A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response.

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1ß secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host's arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host's intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile's virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.

Intestinal Colonization by Campylobacter jejuni, Clostridium difficile, and Clostridium perfringens among Commensal Rattus norvegicus in the Urban Areas of Tehran, Iran.

Background: Rattus norvegicus (R. norvegicus) population plays a significant role in the spread of numerous diseases in urban environments. The present study is aimed at investigating the presence of Campylobacter jejuni (C. jejuni), C. coli, Clostridium difficile (C. difficile), C. difficile toxigenic, and C. perfringens in R. norvegicus captured from urban areas of Tehran, Iran. Methods: From October 2021 to October 2022, 100 urban rats were trapped in 5 different districts of Tehran, Iran. The genomic DNA was extracted from fecal samples, and the presence of C. jejuni, C. coli, C. perfringens, and C. difficile species was evaluated using PCR assay. Moreover, PCR was used to assess the toxicity of C. difficile isolates. Results: Overall, 30% (n = 30/100) of fecal samples were positive for zoonotic pathogens. Based on the PCR on hippuricase (hipO), glycine (gly), CIDIF, and phospholipase C (plc) genes, C. perfringens and C. difficile were isolated from 18.2% (n = 14/77) and 5.2% (n = 4/77) of male rats. The highest frequency of C. perfringens and C. jejuni was 25% (n = 5/20) related to the south of Tehran. Toxigenic C. difficile was not detected in all regions. Conclusion: According to the findings, rats are the main reservoirs for diseases. Therefore, rodent control coupled with the implementation of surveillance systems should be prioritized for urban health.

Incidence of Clostridioides difficile Infections in Republic of Korea: A Prospective Study With Active Surveillance vs. National Data From Health Insurance Review & Assessment Service.

BACKGROUND: Since the emergence of hypervirulent strains of Clostridioides difficile, the incidence of C. difficile infections (CDI) has increased significantly. METHODS: To assess the incidence of CDI in Korea, we conducted a prospective multicentre observational study from October 2020 to October 2021. Additionally, we calculated the incidence of CDI from mass data obtained from the Health Insurance Review and Assessment Service (HIRA) from 2008 to 2020. RESULTS: In the prospective study with active surveillance, 30,212 patients had diarrhoea and 907 patients were diagnosed with CDI over 1,288,571 patient-days and 193,264 admissions in 18 participating hospitals during 3 months of study period; the CDI per 10,000 patient-days was 7.04 and the CDI per 1,000 admission was 4.69. The incidence of CDI was higher in general hospitals than in tertiary hospitals: 6.38 per 10,000 patient-days (range: 3.25-12.05) and 4.18 per 1,000 admissions (range: 1.92-8.59) in 11 tertiary hospitals, vs. 9.45 per 10,000 patient-days (range: 5.68-13.90) and 6.73 per 1,000 admissions (range: 3.18-15.85) in seven general hospitals. With regard to HIRA data, the incidence of CDI in all hospitals has been increasing over the 13-year-period: from 0.3 to 1.8 per 10,000 patient-days, 0.3 to 1.6 per 1,000 admissions, and 6.9 to 56.9 per 100,000 population, respectively. CONCLUSION: The incidence of CDI in Korea has been gradually increasing, and its recent value is as high as that in the United State and Europe. CDI is underestimated, particularly in general hospitals in Korea.

New treatment approaches for Clostridioides difficile infections: alternatives to antibiotics and fecal microbiota transplantation.

Clostridioides difficile causes a range of debilitating intestinal symptoms that may be fatal. It is particularly problematic as a hospital-acquired infection, causing significant costs to the health care system. Antibiotics, such as vancomycin and fidaxomicin, are still the drugs of choice for C. difficile infections, but their effectiveness is limited, and microbial interventions are emerging as a new treatment option. This paper focuses on alternative treatment approaches, which are currently in various stages of development and can be divided into four therapeutic strategies. Direct killing of C. difficile (i) includes beside established antibiotics, less studied bacteriophages, and their derivatives, such as endolysins and tailocins. Restoration of microbiota composition and function (ii) is achieved with fecal microbiota transplantation, which has recently been approved, with standardized defined microbial mixtures, and with probiotics, which have been administered with moderate success. Prevention of deleterious effects of antibiotics on microbiota is achieved with agents for the neutralization of antibiotics that act in the gut and are nearing regulatory approval. Neutralization of C. difficile toxins (iii) which are crucial virulence factors is achieved with antibodies/antibody fragments or alternative binding proteins. Of these, the monoclonal antibody bezlotoxumab is already in clinical use. Immunomodulation (iv) can help eliminate or prevent C. difficile infection by interfering with cytokine signaling. Small-molecule agents without bacteriolytic activity are usually selected by drug repurposing and can act via a variety of mechanisms. The multiple treatment options described in this article provide optimism for the future treatment of C. difficile infection.

The Effects of Encapsulation on the In Vitro Anti-Clostridial Activity of Olive Mill Wastewater Polyphenolic Extracts: A Promising Strategy to Limit Microbial Growth in Food Systems.

Despite the technologies applied to food production, microbial contamination and chemical deterioration are still matters of great concern. In order to limit these phenomena, new natural approaches should be applied. In this context, the present study aimed to assess the antioxidant and anti-Clostridial effects of two different polyphenolic extracts derived from olive mill vegetation water, one liquid (LE) and one encapsulated (EE). The extracts have been preliminary characterized using Liquid Chromatography Quadrupole Time-Of Flight spectrometry. The Oxygen Radical Absorbance Capacity method was used to determine the antioxidant capacity, registering a higher value for EE compared to that for LE (3256 ± 85 and 2446 ± 13 µgTE/g, respectively). The antibacterial activity against C. perfringens, C. botulinum and C. difficile was studied by the agar well diffusion method, MIC and MBC determination and a time-kill test. The results confirm that EE and LE are able to limit microbial growth, albeit with minor effects when the phenolic compounds are encapsulated. Further studies are needed to evaluate the possible application of these extracts in food systems.

[A case of disseminated tuberculosis presenting as a metastasizing tumor, complicated by toxic megacolon caused by Clostridium difficile: Difficulties in diagnosis]. / Metasztatizáló tumor képét adó disszeminált tuberkulózis Clostridium difficile okozta toxicus megacolonnal szövodött esete: a diagnózis nehézségei.

A mára ritkán eloforduló tuberkulózis (tbc) extrapulmonális manifesztációi elorehaladott rosszindulatú daganatok képét utánozhatják, jelentos diagnosztikus dilemmákat okozva. A tbc igazolása gyakorta bonyolult, komplex vizsgálatokat igényel. Egy fiatal vietnámi nobeteg esetét ismertetjük, aki idült hasi fájdalom, fogyás, fejfájás, bal oldali hemiparesis miatt jelentkezett kórházunkban. Az urgens vizsgálatok hasi folyadékgyülemek, lymphadenopathia és peritonealis carcinosis képe mellett az uterushoz asszociált ökölnyi kismedencei térfoglaló képletet, intracranialisan agyödémát és metastaticusnak tuno gócokat ábrázoltak. Neurológiai, belgyógyászati, majd pulmonológiai klinikai vizsgálatok és kezelések során eloször disszeminált gynaecologiai tumor, majd meningealis-, miliaris tüdo- és kiterjedt hasüregi-kismedencei érintettséggel járó tbc gyanúja fogalmazódott meg. Bár mycobactérium jelenléte nem volt igazolható, antituberculoticus- és komplex antibiotikus terápiát alkalmaztak. Ennek szövodményeként Clostridium difficile okozta enterocolitis alakult ki. Átmeneti állapotrosszabbodás miatti intenzív osztályos kezelést követoen a beteget visszahelyezték kórházunk belgyógyászatára. Itt toxicus megacolon, acut peritonitis alakult ki, emiatt sürgos mutétet végeztünk.A hasüregben granulomatosus peritonitis encapsulans, extrém tágult, megrepedt taeniájú colon, hyperaemiás vékonybéltraktus, tuboovarialis tályogok voltak láthatók. Oncotomiát követoen salpingo-oophorectomiát és subtotalis colectomiát végeztünk, Brooke szerinti ileostomát készítettünk. Az intenzív osztályos, majd infektológiai kezelésnek köszönhetoen a beteg reconvalescentiája sikeres volt, kielégíto állapotban emittálták. A specimenek valós ideju PCR-vizsgálata során Mycobacterium DNS nem volt detektálható, végül a hasüregi váladék és granulomák mikroszkópos vizsgálatával sikerült saválló pálcákat identifikálni.Az eset kapcsán áttekintjük az extrapulmonális tbc diagnosztikus lehetoségeit és terápiás nehézségeit.

Evaluation of a surveillance system for Clostridioides difficile infections for Swiss hospitals.

AIMS: This study evaluated an approach to establishing a comprehensive nationwide surveillance system for Clostridioides difficile infection in Switzerland. We report the results of patient-related surveillance and calculate the incidence rate of C. difficile infection in Switzerland in 2022. METHODS: Initiated in 2017 by the National Centre for Infection Prevention (Swissnoso), in collaboration with the Swiss Centre for Antibiotic Resistance (ANRESIS), laboratory surveillance enables the automatic import of C. difficile infection laboratory data and is fully operational. However, the very limited number of participating laboratories impedes the generation of representative results. To address this gap, Swissnoso introduced patient-related surveillance, with a questionnaire-based survey used across Swiss acute care hospitals. RESULTS: This survey revealed an incidence of 3.8 (Poisson 95% CI: 3.2-4.5) C. difficile infection episodes per 10,000 patient-days, just above the mean rate reported by the European Centre for Disease Prevention and Control (ECDC). Additionally, we report substantial heterogeneity in laboratory tests, diagnostic criteria and infection control practices among Swiss hospitals. CONCLUSION: This study underscores the importance of a joint effort towards standardized surveillance practices in providing comprehensive insights into C. difficile infection epidemiology and effective prevention strategies in Swiss healthcare settings. The patient-related approach remains the gold standard for C. difficile infection surveillance, although it demands substantial resources and provides results only annually. The proposed implementation of nationwide automated laboratory-based surveillance would be pragmatic and efficient, empowering authorities and hospitals to detect outbreaks promptly and to correlate infection rates with antibiotic consumption.

Clostridium Difficile Infection in Rectal Cancer Patients after Diverted Loop Ileostomy Closure.

AIM: Clostridium difficile infection is a cause of increased morbidity and mortality in hospitals, particularly in patients with cancer pathology. There are several factors favouring the development of Clostridium difficile infection among cancer patients, including age, exposure to antibiotic and proton pump inhibitors therapy, and chemotherapy. This study was conducted to observe the prevalence of Clostridium difficile infection after the reversal of ileostomy loop for rectal cancer surgery, which were initially operated either open or laparoscopic. METHOD: A retrospective study was performed on patients who were operated in a single surgical team for rectal cancer who benefited of a diverted loop ileostomy over a 4-year period. Results: 23 patients were documented with Clostridium difficile infection out of a total of 63. All 23 patients underwent ileostomy closure later than 3 months after primary surgery, and postoperatively received antibiotic therapy associated with proton pump inhibitors in the first 24 hours. Conclusions: Closure of ileostomy later than 3 months after primary surgery, combined with chemotherapy, antibiotic therapy and proton pump inhibitors, increases the risk of developing Clostridium difficile infection.

Transplant of microbiota from Crohn's disease patients to germ-free mice results in colitis.

Although the role of the intestinal microbiota in the pathogenesis of inflammatory bowel disease (IBD) is beyond debate, attempts to verify the causative role of IBD-associated dysbiosis have been limited to reports of promoting the disease in genetically susceptible mice or in chemically induced colitis. We aimed to further test the host response to fecal microbiome transplantation (FMT) from Crohn's disease patients on mucosal homeostasis in ex-germ-free (xGF) mice. We characterized and transferred fecal microbiota from healthy patients and patients with defined Crohn's ileocolitis (CD_L3) to germ-free mice and analyzed the resulting microbial and mucosal homeostasis by 16S profiling, shotgun metagenomics, histology, immunofluorescence (IF) and RNAseq analysis. We observed a markedly reduced engraftment of CD_L3 microbiome compared to healthy control microbiota. FMT from CD_L3 patients did not lead to ileitis but resulted in colitis with features consistent with CD: a discontinued pattern of colitis, more proximal colonic localization, enlarged isolated lymphoid follicles and/or tertiary lymphoid organ neogenesis, and a transcriptomic pattern consistent with epithelial reprograming and promotion of the Paneth cell-like signature in the proximal colon and immune dysregulation characteristic of CD. The observed inflammatory response was associated with persistently increased abundance of Ruminococcus gnavus, Erysipelatoclostridium ramosum, Faecalimonas umbilicate, Blautia hominis, Clostridium butyricum, and C. paraputrificum and unexpected growth of toxigenic C. difficile, which was below the detection level in the community used for inoculation. Our study provides the first evidence that the transfer of a dysbiotic community from CD patients can lead to spontaneous inflammatory changes in the colon of xGF mice and identifies a signature microbial community capable of promoting colonization of pathogenic and conditionally pathogenic bacteria.

Epidemiological and clinical burden of Clostridioides difficile infections and recurrences between 2015 - 2019: the RECUR Germany study.

BACKGROUND: This real-world study assessed the epidemiology and clinical complications of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in hospital and community settings in Germany from 2015 - 2019. METHODS: An observational retrospective cohort study was conducted among adult patients diagnosed with CDI in hospital and community settings using statutory health insurance claims data from the BKK database. A cross-sectional approach was used to estimate the annual incidence rate of CDI and rCDI episodes per 100,000 insurants. Patients' demographic and clinical characteristics were described at the time of first CDI episode. Kaplan-Meier method was used to estimate the time to rCDIs and time to complications (colonic perforation, colectomy, loop ileostomy, toxic megacolon, ulcerative colitis, peritonitis, and sepsis). A Cox model was used to assess the risk of developing complications, with the number of rCDIs as a time-dependent covariate. RESULTS: A total of 15,402 CDI episodes were recorded among 11,884 patients. The overall incidence of CDI episodes declined by 38% from 2015 to 2019. Most patients (77%) were aged ≥ 65 years. Around 19% of CDI patients experienced at least one rCDI. The median time between index CDI episode to a rCDI was 20 days. The most frequent complication within 12-months of follow-up after the index CDI episode was sepsis (7.57%), followed by colectomy (3.20%). The rate of complications increased with the number of rCDIs. The risk of any complication increased by 31% with each subsequent rCDI (adjusted hazard ratio [HR]: 1.31, 95% confidence interval: 1.17;1.46). CONCLUSIONS: CDI remains a public health concern in Germany despite a decline in the incidence over recent years. A substantial proportion of CDI patients experience rCDIs, which increase the risk of severe clinical complications. The results highlight an increasing need of improved therapeutic management of CDI, particularly efforts to prevent rCDI.

SER-109 (VOWST™): A Review in the Prevention of Recurrent Clostridioides difficile Infection.

SER-109 (VOWST™; fecal microbiota spores, live-brpk) is a live biotherapeutic product indicated to prevent the recurrence of Clostridioides difficile infection (CDI) in patients 18 years of age and older following standard of care (SOC) antibacterial treatment for recurrent CDI. It is a purified bacterial spore suspension sourced from healthy donors. As the first oral faecal microbiota product approved for prevention of recurrent CDI, SER-109 is administered as four capsules once daily for three consecutive days. In a well-designed, placebo-controlled, phase III trial (ECOSPOR III), SER-109 significantly reduced the risk of recurrent CDI at 8 weeks post-treatment, with a durable response seen at 6 months post-treatment. Treatment with SER-109 was also associated with rapid and steady improvement in health-related quality of life compared with placebo. SER-109 was generally well tolerated, with a safety profile similar to that of placebo. The most common adverse events were of mild to moderate severity and generally gastrointestinal in nature. Thus, with the convenience of oral administration and lack of necessity for cold storage, SER-109 is a valuable option for preventing further CDI recurrence in adults following antibacterial treatment for recurrent CDI.

Clostridioides difficile is a type of bacteria that can produce toxins leading to infection of the large intestine. Symptoms of C. difficile infection (CDI) range from mild diarrhoea to severe life-threatening sepsis. Treatment is usually antibiotics to kill the toxin-producing bacteria and resolve symptoms. However, antibiotics can disrupt the gut microbiota and leave individuals at risk of CDI recurrence. SER-109 (VOWST^™; fecal microbiota spores, live-brpk) is a microbiome therapy containing purified live bacterial spores extracted from donated human faecal matter intended to repair the microbiome. It is given as four oral capsules per day over three consecutive days to prevent the recurrence of CDI in adults following standard antibiotic treatment. In a phase III clinical trial, patients with recurrent CDI who received SER-109 had a significantly lower rate of CDI recurrence at 8 weeks than those who received placebo, and this response was sustained through 6 months. SER-109 was generally well tolerated, and most adverse events were mild or moderate in severity. With the convenience of oral administration and no refrigeration requirements, SER-109 is a valuable option for preventing further CDI recurrence in adults who have received antibiotics for recurrent CDI.

Biophysical library screening using a Thermo-FMN assay to identify and characterize Clostridioides difficile FabK inhibitors.

Clostridioides difficile, a gram-positive anaerobic bacterium, is one of the most frequent causes of nosocomial infections. C. difficile infection (CDI) results in almost a half a million infections and approximately 30,000 deaths in the U.S. each year. Broad-spectrum antibacterial use is a strong risk factor for development of recurring CDI. There is a critical need for narrow-spectrum antibacterials with activity limited to C. difficile. The C. difficile enoyl-acyl carrier protein (ACP) reductase II enzyme (CdFabK), an essential and rate-limiting enzyme in the organism's fatty acid biosynthesis pathway (FAS-2), is an attractive target for narrow-spectrum CDI therapeutics as it is not present in many of the non-pathogenic gut organisms. We have previously characterized inhibitors of the CdFabK enzyme with narrow-spectrum anti-difficile activity and favorable in vivo efficacy, ADME, and low dysbiosis. To expand our knowledge of the structural requirements for CdFabK inhibition, we seek to identify new inhibitors with novel chemical scaffolds. Herein we present the optimization of a thermo-FMN biophysical assay based on the principles of differential scanning fluorimetry, or thermal shift, which leverages the fluorescence signal of the FabK enzyme's FMN prosthetic group. The optimized assay was validated by pilot testing a 10K diversity-based chemical library and novel scaffold hit compounds were identified and biochemically characterized. Additionally, we show that the thermo-FMN assay can be used to determine the thermodynamic dissociation constant, Kd, of CdFabK inhibitors.

Clostridioides difficile detection and infection in children: are they just small adults?

Clostridioides difficile is a well-recognized healthcare-associated pathogen, with its significance widely recognized in adult populations. Despite this, there is limited data on the significance of detection within paediatric populations, both for individual patient management and wider transmission risk-based considerations. High rates of colonization are understood to occur in infants, with increasing levels up to 11 months, and colonization rates similar to adults by 8 years old. Sources of C. difficile are ubiquitous, with detection in companion animals and food sources, as well as within the clinical and wider environment. Due to the close interactions that occur between children and the environment, it is understandable that increasing recognition is afforded to the community acquisition of C. difficile in children. Other risk factors for the detection of C. difficile in children are similar to those observed in adults, including prior hospitalization and underlying conditions affecting gut health and motility. Recent studies have shown rising awareness of the role of asymptomatic carriage of C. difficile in healthcare transmission. Prior to this, paediatric patient populations were less likely to be screened due to uncertainty regarding the significance of detection; however, this increased awareness has led to a review of possible carriage testing pathways. Despite this increased attention, C. difficile infection remains poorly defined in paediatric populations, with limited dedicated paediatric data sets making comparison challenging. This is further complicated by the fact that infection in children frequently self resolves without additional therapies. Due to this, C. difficile remains a management challenge in paediatric settings.

CDC's Hospital-Onset Clostridioides difficile Prevention Framework in a Regional Hospital Network.

Importance: Despite modest reductions in the incidence of hospital-onset Clostridioides difficile infection (HO-CDI), CDI remains a leading cause of health care-associated infection. As no single intervention has proven highly effective on its own, a multifaceted approach to controlling HO-CDI is needed. Objective: To assess the effectiveness of the Centers for Disease Control and Prevention's Strategies to Prevent Clostridioides difficile Infection in Acute Care Facilities Framework (hereafter, the Framework) in reducing HO-CDI incidence. Design, Setting, and Participants: This quality improvement study was performed within the Duke Infection Control Outreach Network from July 1, 2019, through March 31, 2022. In all, 20 hospitals in the network participated in an implementation study of the Framework recommendations, and 26 hospitals did not participate and served as controls. The Framework has 39 discrete intervention categories organized into 5 focal areas for CDI prevention: (1) isolation and contact precautions, (2) CDI confirmation, (3) environmental cleaning, (4) infrastructure development, and (5) antimicrobial stewardship engagement. Exposures: Monthly teleconferences supporting Framework implementation for the participating hospitals. Main Outcomes and Measures: Primary outcomes were HO-CDI incidence trends at participating hospitals compared with controls and postintervention HO-CDI incidence at intervention sites compared with rates during the 24 months before the intervention. Results: The study sample included a total of 2184 HO-CDI cases and 7 269 429 patient-days. In the intervention cohort of 20 participating hospitals, there were 1403 HO-CDI cases and 3 513 755 patient-days, with a median (IQR) HO-CDI incidence of 2.8 (2.0-4.3) cases per 10 000 patient-days. The first analysis included an additional 3 755 674 patient-days and 781 HO-CDI cases among the 26 controls, with a median (IQR) HO-CDI incidence of 1.1 (0.7-2.7) case per 10 000 patient-days. The second analysis included an additional 2 538 874 patient-days and 1751 HO-CDI cases, with a median (IQR) HO-CDI incidence of 5.9 (2.7-8.9) cases per 10 000 patient-days, from participating hospitals 24 months before the intervention. In the first analysis, intervention sites had a steeper decline in HO-CDI incidence over time relative to controls (yearly incidence rate ratio [IRR], 0.79 [95% CI, 0.67-0.94]; P = .01), but the decline was not temporally associated with study participation. In the second analysis, HO-CDI incidence was declining in participating hospitals before the intervention, and the rate of decline did not change during the intervention. The degree to which hospitals implemented the Framework was associated with steeper declines in HO-CDI incidence (yearly IRR, 0.95 [95% CI, 0.90-0.99]; P = .03). Conclusions and Relevance: In this quality improvement study of a regional hospital network, implementation of the Framework was not temporally associated with declining HO-CDI incidence. Further study of the effectiveness of multimodal prevention measures for controlling HO-CDI is warranted.

Structural and functional insight into the interaction of Clostridioides difficile toxin B and FZD7.

The G protein-coupled receptors of the Frizzled (FZD) family, in particular FZD1,2,7, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible for pathogenesis associated with Clostridioides difficile infection. We employ a live-cell assay examining the affinity between full-length FZDs and TcdB. Moreover, we present cryoelectron microscopy structures of TcdB alone and in complex with full-length FZD7, which reveal that large structural rearrangements of the combined repetitive polypeptide domain are required for interaction with FZDs and other TcdB receptors, constituting a first step for receptor recognition. Furthermore, we show that bezlotoxumab, an FDA-approved monoclonal antibody to treat Clostridioides difficile infection, favors the apo-TcdB structure and thus disrupts binding with FZD7. The dynamic transition between the two conformations of TcdB also governs the stability of the pore-forming region. Thus, our work provides structural and functional insight into how conformational dynamics of TcdB determine receptor binding.

Estimating excess mortality and economic burden of Clostridioides difficile infections and recurrences during 2015-2019: The RECUR England study.

OBJECTIVES: To generate real-world evidence on all-cause mortality and economic burden of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in England. METHODS: We conducted a cohort study using retrospective data from Clinical Practice Research Datalink linked to Hospital Episode Statistics. Patients diagnosed with CDI in hospital and community settings during 2015-2018 were included and followed for ≥1 year. All-cause mortality was described at 6, 12, and 24 months. Healthcare resource usage (HCRU) and associated costs were assessed at 12 months of follow-up. A cohort of non-CDI patients, matched by demographic and clinical characteristics including Charlson Comorbidity Index score, was used to assess excess mortality and incremental costs of HCRU. RESULTS: All-cause mortality among CDI patients at 6, 12, and 24 months was 15.87%, 20.37%, and 27.03%, respectively. A higher proportion of rCDI patients died at any point during follow-up. Compared with matched non-CDI patients, excess mortality was highest at 6 months with 1.81 and 2.53 deaths per 100 patient-months among CDI and ≥1 rCDI patients. Hospitalizations were the main drivers of costs, with an incremental cost of £1209.21 per CDI patient. HCRU and costs increased with rCDIs. CONCLUSION: CDI poses a substantial mortality and economic burden, further amplified by rCDIs.