Treatment Of Clostridium Difficile Infection Research Articles

Probiotics for Prevention and Treatment of Clostridium difficile Infection.

Probiotics have been claimed as a valuable tool to restore the balance in the intestinal microbiota following a dysbiosis caused by, among other factors, antibiotic therapy. This perturbed environment could favor the overgrowth of Clostridium difficile, and in fact, the occurrence of C. difficile-associated infections (CDI) is increasing in recent years. In spite of the high number of probiotics able to in vitro inhibit the growth and/or toxicity of this pathogen, its application for treatment or prevention of CDI is still scarce since there are not enough well-defined clinical studies supporting efficacy. Only a few strains, such as Lactobacillus rhamnosus GG and Saccharomyces boulardii, have been studied in more extent. The increasing knowledge about the probiotic mechanisms of action against C. difficile, some of them reviewed here, makes promising the application of these live biotherapeutic agents against CDI. Nevertheless, more effort must be paid to standardize the clinical studies conducted to evaluate probiotic products, in combination with antibiotics, in order to select the best candidate for C. difficile infections.

Transcriptional regulation of the fidaxomicin gene cluster and cellular development in Actinoplanes deccanensis YP-1 by the pleiotropic regulator MtrA

ABSTRACT Fidaxomicin is an 18-membered glycosidic macrolide polyketide that was clinically used in the treatment of Clostridium difficile infection in 2011. Although the biosynthetic mechanism and pathway-specific regulator of fidaxomicin were well elaborated, little is known about the pleiotropic regulators outside the fidaxomicin gene cluster. To further reveal the transcriptional regulatory mechanism of fidaxomicin biosynthesis in Actinoplanes deccanensis YP-1, we used the 5′-biotin-labeled fadR1 promoter ( fadS5R1p ) as a probe to affinity isolate the fadS5R1p -interactive protein MtrA, a response regulator of the two-component system MtrAB, from the proteome of mycelia. MtrA is bound directly to fadS5R1p to positively regulate gene cluster expression and fidaxomicin production. Fidaxomicin production was improved by 37% in the mtrA overexpressed strain. Furthermore, we revealed that MtrA tends to bind GTKAYS motifs and influence genes involved in secondary metabolites, phosphate transport, methionine transport, nitrogen metabolism, drug transport, membrane properties, etc. Overall, for the first time at the transcriptional level, we comprehensively revealed a pleiotropic regulator, MtrA, that not only directly mediates the FadR1-specific pathway to regulate the proper production of fidaxomicin but also participates in bacterial growth and development. IMPORTANCE Cascade regulation networks are almost present in various kinds of microorganisms, but locating and systematically elucidating specific pleiotropic regulators related to a certain gene cluster can be a tricky problem. Here, based on the promoter of the fidaxomicin pathway-specific regulator FadR1, we utilized a “DNA to Proteins” affinity purification method and captured a global regulator MtrA, which positively regulates fidaxomicin biosynthesis. In the mtrA overexpressed strain, the production of fidaxomicin was improved by 37% compared to the native strain. Then, we combined the “Protein to DNAs” affinity purification method (DAP-seq) with the results of RNA-seq and systematically elucidated the primary and secondary metabolic processes in which MtrA directly or indirectly participates. Thus, our work brought up a new way to improve fidaxomicin production from the perspective of global regulation and analyzed the regulatory mechanism of MtrA. Meanwhile, we provided a novel methodology for the research of cascade regulation networks and vital secondary metabolites.

Shengjiang Xiexin decoction mitigates murine Clostridium difficile infection through modulation of the gut microbiota and bile acid metabolism

Ethnopharmacological relevanceThe overuse of antibiotics has resulted in Clostridium difficile infection (CDI) as a significant global public health concern. Studies have shown that imbalances in gut microbiota and metabolism play a vital role in the onset of CDI. Shengjiang Xiexin decoction (SJT), a traditional Chinese medicinal formula widely employed in the treatment of gastrointestinal ailments, demonstrates effectiveness in addressing murine CDI. However, the precise mechanistic role of SJT in CDI treatment remains uncertain, particularly regarding its impact on gut microbiota and intestinal metabolism. Thus, further investigation is imperative to shed light on these mechanisms. Aim of the studyThis study aims to thoroughly investigate the therapeutic potential of SJT in the treatment of CDI, while also examining its impact on the intricate interplay between gut microbiota and bile acid metabolism. By employing a mouse model, we aspire to uncover novel insights that could pave the way for the development of more effective strategies in combating CDI. Materials and methodsWe developed a mouse model for CDI and assessed SJT's potential as a therapeutic agent through pharmacological analyses. Our study employed high-throughput sequencing of 16S rRNA to identify changes in gut microbiota composition and untargeted metabolomics analysis to evaluate SJT's intervention on intestinal metabolism. We also conducted targeted analysis of bile acid metabolism to examine the specific effects of SJT. Finally, the growth-inhibitory effect of SJT on C. difficile was confirmed through ex vivo cultivation of the pathogen using cecal contents, supporting its potential role in treating CDI by modulating gut microbiota and bile acid metabolism. ResultsIn pharmacological studies, SJT was found to effectively reduce the levels of A&B toxins and alleviate colonic inflammation in CDI mice. Mechanistically, SJT demonstrated a mild increase in the abundance and diversity of the gut microbiota. However, its most significant impact was observed in the substantial improvement of the structural composition of the gut microbiota. Specifically, SJT decreased the abundance of gut Polymorphs and Firmicutes while restoring the proportions of family Trichophyton and Bacteroides_S24-7 spp (P < 0.001). Moreover, SJT not only decreased the levels of primary bile acids but also elevated the levels of secondary bile acids. Notably, it enhanced the conversion of taurocholic acid (TCA) to deoxycholic acid (DCA), leading to a balanced bile acid metabolism. Finally, cecal contents of SJT-treated mice showed a significant reduction in the growth of C. difficile, underscoring the therapeutic potential of SJT via modulation of gut microbiota and bile acid metabolism. ConclusionSJT demonstrates remarkable efficacy in treating CDI in mice by not only effectively combating the infection but also restoring the intricate balance of gut microbiota and bile acid metabolism. Furthermore, promising indications suggest that SJT may have the potential to prevent CDI recurrence. These findings underscore the comprehensive therapeutic value of SJT in managing CDI. Moving forward, we plan to transition from the laboratory to clinical settings to conduct further studies, validating our conclusions on SJT's efficacy.

Infectious complications in patients with inflammatory bowel disease in Asia: the results of a multinational web-based survey in the 8th Asian Organization for Crohn's and Colitis meeting.

Infectious complications are major concerns when treating patients with inflammatory bowel disease (IBD). This study evaluated clinical differences across countries/regions in the management of infectious diseases in patients with IBD. A multinational online questionnaire survey was administered to participants at the 8th meeting of the Asian Organization for Crohn's and Colitis. The questionnaire included questions regarding surveillance, diagnosis, management, and prevention of infection in patients with IBD. A total of 384 physicians responded to the questionnaire. The majority of Korean (n=70, 63.6%) and Chinese (n=51, 51.5%) physicians preferred vancomycin to metronidazole in the treatment of Clostridium difficile infection, whereas more than half of the Japanese physicians (n=62, 66.7%) preferred metronidazole. Physicians in Korea (n=88, 80.0%) and China (n=46, 46.5%) preferred a 3-month course of isoniazid and rifampin to treat latent tuberculosis infection, whereas most physicians in Japan (n=71, 76.3%) favored a 9-month course of isoniazid. Most Korean physicians (n=89, 80.9%) recommended hepatitis B virus (HBV) vaccination in patients lacking HBV surface antigen, whereas more than half of Japanese physicians (n=53, 57.0%) did not consider vaccination. Differences in the diagnosis, prevention, and management of infections in patients with IBD across countries/regions reflect different prevalence rates of infectious diseases. This survey may broaden understanding of the real-world clinical settings across Asian countries/regions and provide information for establishing practical guidelines to manage patients with IBD.

Butyrate Protects against Clostridium difficile Infection by Regulating Bile Acid Metabolism.

Clostridium difficile infection (CDI) is caused by a prevalent nosocomial enteric pathogen, leading to high morbidity and mortality. CDI recurrence after antibiotic treatment is high; therefore, it is necessary to develop novel therapeutics against this enteric pathogen. Butyrate is used to treat many diseases because it provides energy, has anti-inflammatory properties, and maintains intestinal barrier function. An anti-CDI effect for butyrate has been reported; however, the specific mechanism remains elusive. This study aimed to explore the potential role and mechanism of butyrate in the treatment of CDI. Using a CDI mouse model, we found that butyrate significantly inhibited CDI development by regulating bile acid metabolism. Dysregulation of fecal bile acid was significantly higher, and levels of short-chain fatty acids were significantly lower in patients with CDI than those in controls. In CDI mice, butyrate exhibited a protective role by enhancing barrier protection, exerting anti-inflammatory effects, and regulating bile acid metabolism. Butyrate treatment also regulated the production of bile salt hydrolase (BSH) flora and activated farnesoid X receptor (FXR), and its therapeutic effects were reduced in CDI mice treated with BSH or FXR inhibitors. Thus, butyrate treatment may serve as a novel therapeutic approach for patients with CDI. IMPORTANCE Here, we show that levels of fecal short-chain fatty acids (SCFAs), particularly butyrate, are reduced, and normal colon structure is damaged in patients with CDI compared with those in healthy individuals. Bile acid (BA) metabolic disorder in patients with CDI is characterized by increased primary BA levels and decreased secondary BAs. In mice, butyrate alters BA metabolism in CDI and may play a vital role in CDI treatment by promoting secondary BA metabolism. Lastly, butyrate-mediated therapeutic effects in CDI require FXR. Our findings demonstrate that butyrate treatment significantly decreases the severity of CDI-induced colitis in mice and affects BA metabolism and FXR activation, which provides a potential alternative treatment for CDI.

Comparison between Vancomycin and Fidaxomicin in treatment ofCDI

Clostridium difficile infection (CDI) has become more and more prevalent worldwide, requiring more attention frompeople to treat this infection. In this work, the epidemiology of Clostridium difficile infection in the world and China isdemonstrated, which can contribute to a better understanding of the way of infection and patients’ conditions of CDI andlook for possible methods or policies to help prevent the spread of this disease. On the other hand, there is a growingdemand for more reliable and efficient antibiotic treatments for CDI, of which fidaxomicin and vancomycin are regardedas the most common. This work aims to compare the chemical structures, action mechanisms, and cost-effectiveness offidaxomicin and vancomycin to assist choices between two antibiotics for CDI patients and healthcare workers.

Integrated serum pharmacochemistry and metabolomics reveal potential effective components and mechanisms of Shengjiang Xiexin decoction in the treatment of Clostridium difficile infection

Shengjiang Xiexin Decoction (SXD) is a widely recognized formula in Traditional Chinese Medicine (TCM) for treating diarrhea and is commonly used in clinical practice. Clostridium difficile infection (CDI) is a type of antibiotic-associated diarrhea with a rising incidence rate that has severe consequences for humans. Recent clinical applications have found significant efficacy in using SXD as an adjunct to CDI treatment. However, the pharmacodynamic substance basis and therapeutic mechanism of SXD remain unclear. This study aimed to systematically analyze the metabolic mechanisms and key pharmacodynamic components of SXD in CDI mice by combining non-targeted metabolomics of Chinese medicine and serum medicinal chemistry. We established a CDI mouse model to observe the therapeutic effect of SXD on CDI. We investigated the mechanism of action and active substance composition of SXD against CDI by analyzing 16S rDNA gut microbiota, untargeted serum metabolomics, and serum pharmacochemistry. We also constructed a multi-scale, multifactorial network for overall visualization and analysis. Our results showed that SXD significantly reduced fecal toxin levels and attenuated colonic injury in CDI model mice. Additionally, SXD partially restored CDI-induced gut microbiota composition. Non-targeted serum metabolomics studies showed that SXD not only regulated Taurine and hypotaurine metabolism but also metabolic energy and amino acid pathways such as Ascorbate and aldarate metabolism, Glycerolipid metabolism, Pentose and glucuronate interconversions, as well as body and other metabolite production in the host. Through the implementation of network analysis methodologies, we have discerned that Panaxadiol, Methoxylutcolin, Ginsenoside-Rf, Suffruticoside A, and 10 other components serve as critical potential pharmacodynamic substance bases of SXD for CDI. This study reveals the metabolic mechanism and active substance components of SXD for the treatment of CDI mice using phenotypic information, gut microbiome, herbal metabolomics, and serum pharmacochemistry. It provides a theoretical basis for SXD quality control studies.

Biosynthetic Diversification of Fidaxomicin Aglycones by Heterologous Expression and Promoter Refactoring.

Fidaxomicin (Dificid) is a commercial macrolide antibiotic for treating Clostridium difficile infection. Total synthesis of fidaxomicin and its aglycone had been achieved through different synthetic schemes. In this study, an alternative biological route to afford the unique 18-membered macrolactone aglycone of fidaxomicin was developed. The promoter refactored fidaxomicin biosynthetic gene cluster from Dactylosporangium aurantiacum was expressed in the commonly used host Streptomyces albus J1074, thereby delivering five structurally diverse fidaxomicin aglycones with the corresponding titers ranging from 4.9 to 15.0 mg L-1. In general, these results validated a biological strategy to construct and diversify fidaxomicin aglycones on the basis of promoter refactoring and heterologous expression.

Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant

Bezlotoxumab is approved for prevention of recurrent Clostridioides (Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI who are at high risk for recurrent CDI. Previous studies have shown that although serum albumin levels are an important predictor for bezlotoxumab exposure, this has no clinically meaningful impact on efficacy. This pharmacokinetic modeling study assessed whether hematopoietic stem cell transplant (HSCT) recipients, at increased risk of CDI and exhibiting decreased albumin levels within the first month posttransplant, are at risk of clinically relevant reductions in bezlotoxumab exposure. Observed bezlotoxumab concentration-time data pooled from participants in Phase III trials MODIFY I and II (ClinicalTrials.gov identifiers NCT01241552/NCT01513239) and three Phase I studies (PN004, PN005, and PN006) were used to predict bezlotoxumab exposures in two adult post-HSCT populations: A Phase Ib study of posaconazole including allogeneic HSCT recipients (ClinicalTrials.gov identifier NCT01777763; posaconazole-HSCT population); and a Phase III study of fidaxomicin for CDI prophylaxis (ClinicalTrials.gov identifier NCT01691248; fidaxomicin-HSCT population). The bezlotoxumab PK model used the minimum albumin level for each individual in post-HSCT populations to mimic a "worst-case scenario." Predicted worst-case bezlotoxumab exposures for the posaconazole-HSCT population (N=87) were decreased by 10.8% versus bezlotoxumab exposures observed in the pooled Phase III/Phase I data set (N=1587). No further decrease was predicted for the fidaxomicin-HSCT population (N=350). Based on published population pharmacokinetic data, the predicted decrease in bezlotoxumab exposure in the post-HSCT populations is not expected to have a clinically meaningful effect on bezlotoxumab efficacy at the recommended 10 mg/kg dose. Dose modification is therefore not required in the hypoalbuminemia setting expected post-HSCT.

Two-step algorithm-based Clostridioides difficile testing as a tool for antibiotic stewardship

ObjectivesDiagnosis of Clostridium difficile infection (CDI) can be challenging due to high colonization rates. Unlike PCR-only testing, two-step algorithm testing (that includes toxin and PCR) may help differentiate colonization from active infection, but it is unknown if this type of testing impacts treatment decisions. We examined the association between changing CDI diagnostic methods, the way the testing results were displayed, and the rates of CDI-specific treatment. MethodsWe performed a retrospective analysis of positive C. difficile cases over 2 years, a year preceding and following our institution's transition from PCR to two-step testing. During the PCR period, results were displayed in the electronic medical record as ‘positive’. In the two-step period, positive results were either displayed as 'likely colonized' or 'toxin positive'. Rates of CDI-specific therapy and adverse patient outcomes (30-day mortality and intensive care unit admission) were compared among the three groups. ResultsA total of 610 patients had positive results over the study period. Of the 354 patients in the PCR group, 329 (93%) were treated with CDI-specific therapy. Of the 142 patients in the likely colonized group, 59 (42%) were treated. All 114 patients in the toxin-positive group were treated. Multivariate analysis of patients who were PCR positive or likely colonized showed that tests sent in the two-step era were less likely to be associated with treatment for CDI (odds ratio 0.05, 95% CI 0.03-0.09). DiscussionWe found a correlation between changing the type of test and the way the results were displayed and reduction in CDI-specific antibiotic use without restricting clinician diagnostic ordering.

Delivery of a therapeutic antibody to the lower gastrointestinal tract for the treatment of Clostridium difficile infection (CDI)

The colonic delivery system of toxin neutralizing antibody is a promising method for treating Clostridium difficile infection (CDI) and has some advantages over the parental administration of a neutralizing antibody. However, colonic delivery of biologics presents several challenges, including instability of biologics during encapsulation into the delivery system and harsh conditions in the upper GI tract. In this work, we described a multi-particulate delivery system encapsulating a tetra-valent antibody ABAB-IgG1 with the potential to treat CDI. This work first approved that the cecum injection of ABAB-IgG1 into the lower GI tract of mice could relieve the symptoms, enhance the clinical score, and improve the survival rate of mice during CDI. Then, the antibody was spray layered onto mannitol beads and then enteric coated with pH-sensitive polymers to achieve colon-targeting release. The in vitro release of antibody from the multi-particulate system and the pH-sensitive release of antibody was monitored. The in vivo efficacy of this system was further examined and confirmed in mice and hamsters. In summary, the findings of this study should provide practical information and potential treatment options for CDI through colonic delivery of antibody therapeutics to the lower GI tract using a multi-particulate delivery system.

S1567 Celiac Disease Patients Have Higher Risk for Clostridium difficile Infections: A Population-Based Study

Introduction: Clostridium difficile infection (CDI) is a common gastrointestinal pathology with the incidence in the United States to 20-30 per 100 000 population. Previous studies showed association of Celiac disease and CDI, however the prevalence of CDI in patients with celiac disease has not been described in literature. Our aim is to estimate the prevalence of CDI among celiac patients, and to assess whether celiac disease is an independent risk factor for CDI. Methods: A large multi-center database (Explorys Inc., Cleveland, OH, USA) of aggregated electronic health records of 26 different healthcare systems with a total of 360 hospitals and more than 70 million patients across the United States was utilized for this study. A cohort of patients with Celiac disease was identified. Later, a second sub-cohort of those who also had CDI was identified. We excluded all the patients age < 18, patients with inflammatory bowel diseases, immunosuppressed, HIV, Roux-en-Y bypass. Statistical Package for Social Sciences (SPSS version 25, IBM Corp) was used for statistical analysis, and for all analyses, a 2-sided P-value of < 0.05 was considered statistically significant. Multivariate analysis was performed to adjust for multiple factors including age, sex, race, smoking, use of proton pump inhibitors, diagnosis of celiac disease. Results: Among the 80,884,400 individuals screened in the database there were total of 143,180 with Celiac disease (0.17%). The baseline characteristics of patients with Celiac disease are represented in Table. Celiac disease was independently associated with a higher risk of developing CDI (OR= 2.592). Other factors associated with risk of CDI included age 18-65 (OR= 2.764), White race (OR =1.880), smoking (OR= 1.540), use of proton pump inhibitors (OR= 8.468) as in the Figure. Conclusion: Celiac disease seems to be an independent risk factor for CDI. Further studies are required to investigate specifics of pathophysiology, diagnosis and treatment of CDI in patient with celiac disease.Figure 1.: Multivariable analysis for risk factors in individuals with Clostridium Difficile Infection Table 1. - Baseline Catachrestic of Study Population. Celiac disease (%)N=143,180 No celiac disease (%)N=80,741,220 Age 18-65 9,7340 (67.9) 47,893,510 (59.3) >65 39,400 (27.5) 21,266,990 (26.2) Sex Male 1,640 (1.15) 189,850 (0.24) Race Caucasian 117,430 (82.0) 42,011,260 (52.0) Comorbidities Clostridium difficile 2,050 (1.43) 231,830 (0.29) Hypertension 45,710 (31.9) 14,183,650 (17.5) Type 2 Diabetes 20,050 (13.9) 5,651,930 (6.9) Hyperlipidemia 51,170 (35.7) 11,782,380 (14.5) Smoking 19,480 (13.6) 3,874,810 (52.0) Medications PPI 54,790 (38.27) 86,37,610 (10.70)

Does Nifuroxazide Enhance the Effect of Metronidazole Oral Administration in the Treatment of Clostridium difficile Infection?

Aims: To evaluate the efficacy of metronidazole monotherapy and modified therapy with metronidazole + nifuroxazidefor the for treatment of a mild form of Clostridium difficile infection (CDI).&#x0D; Study Design: A prospective, randomized, controlled clinical trial.&#x0D; Place and Duration of Study: University of Applied Sciences Tuzla in the period from June 2018 to June 2019.&#x0D; Methodology: Sixty patients were included in the study, divided into two groups. One group received standard therapy (metronidazole) for the treatment of a mild form of CDI, while the other group was treated with modified therapy (metronidazole + nifuroxazide). Subjects with a developed clinical picture and a positive toxin test for Clostridium difficile were surveyed on the day of admission, then on the 4th, 10th, 14th and 30th days from the start of therapy. The goal of the research was to determine the impact of the modified therapy protocol on the number of stools and the presence of pain compared to standard therapy.&#x0D; Results: The modified therapy with metronidazole + nifuroxazide showed better pharmacological efficacy in the treatment of CDI compared to the standard therapy with metronidazole alone. The group of subjects who were treated with modified therapy reported a significantly lower number of stools (P=.001) and the absence of pain at the first and second check-ups.&#x0D; Conclusion: Nifuroxazide and metronidazole represent a combination of drugs that reduce the number of stools in the shortest possible time and result in the absence of abdominal pain in patients diagnosed with a mild form of CDI.

The global incidence of adverse events associated with fecal microbiota transplantation in children over the past 20years: A systematic review and meta-analysis.

To understand the global incidence of the adverse events associated with fecal microbiota transplantation (FMT) in children over the past 20years. We searched PubMed, Web of Science, Embase, and three Chinese databases (CNKI, Wanfang, and Chongqing Weipu) for high-quality articles written over the past 20years and made selections based on the quality standard score. The study characteristics and incidences of adverse events were extracted from each article, meta-analysis was performed using the R.3.6.3 software, and randomized-effect or fixed-effect meta-analyses were used to determine the incidence of adverse events. Subgroup analysis was performed to determine heterogeneity. A total of 18 articles involving 681 children were included in the analysis. The total effective rate of FMT in children was 85.75% (95% CI: 76.23-93.15%), of which the overall efficacy of FMT for the treatment of Clostridium difficile infection was 91.22% (95% CI: 83.49-96.68%) and the overall adverse event rate was 28.86% (95% CI: 19.56-39.15%), with a mild to moderate adverse event rate of 27.72% (95% CI: 17.86-38.83%) and a severe adverse event rate of 0.90% (95% CI: 0.33-1.76%). The most common mild to moderate adverse events were as follows: bellyache, 14.02% (95% CI: 5.43-25.77%); diarrhea, 7.75% (95% CI: 2.69-15.11%); and bloating, 7.36% (95% CI: 1.79-16.28%). Other adverse events included fever, 2.34%; vomiting, 3.12%; nausea, 1.50%; hematochezia, 2.30%; anorexia, 1.94%; and fatigue, 0.03%. The only death reported was in a study from China, in which the patient died of sepsis and liver failure 4weeks after FMT. The other serious adverse event was an immunodeficiency patient with severe hematochezia. Another study in the United States described seven serious adverse events including one death that was not considered to be related to FMT; however, they did not describe the events in detail. There was no difference in the incidence of adverse events between the upper and lower gastrointestinal tracts (OR=0.61, 95% CI: 0.02-15.42, P=0.76). Adverse events related to FMT in children are mostly mild to moderate, of short duration, and self-limiting. Therefore, the use of FMT in children is safe and worthy of widespread promotion.

Real-world comparison of fidaxomicin versus vancomycin or metronidazole in the treatment of Clostridium difficile infection: a systematic review and meta-analysis.

There is a lack of real-world evidence of the comparative effectiveness of fidaxomicin versus vancomycin or metronidazole for treating patients with Clostridium difficile (CDI) infection. No systematic evidence comparing these treatment regimens using real-world observational studies was published up to date. The goal of this study is to compare the fidaxomicin and vancomycin/metronidazole regimens in terms of treatment outcomes in CDI patients. Systematic and comprehensive search was carried out in the following databases and search engines: EMBASE, Cochrane, MEDLINE, ScienceDirect, and Google Scholar from 1954 until January 2022. Newcastle-Ottawa (NO) scale was used to assess the risk of bias. Meta-analysis was carried out using random effects model, and pooled odds ratios (OR) with 95% confidence interval (CI) were reported. A total of 10 studies satisfied the inclusion criteria, most of them were with poorer quality. The pooled OR was 0.40 (95% CI: 0.09-1.68; I2 = 82.4%) for clinical cure and 2.02 (95% CI: 0.36-11.39; I2 = 88.4%) for sustained cure. We reported pooled OR of 0.69 (95% CI: 0.40-1.20; I2 = 65.7%) for the recurrence rate, 2.81 (95% CI: 1.08-7.29; I2 = 70.6%) for the treatment failure, and 0.73 (95% CI: 0.50-1.07; I2 = 0%) for all-cause mortality between patients that received fidaxomicin and vancomycin. The pooled OR was 0.71 (95% CI: 0.05-9.47; I2 = 69.6%) in terms of recurrence between patients receiving fidaxomicin and metronidazole. Fidaxomicin and vancomycin/metronidazole regimens did not have significant difference in terms of treatment outcomes, such as clinical cure, sustained cure, recurrence, and all-cause mortality. However, there was significantly higher risk of treatment failure in CDI patients taking fidaxomicin.

Faecal Microbiota Transplantation and Chronic Kidney Disease.

Faecal microbiota transplantation (FMT) has attracted increasing attention as an intervention in many clinical conditions, including autoimmune, enteroendocrine, gastroenterological, and neurological diseases. For years, FMT has been an effective second-line treatment for Clostridium difficile infection (CDI) with beneficial outcomes. FMT is also promising in improving bowel diseases, such as ulcerative colitis (UC). Pre-clinical and clinical studies suggest that this microbiota-based intervention may influence the development and progression of chronic kidney disease (CKD) via modifying a dysregulated gut–kidney axis. Despite the high morbidity and mortality due to CKD, there are limited options for treatment until end-stage kidney disease occurs, which results in death, dialysis, or kidney transplantation. This imposes a significant financial and health burden on the individual, their families and careers, and the health system. Recent studies have suggested that strategies to reverse gut dysbiosis using FMT are a promising therapy in CKD. This review summarises the preclinical and clinical evidence and postulates the potential therapeutic effect of FMT in the management of CKD.

Fecal Microbiota Transplantation:Traditional Chinese Medicine Meets Western Medicine

Fecal microbiota transplantation (FMT) is a therapy of transplanting the functional flora from the feces of a healthy donor into the gastrointestinal tract of a patient to reconstruct the normal flora.The application of FMT in western medicine dates from the 1950s.After decades of development,the efficacy of FMT has been proven in a variety of diseases.The record of FMT in traditional Chinese medicine (TCM) dates early from the 3rd century A.D.,and relevant theories have been recorded in many TCM works in the past dynasties.FMT as a therapy that has been written into guidelines has been accepted by some countries and regions such as the United States and the United Kingdom in the treatment of Clostridium difficile infection,and its clinical indications are expanding.TCM and western medicine,with different medical thoughts,meet in the application of FMT.Exploring a normative and effective FMT procedure reflects not only the patient-centered principle but also the mutual promotion of TCM and western medicine.

Species- and strain-level assessment using rrn long-amplicons suggests donor’s influence on gut microbial transference via fecal transplants in metabolic syndrome subjects

ABSTRACT Fecal microbiota transplantation (FMT) is currently used for treating Clostridium difficile infection and explored for other clinical applications in experimental trials. However, the effectiveness of this therapy could vary, and partly depend on the donor’s bacterial species engraftment, whose evaluation is challenging because there are no cost-effective strategies for accurately tracking the microbe transference. In this regard, the precise identification of bacterial species inhabiting the human gut is essential to define their role in human health unambiguously. We used Nanopore-based device to sequence bacterial rrn operons (16S-ITS-23S) and to reveal species-level abundance changes in the human gut microbiota of a FMT trial. By assessing the donor and recipient microbiota before and after FMT, we further evaluated whether this molecular approach reveals strain-level genetic variation to demonstrate microbe transfer and engraftment. Strict control over sequencing data quality and major microbiota covariates was critical for accurately estimating the changes in gut microbial species abundance in the recipients after FMT. We detected strain-level variation via single-nucleotide variants (SNVs) at rrn regions in a species-specific manner. We showed that it was possible to explore successfully the donor-bacterial strain (e.g., Parabacteroides merdae) engraftment in recipients of the FMT by assessing the nucleotide frequencies at rrn-associated SNVs. Our findings indicate that the engraftment of donors’ microbiota is to some extent correlated with the improvement of metabolic health in recipients and that parameters such as the baseline gut microbiota configuration, sex, and age of donors should be considered to ensure the success of FMT in humans. The study was prospectively registered at the Dutch Trial registry – NTR4488 (https://www.trialregister.nl/trial/4488).

A Novel Bacteriophage with Broad Host Range against Clostridioides difficile Ribotype 078 Supports SlpA as the Likely Phage Receptor.

ABSTRACTBacteriophages represent a promising option for the treatment of Clostridioides difficile (formerly Clostridium difficile) infection (CDI), which at present relies on conventional antibiotic therapy. The specificity of bacteriophages should prevent dysbiosis of the colonic microbiota associated with antibiotic treatment of CDI. While numerous phages have been isolated, none have been characterized with broad host range activity toward PCR ribotype (RT) 078 strains, despite their relevance to medicine and agriculture. In this study, we isolated four novel C. difficile myoviruses: ΦCD08011, ΦCD418, ΦCD1801, and ΦCD2301. Their characterization revealed that each was comparable with other C. difficile phages described in the literature, with the exception of ΦCD1801, which exhibited broad host range activity toward RT 078, infecting 15/16 (93.8%) of the isolates tested. In order for wild-type phages to be exploited in the effective treatment of CDI, an optimal phage cocktail must be assembled that provides broad coverage against all C. difficile RTs. We conducted experiments to support previous findings suggesting that SlpA, a constituent of the C. difficile surface layer (S-layer) is the likely phage receptor. Through interpretation of phage-binding assays, our data suggested that ΦCD1801 could bind to an RT 012 strain only in the presence of a plasmid-borne S-layer cassette corresponding to the slpA allele found in RT 078. Armed with this information, efforts should be directed toward the isolation of phages with broad host range activity toward defined S-layer cassette types, which could form the basis of an effective phage cocktail for the treatment of CDI.IMPORTANCE Research into phage therapy has seen a resurgence in recent years owing to growing concerns regarding antimicrobial resistance. Phage research for potential therapy against Clostridioides difficile infection (CDI) is in its infancy, where an optimal “one size fits all” phage cocktail is yet to be derived. The pursuit thus far has aimed to find phages with the broadest possible host range. However, for C. difficile strains belonging to certain PCR ribotypes (RTs), in particular RT 078, phages with broad host range activity are yet to be discovered. In this study, we isolate four novel myoviruses, including ΦCD1801, which exerts the broadest host range activity toward RT 078 reported in the literature. Through the application of ΦCD1801 to phage-binding assays, we provide data to support the prior notion that SlpA represents the likely phage receptor on the bacterial cell surface. Our finding directs research attention toward the isolation of phages with activity toward strains possessing defined S-layer cassette types.

Efficacy and safety of fecal microbiota transplant for recurrent Clostridium difficile infection in inflammatory bowel disease: a systematic review and meta-analysis.

the objective of this systematic review and meta-analysis was to evaluate the outcomes of fecal microbiota transplantation (FMT) therapy for recurrent Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD) patients. electronic databases were searched for studies reporting on the efficacy and/or safety of FMT therapy for recurrent CDI in IBD. The meta-prop command of the meta package in R was used to assess efficacy and safety. Subgroup analyses were performed to explore heterogeneity regarding all outcomes. eleven trials were included in the study. A pooled analysis showed that the initial cure rate of recurrent CDI among IBD patients was 80 % (95 % CI, 0.76, 0.84), and the overall cure rate after two or more FMT procedures was 90 % (95 % CI, 0.84, 0.94). The recurrence rate post-FMT therapy was 25 % (95 % CI: 0.20, 0.32). Sub-analyses suggested that the initial cure rate of CDI in ulcerative colitis (UC) patients was higher than in Crohn's disease (CD) patients (85 % vs. 79 %), with no statistically significant differences (p > 0.05). No serious adverse events were noted in any of the patients post-FMT. FMT is an effective and safe treatment for recurrent CDI in patients with IBD. FMT should be considered early in cases of recurrent or refractory CDI. Multiple FMT procedures can improve the cure rate of CDI.