUROC ranged from 0.60 to 0.81 for predicting CDI incidence, 0.59 to 0.80 for recurrence, and 0.64 to 0.88 for predicting complications. Advanced ML models demonstrated similar performance to traditional logistic regression. However, there was notable heterogeneity in defining CDI and the different outcomes, including incidence, recurrence, and complications, and a lack of external validation in most studies. CONCLUSION: ML models show promise in predicting CDI incidence and outcomes. However, the observed heterogeneity in CDI definitions and the lack of real-world validation highlight challenges in clinical implementation. Future research should focus on external validation and the use of standardized definitions across studies.

Safety, feasibility, and impact on the gut microbiome of kefir administration in critically ill adults.

BACKGROUND: Dysbiosis of the gut microbiome is frequent in the intensive care unit (ICU), potentially leading to a heightened risk of nosocomial infections. Enhancing the gut microbiome has been proposed as a strategic approach to mitigate potential adverse outcomes. While prior research on select probiotic supplements has not successfully shown to improve gut microbial diversity, fermented foods offer a promising alternative. In this open-label phase I safety and feasibility study, we examined the safety and feasibility of kefir as an initial step towards utilizing fermented foods to mitigate gut dysbiosis in critically ill patients. METHODS: We administered kefir in escalating doses (60 mL, followed by 120 mL after 12 h, then 240 mL daily) to 54 critically ill patients with an intact gastrointestinal tract. To evaluate kefir's safety, we monitored for gastrointestinal symptoms. Feasibility was determined by whether patients received a minimum of 75% of their assigned kefir doses. To assess changes in the gut microbiome composition following kefir administration, we collected two stool samples from 13 patients: one within 72 h of admission to the ICU and another at least 72 h after the first stool sample. RESULTS: After administering kefir, none of the 54 critically ill patients exhibited signs of kefir-related bacteremia. No side effects like bloating, vomiting, or aspiration were noted, except for diarrhea in two patients concurrently on laxatives. Out of the 393 kefir doses prescribed for all participants, 359 (91%) were successfully administered. We were able to collect an initial stool sample from 29 (54%) patients and a follow-up sample from 13 (24%) patients. Analysis of the 26 paired samples revealed no increase in gut microbial α-diversity between the two timepoints. However, there was a significant improvement in the Gut Microbiome Wellness Index (GMWI) by the second timepoint (P = 0.034, one-sided Wilcoxon signed-rank test); this finding supports our hypothesis that kefir administration can improve gut health in critically ill patients. Additionally, the known microbial species in kefir were found to exhibit varying levels of engraftment in patients' guts. CONCLUSIONS: Providing kefir to critically ill individuals is safe and feasible. Our findings warrant a larger evaluation of kefir's safety, tolerability, and impact on gut microbiome dysbiosis in patients admitted to the ICU. TRIAL REGISTRATION: NCT05416814; trial registered on June 13, 2022.

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.

INTRODUCTION: 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 phase 3 randomized, double-blind placebo-controlled clinical trial, PUNCH CD3. METHODS: This post hoc analysis included patients at first rCDI fromPUNCH CD3. Treatment success (i.e., absence of diarrhea within 8 weeks 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. RESULTS: 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 week 8 vs. placebo (odds ratio 0.35 [95% confidence interval 0.13, 0.98]). Probability of treatment success at week 8 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 week 8. CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03244644.

Clostridioides difficile Infection: Landscape and Microbiome Therapeutics.

Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea and is common in the community. Both younger individuals who may be healthy otherwise and older individuals with comorbid conditions are at risk for developing CDI, with the predominant risk factor being antibiotic use. Unlike other gastrointestinal infections, CDI is not self-limited, requires antimicrobial therapy, and tends to recur at high rates even without additional risk factor exposure. The goals of CDI management include controlling active symptoms and using a recurrence prevention strategy such as a narrow-spectrum antibiotic, tapered and pulsed regimens, antibody- based therapies (directed against toxin B), or microbiome restoration. In recent years, fecal microbiota transplantation (FMT) has been the most used modality to prevent recurrent CDI with high cure rates. Heterogeneity, lack of scalability, and serious adverse events from FMT have led to development of standardized microbiota restoration therapies (MRTs). The US Food and Drug Administration has approved 2 stool-derived MRTs for prevention of recurrent CDI: fecal microbiota, live-jslm, an enema-based therapy; and fecal microbiota spores, live-brpk, an oral therapy. A phase 3 trial for a synthetic oral MRT is underway. This article outlines the pathophysiology and treatment of CDI, focusing primarily on the gut microbiome and standardized MRTs.

Effectiveness and Safety Profile of Budesonide Maintenance in Microscopic Colitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Microscopic colitis (MC) is a common cause of chronic diarrhea. Randomized controlled trials (RCTs) have demonstrated the efficacy of budesonide treatment for MC. However, relapse is frequent after discontinuation of budesonide, and data on maintenance therapy are limited. We performed a systematic review and meta-analysis evaluating these outcomes in clinical trials and real-world settings. METHODS: A systematic search was performed on October 31, 2022, of Medline, Embase, Cochrane, and Scopus. Case series, case-control, cohort studies, and RCTs of adults with MC were included. Data were pooled using random effects models to calculate weighted pooled estimates and 95% confidence intervals. Heterogeneity was assessed using the I2 statistic. RESULTS: We included 35 studies (11 RCTs, 24 observational studies) with 1657 MC patients treated with budesonide induction and 146 for maintenance. The overall pooled clinical remission rate with budesonide treatment was similar between RCTs and observational studies. The pooled remission rate with budesonide maintenance therapy was 84% (95% CI, 0.60-1.00; I2 = 91%). After budesonide discontinuation, the pooled relapse rate was 53% (95% CI, 0.42-0.63; I2 = 76%). On maintenance therapy, no differences were noted in adverse events (eg, metabolic bone disease, hypertension, hyperglycemia, cataracts/glaucoma) in those on budesonide vs placebo or other noncorticosteroid medications for MC (P = .9). CONCLUSIONS: Budesonide is an effective maintenance treatment for MC. There is a high risk of recurrence after budesonide discontinuation, but long-term use at the lowest effective dose appears to be relatively safe and have limited adverse effects.

Manufacturing Processes of a Purified Microbiome Therapeutic Reduce Risk of Transmission of Potential Bacterial Pathogens in Donor Stool.

BACKGROUND: Although fecal microbiota transplant has been used to prevent recurrent Clostridioides difficile infection (rCDI), documented pathogen transmissions highlight inherent safety risks of minimally processed stool. We describe manufacturing processes for fecal microbiota spores, live (VOWST; VOS, formerly SER-109), a microbiota-based oral therapeutic of Firmicutes spores. METHODS: Bacterial inactivation kill curves were obtained after ethanol exposure for 4 model organisms spiked into process intermediates. RESULTS: Bacterial log reduction factors ranged from 6.5 log10 to 7.4 log10 and lysis of spiked organisms occurred rapidly within 30 seconds. CONCLUSIONS: These experiments demonstrate substantial and rapid inactivation of representative organisms, supporting the potential benefit of VOS manufacturing processes to mitigate risk.

Therapeutics for Clostridioides difficile infection: molecules and microbes.

INTRODUCTION: Clostridioides difficile infection (CDI) is a major healthcare problem in the developed world, and effective management of recurrent infection remains one of the biggest challenges. Several advances have occurred in the management of CDI, and in the last 15 years, multiple new agents have been tested. Since 2011, four new products have been approved by the US FDA for treatment of CDI or prevention of recurrent CDI. AREAS COVERED: This review focuses on therapeutics of CDI and includes sections on primary prevention, management of active infection, and prevention of recurrent CDI. Specifically, data are included on fecal microbiota transplantation and live biotherapeutics. A comprehensive search of several databases including Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from inception to 1 May 2023 was conducted. EXPERT OPINION: Metronidazole is no longer advised for management of outpatient CDI. The preferred medication of choice for a first episode is oral vancomycin or fidaxomicin. For those patients who recur after the first episode, vancomycin taper pulse or fidaxomicin can be used. Intravenous bezlotoxumab, a monoclonal antibody, is available to prevent recurrences. There are now two FDA-approved microbiome-based therapies or live biotherapeutics for prevention of recurrent CDI, for any recurrent CDI and not necessarily multiply recurrent C difficile. Fecal microbiota transplantation remains available in limited settings for recurrent CDI.

Recurrent Clostridioides difficile Infection: Current Clinical Management and Microbiome-Based Therapies.

Clostridioides difficile is one of the most important causes of healthcare-associated diarrhea. The high incidence and recurrence rates of C. difficile infection, as well as its associated morbidity and mortality, are great concerns. The most common complication of C. difficile infection is recurrence, with rates of 20-30% after a primary infection and 60% after three or more episodes. Medical management of recurrent C. difficile infection involves a choice of therapy that is different from the antibiotic used in the primary episode. Patients with recurrent C. difficile infection also benefit from fecal microbiota transplantation or standardized microbiome restoration therapies (approved or experimental) to restore eubiosis. In contrast to antibiotics, microbiome restoration therapies restore a normal gut flora and eliminate C. difficile colonization and infection. Fecal microbiota transplantation in recurrent C. difficile infection has demonstrated higher success rates than vancomycin, fidaxomicin, or placebo. Fecal microbiota transplantation has traditionally been considered safe, with the most common adverse reactions being abdominal discomfort, and diarrhea, and rare serious adverse events. Significant heterogeneity and a lack of standardization regarding the process of preparation, and administration of fecal microbiota transplantation remain a major pitfall. Standardized microbiome-based therapies provide a promising alternative. In the ECOSPOR III trial of SER-109, an oral formulation of bacterial spores, a significant reduction in the recurrence rate (12%) was observed compared with placebo (40%). In the phase III PUNCH CD3 trial, RBX2660 also demonstrated high efficacy rates of 70.6% versus 57.5%. Both these agents are now US Food and Drug Administration approved for recurrent C. difficile infection. Other standardized microbiome-based therapies currently in the pipeline are VE303, RBX7455, and MET-2. Antibiotic neutralization strategies, vaccines, passive monoclonal antibodies, and drug repurposing are other therapeutic strategies being explored to treat C. difficile infection.

Fidaxomicin treatment for Clostridioides difficile infection in patients with inflammatory bowel disease.

BACKGROUND AND AIM: Although fidaxomicin is an effective first-line treatment for Clostridioides difficile infection, it has not been well studied in patients with inflammatory bowel disease. We aimed to assess the effectiveness of fidaxomicin for the treatment of C. difficile infection in patients with inflammatory bowel disease. METHODS: This was a multicenter retrospective study of adults with inflammatory bowel disease and C. difficile infection treated with fidaxomicin with at least 3 months of follow up. The primary outcomes were treatment response, defined as resolution of C. difficile infection-attributed diarrhea and/or negative C. difficile infection stool test, and time to C. difficile infection recurrence after fidaxomicin. RESULTS: Thirty-three patients (median age 42 years; 60.6% female) were included. Most patients had ulcerative colitis (26, 78.8%), were receiving treatment with a biologic or small molecule medication (19, 57.6%), and had a prior episode of C. difficile infection (26, 78.8%, median 2 episodes, range 0-15). Fidaxomicin led to resolution of C. difficile infection in 20 (60.6%) patients, with 6/20 (30.0%) developing a recurrence at a median of 55 days. Most patients who failed to respond to fidaxomicin underwent fecal microbiota transplantation (10/13, 76.9%) with resolution. CONCLUSIONS: In this cohort of patients with inflammatory bowel disease and C. difficile infection, 60.6% responded to treatment with fidaxomicin. Of those who did not respond, fecal microbiota transplantation was an effective therapy.

Safety of fecal microbiota, live-jslm (REBYOTA™) in individuals with recurrent Clostridioides difficile infection: data from five prospective clinical trials.

Background: Microbiota-based treatments reduce the incidence of recurrent Clostridioides difficile infections (rCDIs), but prospectively collected safety data needed to broaden patient access and protect public health have been limited. Objectives: We provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) - the first microbiota-based live biotherapeutic product approved by the US Food and Drug Administration - for preventing rCDI in adults. Design: Integrated safety analysis includes three phase II trials (PUNCH CD, PUNCH CD2, PUNCH Open-Label) and two phase III trials (PUNCH CD3, PUNCH CD3-OLS) of RBL. Methods: Trial participants were at least 18 years of age with documented rCDI who completed standard-of-care antibiotic therapy before treatment with RBL. Assigned study treatment regimen was one or two doses of RBL (or placebo) administered rectally, depending on the trial design. In four of the five trials, participants with CDI recurrence within 8 weeks after RBL or placebo administration were eligible for treatment with open-label RBL. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; in PUNCH CD2 and PUNCH Open-Label trials, TEAEs and serious TEAEs were collected through 12 and 24 months, respectively. Results: Among the five trials, 978 participants received at least one dose of RBL (assigned treatment or after recurrence) and 83 participants received placebo only. TEAEs were reported in 60.2% of Placebo Only participants and 66.4% of RBL Only participants. Only abdominal pain, nausea, and flatulence were significantly higher in the RBL Only group compared with the Placebo Only group. Most TEAEs were mild or moderate in severity and were most frequently related to preexisting conditions. There were no reported infections for which the causative pathogen was traced to RBL. Potentially life-threatening TEAEs were infrequent (3.0% of participants). Conclusion: Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL.

Resolution rates in clinical trials for microbiota restoration for recurrent Clostridioides difficile infection: an updated systematic review and meta-analysis.

Background: Microbiota restoration is highly effective to treat recurrent Clostridioides difficile infection (CDI) in observational studies (cure rates >90%) but efficacy in controlled clinical trials appears to be lower. Objectives: To perform an updated meta-analysis to assess the efficacy of microbiota restoration for recurrent CDI in open-label registered prospective clinical trials compared to randomized controlled trials (RCTs). Design: A systematic review and meta-analysis was conducted. Data Sources and Methods: A systematic search of various databases was performed up to July 2022 to identify studies of interest. Clinical trials of microbiota restoration for recurrent CDI with clinical resolution with one dose were included. We calculated weighted pooled rates (WPRs) with 95% confidence intervals (CIs). Results: In all, 19 clinical trials with 1176 recurrent CDI patients were included. Of the patients treated with microbiota restoration, 897 experienced a clinical cure with a single microbiota restoration therapy (WPR, 78%; 95% CI, 71-85%). There was significant heterogeneity among studies with an I2 of 88%. Analysis of trials with a control arm (non-microbiota restoration) revealed CDI resolution in 373 of 523 patients (WPR, 72%; 95% CI, 60-82%) with microbiota restoration. Among the nine open-label clinical trials, CDI resolution was seen in 524 of 653 patients after initial microbiota restoration (WPR, 84%; 95% CI, 74-92%). Comparison of resolution rates between RCTs and open-label trials revealed a lower cure rate in RCTs compared to open-label trials (WPR, 73 versus 84%, p < 0.0001). Conclusions: Microbiota restoration in a randomized controlled setting leads to lower resolution rates compared to open label and observational settings, likely due to stricter definitions and inclusion criteria. Resolution rates in open-label studies were similar to observational studies.