Factors Related to Outcomes of Fecal Microbiota Transplantation in Patients with Clostridioides difficile Infection

Background/AimsThe aim of this study was to evaluate factors related to outcomes of fecal microbiota transplantation (FMT) in patients with Clostridioides difficile infection (CDI) and viability of frozen stock for FMT.MethodsClinical data of patients who had received FMT for CDI were prospectively collected. Next-generation 16S rRNA gene sequencing of bacteria was performed from donors’ and recipients’ stool. Colony-forming units (CFUs) of cultures from frozen stock solutions for FMT were measured at 0, 4, 8, 12, 24, 48 weeks after preparation of the solutions.ResultsIn total, 25 FMT procedures were performed in 20 cases (14 fresh and 11 frozen FMT). Forty-five percent of cases involved fulminant CDI. The overall success rate was 55% after the 1st FMT and 75% after the 2nd FMT. The success rate was significantly higher in partially treated CDI than in refractory CDI (100% vs 71.4%; p=0.001). In successful cases only, the decrease in alpha-diversity in the recipient stool microbiomes was recovered after FMT to a level similar to that in donor stools. There was a significant difference in the microbiome composition in pre-FMT recipients’ stool between successful and failed cases (p=0.001). The CFUs of frozen solution for FMT did not decrease for 48 weeks in both aerobic and anaerobic cultures.ConclusionsFMT is highly effective in partially treated CDI but not in refractory CDI. The microbiome differs between failed and successful cases. Frozen stock for FMT is viable up to 48 weeks.     

Immunological mechanisms of fecal microbiota transplantation in recurrent Clostridioides difficile infection

Fecal microbiota transplantation (FMT) is a successful method for treating recurrent Clostridioides difficile (C. difficile) infection (rCDI) with around 90% efficacy. Due to the relative simplicity of this approach, it is being widely used and currently, thousands of patients have been treated with FMT worldwide. Nonetheless, the mechanisms underlying its effects are just beginning to be understood. Data indicate that FMT effectiveness is due to a combination of microbiological direct mechanisms against C. difficile, but also through indirect mechanisms including the production of microbiota-derived metabolites as secondary bile acids and short chain fatty acids. Moreover, the modulation of the strong inflammatory response triggered by C. difficile after FMT seems to rely on a pivotal role of regulatory T cells, which would be responsible for the reduction of several cells and soluble inflammatory mediators, ensuing normalization of the intestinal mucosal immune system. In this minireview, we analyze recent advances in these immunological aspects associated with the efficacy of FMT.     

Freeze-dried fecal samples are biologically active after long-lasting storage and suited to fecal microbiota transplantation in a preclinical murine model of Clostridioides difficile infection

ABSTRACT

Fecal microbiota transplantation is now recommended for treating recurrent forms of Clostridioides difficile infection. Recent studies have reported protocols using capsules of either frozen or freeze-dried stool allowing oral administration in in- and out-patient settings. However, a central question remains the viability, engraftment, and efficacy of the microbiome over time during storage life. This study shows that both the freeze-drying and freezing procedures for fecal samples allowed preserving viability, short-chain fatty acids concentration, and anti-Clostridioides difficile properties of microbiota without significant alteration after storage for 12 months. Fecal transplantation with freeze-dried microbiota allowed engraftment of microbiota leading to clearance of Clostridioides difficile infection in a preclinical murine model with a survival rate of 70% versus 53-60% in mice treated with frozen inocula, and 20% in the untreated group. Moreover, the freeze-dried powder can be used to fill oral hard capsules using a very low amount (0.5%) of glidant excipient, allowing oral formulation. Altogether, this study showed that freeze-dried inocula can be used for the treatment of Clostridioides difficile infection with long-lasting stability of the fecal microbiota. This formulation facilitates biobanking and allows the use of hard capsules, an essential step to simplify patient access to treatment.     

Clostridioides difficile infection in patients with nonalcoholic fatty liver disease-current status

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, leading to fibrosis, cirrhosis and hepatocellular carcinoma and also associated with increased cardiovascular disease mortality. The pathogenesis of NAFLD is not fully understood, although NAFLD is thought to be a hepatic form of metabolic syndrome. There is an increasing understanding of the role of microbiota disturbances in NAFLD pathogenesis, and as with many other conditions affecting the microbiota, NAFLD may be a novel risk factor for Clostridioides difficile (C. difficile) colonization (CDC) and C. difficile infection (CDI). CDI is an emerging nosocomial disease, and community-acquired cases of infection are growing, probably due to an increase in CDC rates. The association of NAFLD with CDI has been shown in only 4 studies to date, three of which included less than 1000 patients, although the frequency of NAFLD in these studies was observed in almost 20% of the total patient cohort. These data revealed that NAFLD is a risk factor for CDI development and, moreover, is a risk factor for intestinal complications of CDI. More studies are needed to investigate this association and move forward CDC and CDI screening efforts for this group of patients.     

Faecal microbiota transplantation for eradication of co-infection with Clostridioides difficile and extensively drug-resistant KPC-producing Klebsiella pneumoniae

Abstract

Clostridioides difficile infection may be complicated by co-infection with other pathogens. We here describe the successful use of faecal microbiota transplantation to eradicate concomitant C. difficile and extensively drug-resistant (XDR) KPC-producing Klebsiella pneumoniae. Donor microbiota efficiently engrafted in the patient, and a donor-like microbial assemblage persisted in the patient during six months follow-up. The report explores the potential for the donor microbiota to eradicate and replace multi-resistant microorganisms.     

Bacteriophage endolysins as a potential weapon to combat Clostridioides difficile infection

ABSTRACT

Clostridioides difficile is the leading cause of health-care-associated infection throughout the developed world and contributes significantly to patient morbidity and mortality. Typically, antibiotics are used for the primary treatment of C. difficile infections (CDIs), but they are not universally effective for all ribotypes and can result in antibiotic resistance and recurrent infection, while also disrupting the microbiota. Novel targeted therapeutics are urgently needed to combat CDI. Bacteriophage-derived endolysins are required to disrupt the bacterial cell wall of their target bacteria and are possible alternatives to antibiotics. These lytic proteins could potentially replace or augment antibiotics in CDI treatment. We discuss candidate therapeutic lysins derived from phages/prophages of C. difficile and their potential as antimicrobials against CDI. Additionally, we review the antibacterial potential of some recently identified homologues of C. difficile endolysins. Finally, the challenges of endolysins are considered with respect to the development of novel lysin-based therapies.     

Successful treatment of fulminant Clostridioides difficile infection with emergent fecal microbiota transplantation in a patient with acute myeloid leukemia and prolonged,severe neutropenia

We present a patient with acute myeloid leukemia and prolonged, severe neutropenia who developed fulminant Clostridioides difficile infection refractory to medical therapy and was high‐risk for surgical intervention. He was treated with fecal microbiota transplantation (FMT) for life‐saving cure. The patient had subsequent clinical improvement, however, developed multidrug‐resistant Pseudomonas aeruginosa bacteremia 2 days post‐procedure. We describe subsequent investigation of this event that found this bacteremia was not related to the donor stool administered during FMT. This case adds to the literature that FMT could be considered in heavily immunocompromised patients with fulminant Clostridioides difficile infection where maximal medical therapy has been ineffective and surgery may carry an excessively high mortality risk.     

Microbiota restoration for recurrent Clostridioides difficile: Getting one step closer every day!

Clostridioides difficile infection (CDI) is an urgent health threat being the most common healthcare-associated infection, and its management is a clinical conundrum. Over 450 000 infections are seen in the United States with similar incidence seen in the rest of the developed world. The majority of infections seen are mild–moderate with fulminant disease and mortality being rare complications seen in the elderly and in those with comorbidities. The most common complication of CDI is recurrent infection with rates as high as 60% after three or more infections. A dilemma in the management of primary and recurrent CDI is testing due to the high sensitivity of the nucleic acid amplification tests such as the polymerase chain reaction, which leads to clinical false positives if patients are not chosen carefully (with symptoms) before testing. A newer testing regimen involving a 2-step strategy is emerging using glutamate dehydrogenase as a screening strategy followed by enzyme immunoassay for the C. difficile toxin. Microbiota restoration therapies are the cornerstone of management of recurrent CDI to prevent future recurrences. The most common modality of microbiota restoration is faecal microbiota transplantation, which has been tainted with heterogeneity and adverse events such as serious infectious transmission. The success rates for recurrence prevention from microbiota restoration therapies are over 90% compared with less than 50% of recurrence prevention with courses of antibiotics. This has led to development and emergence of standardized microbiota restoration therapies in capsule and enema forms. Capsule-based therapies include CP101 (positive phase II results), RBX7455 (positive phase I results), SER-109 (positive phase III results) and VE303 (ongoing phase II trial). Enema-based therapy includes RBX2660 (positive phase III data). This review summarizes the principles of management and diagnosis of CDI and focuses on emerging and existing data on faecal microbiota transplantation and standardized microbiota restoration therapies.     

Overview of current detection methods and microRNA potential in Clostridioides difficile infection screening

Clostridioides difficile (formerly called Clostridium difficile,C.difficile) infection (CDI)is listed as an urgent threat on the 2019 antibiotic resistance threats report in the United States by the Centers for Disease Control and Prevention.Early detection and appropriate disease management appear to be essential.Meanwhile,although the majority of cases are hospital-acquired CDI,community-acquired CDI cases are also on the rise,and this vulnerability is not limited to immunocompromised patients...     

Clostridioides difficile infection in liver cirrhosis patients: A population-based study in United States

BACKGROUNDClostridioides (formerly Clostridium) difficile infection (CDI) is an increasingly frequent cause of morbidity and mortality in hospitalized patients. Multiple risk factors are documented in the literature that includes, but are not limited to, antibiotics use, advanced age, and gastric acid suppression. Several epidemiological studies have reported an increased incidence of CDI in advanced liver disease patients. Some have also demonstrated a higher prevalence of nosocomial infections in cirrhotic patients. AIMTo use a large nationwide database, we sought to determine CDI’s risk among liver cirrhosis patients in the United States.METHODSWe queried a commercial database (Explorys Inc^TM, Cleveland, OH, United States), and obtained an aggregate of electronic health record data from 26 major integrated United States healthcare systems comprising 360 hospitals in the United States from 2018 to 2021. Diagnoses were organized into the Systematized Nomenclature of Medicine Clinical Terms (SNOMED–CT) hierarchy. Statistical analysis for the multivariable model was performed using Statistical Package for Social Sciences (SPSS version 25, IBM Corp^TM). For all analyses, a two-sided P value of < 0.05 was considered statistically significant.RESULTSThere were a total of 19387760 patients in the database who were above 20 years of age between the years 2018-2021. Of those, 133400 were diagnosed with liver cirrhosis. The prevalence of CDI amongst the liver cirrhosis population was 134.93 per 100.000 vs 19.06 per 100.000 in non-cirrhotic patients (P < 0.0001). The multivariate analysis model uncovered that cirrhotic patients were more likely to develop CDI (OR: 1.857; 95%CI: 1.665-2.113, P < 0.0001) compared to those without any prior history of liver cirrhosis. CONCLUSIONIn this large database study, we uncovered that cirrhotic patients have a significantly higher CDI prevalence than those without cirrhosis. Liver cirrhosis may be an independent risk factor for CDI. Further prospective studies are needed to clarify this possible risk association that may lead to the implementation of screening methods in this high-risk population.     

Nonalcoholic fatty liver disease is associated with worse intestinal complications in patients hospitalized for Clostridioides difficile infection

BACKGROUNDNonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease with increasing prevalence worldwide. Clostridioides difficile infection (CDI) remains the most common cause of nosocomial diarrhea in developed countries. AIMTo assess the impact of NAFLD on the outcomes of hospitalized patients with CDI.METHODSThis study was a retrospective cohort study. The Nationwide Inpatient Sample database was used to identify a total of 7239 adults admitted as inpatients with a primary diagnosis of CDI and coexisting NAFLD diagnosis from 2010 to 2014 using ICD-9 codes. Patients with CDI and coexisting NAFLD were compared to those with CDI and coexisting alcoholic liver disease (ALD) and viral liver disease (VLD), individually. Primary outcomes included mortality, length of stay, and total hospitalization charges. Secondary outcomes were in-hospital complications. Multivariate regression was used for outcome analysis after adjusting for possible confounders. RESULTSCDI with NAFLD was independently associated with lower rates of acute respiratory failure (2.7% vs 4.2%, P < 0.01; 2.7% vs 4.2%, P < 0.05), shorter length of stay (days) (5.75 ± 0.16 vs 6.77 ± 0.15, P < 0.001; 5.75 ± 0.16 vs 6.84 ± 0.23, P <0.001), and lower hospitalization charges (dollars) (38150.34 ± 1757.01 vs 46326.72 ± 1809.82, P < 0.001; 38150.34 ± 1757.01 vs 44641.74 ± 1660.66, P < 0.001) when compared to CDI with VLD and CDI with ALD, respectively. CDI with NAFLD was associated with a lower rate of acute kidney injury (13.0% vs 17.2%, P < 0.01), but a higher rate of intestinal perforation (P < 0.01) when compared to VLD. A lower rate of mortality (0.8% vs 2.7%, P < 0.05) but a higher rate of intestinal obstruction (4.6% vs 2.2%, P = 0.001) was also observed when comparing CDI with NAFLD to ALD.CONCLUSIONHospitalized CDI patients with NAFLD had more intestinal complications compared to CDI patients with VLD and ALD. Gut microbiota dysbiosis may contribute to the pathogenesis of intestinal complications.     

Faecal microbiota transplantation for recurrent Clostridioides difficile infection: an Australian experience − effective,safe, yet room for improvement

Faecal microbiota transplantation (FMT) is reportedly effective and safe for the management of recurrent or refractory Clostridioides difficile infection (CDI), yet real‐world data of outcomes of FMT in Australia are limited. In this series, FMT safely resulted in resolution of CDI in 19 patients with reduced healthcare utilisation after 25 FMT, but one patient was diagnosed with an anti‐nuclear antibody‐positive constitutional illness and Hashimoto thyroiditis following FMT. Further prospective evaluation of the utility of FMT earlier in CDI treatment algorithms to minimise cost and morbidity, and recipient follow up for immune‐mediated conditions, is required.     

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

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

The outcomes of Clostridioides difficile infection in patients with diverticular disease: a nationwide analysis

Abstract

Background: Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections. It contributes to significant morbidity and mortality among hospitalized patients in the United States. Prior studies suggest worse outcomes of CDI in patients with diverticulitis and increased risk for recurrent CDI. We conducted this study to evaluate the outcomes of CDI in patients with diverticular disease from a nationwide data sample (2012–2015).

Methods: The National Inpatient Sample (NIS) database between January 2012 and September 2015 was queried for CDI admissions using the International Classification of Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] codes 008.45, 562.11, 562.10, 562.12, and 562.13 for diagnoses of CDI and diverticular disease.

Results: The study included 1,327,595 patients who were admitted between 2012 and 2105 for CDI. Out of all of the patients, 84,170 (6.34%) had a concurrent diagnosis of diverticular disease. After adjusting for confounding variables, the in-hospital mortality was lower [odd ratio (OR): 0.48, 95% CI: 0.44–0.52, p?<?.001] for patients with diverticular disease. The length of stay (LOS) was longer [10.5 versus 9.3?days, p?<?.001] and mean cost of hospitalization was significantly higher in patients without a history of diverticular disease.

Discussion: In a nationwide population study, admissions with CDI, patients with a concurrent diagnosis of diverticular disease had lower in-hospital mortality. The observed results are different from prior studies and might be attributed to a higher burden of normal flora in those patients and increased use of antibiotic stewardship program across many hospitals nationwide.     

Clinical Usefulness of the “MN Criteria” - the Clostridioides difficile Infection Severity Scoring System - in the Japanese Setting

Objective The severity of Clostridioides difficile infection (CDI) is an important prognostic factor. The “MN criteria,” proposed in Japan in 2017, attempted to remedy the shortfalls in the reported guidelines proposed globally to determine CDI severity. We therefore assessed the accuracy of the MN criteria and validated the important factors associated with predicting CDI severity. Methods Sixty-six CDI cases were investigated retrospectively at a Japanese University Hospital from January 2015 to December 2018. The fulminant cases were screened out, and the non-fulminant cases were classified according to their severity stages using the nine variables included in the MN criteria. Clinical events, such as death within 28 days, colectomy, and admission to the intensive care unit, were evaluated. First, the sensitivity and specificity of the MN criteria for predicting clinical events were determined. The relationships between clinical events and the explanatory variables were then evaluated through univariate and multivariate analyses. Results The screening of the fulminant cases and classification of the non-fulminant cases into mild/moderate and severe/super severe cases resulted in a sensitivity of 1.00 and a specificity of 0.89. Univariate and multivariate analyses revealed a significant association of the serum albumin (Alb) level as well as white blood cell (WBC) count with clinical events. Conclusion The findings provide evidence supporting the accuracy of the MN criteria in predicting CDI severity and show that the Alb and WBC are important variables in predicting CDI severity.     

Challenges in management of recurrent and refractory Clostridium difficile infection

Clostridium difficile infection (CDI) is the most common nosocomial infection in the United States and is associated with a high mortality. One quarter of patients treated for CDI have at least one recurrence. Spore persistence, impaired host immune response and alteration in the gastrointestinal microbiome due to antibiotic use are factors in recurrent disease. We review the etiology of recurrent CDI and best approaches to management including fecal microbiota transplantation.