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OBJECTIVES: The study aimed to compare the risk of gastrointestinal infections among patients with and without metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: This was a population-based, retrospective, observational study using data from the National Inpatient Sample (NIS), the largest all-payer US inpatient care database. SETTING: Hospitalisation of adults aged ≥18 years old admitted in 2020 was identified using the NIS. Patients were stratified by the presence and absence of MAFLD. PARTICIPANTS: 26.4 million adults aged ≥18 years old were included in the study. Patients younger than 18 and those with missing demographic or mortality data were excluded. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was to assess the overall risk of gastrointestinal infections in patients with and without MAFLD. Secondary outcomes were demographics and comorbidities stratified by the presence or absence of gastrointestinal infection, and the risk of specific gastrointestinal pathogens. RESULTS: Of 26.4 million patients admitted in 2020, 755 910 (2.85%) had the presence of MAFLD. There was a higher prevalence of bacterial gastrointestinal infections in patients with MAFLD than those without (1.6% vs 0.9%, p

Hospital surfaces are known to contribute to the spread of healthcare-associated antimicrobial pathogens. Environmental sampling can help locate reservoirs and determine intervention strategies, although sampling and detection can be labor intensive. Composite approaches may help reduce time and costs associated with sampling and detection. We investigated optimum surface areas for sampling antimicrobial-resistant organisms (AROs) with a single side of cellulose sponge, created theoretical composites (TC) by adding recovery results from multiple optimum areas, then compared the TC to the standard Centers for Disease Control and Prevention sampling method (one sponge using all sides, whole tool; (WT)). Five AROs were evaluated: carbapenemase-producing KPC+ Klebsiella pneumoniae (KPC), Acinetobacter baumannii (AB), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE) and Clostridioides difficile spores (CD). Steel coupons comprising four surface areas (323; 645; 1,290 and 2,258 cm2) were inoculated, dried, and sampled with one sampling pass using the larger side (face) or the smaller side (edge) of a pre-moistened cellulose sponge tool. Based on the optimum areas determined for each organism, composite areas were 1,290 cm2 for MRSA and VRE, 1,936 cm2 for AB, 2,580 cm2 for CD spores and 3,870 cm2 for KPC. Total colony forming units (CFU) recovered using a composite approach was greater or comparable than using multiple WT samplings (over the same area as the composite) for MRSA, VRE and AB (130%; 144% and 95%) yet less than if using multiple WT samplings for KP and CD (47% and 66%). We propose a conservative composite sampling strategy if the target organism is unknown; 323 cm2 sampling area for each of the four sides of the sponge, (1290 cm2 total). The conservative composite sampling strategy improved the recovery of KP (from 47% to 85% of multiple WT samplings), while MRSA, VRE, AB and CD (131%; 144%; 97% and 66%) remained within 5% to that of the optimum area TC. [ABSTRACT FROM AUTHOR]

Introduction: Patients suffering from a Clostridioides difficile infection have a higher overall mortality than patients with similar comorbidities. Methods: Whole blood samples of 15 patients with C. difficile enteritis and 15 control patients matched for age and sex were used to analyze the capacity of blood phagocytes to internalize and kill encapsulated Escherichia (E.) coli. The median age of C. difficile patients and control patients was 81 and 82 years, respectively. Blood samples were co-incubated with E. coli for 15 or 30 min. After 15 min of co-incubation, extracellular bacteria were killed by gentamicin for 15–45 min. Then eukaryotic cells were lysed with distilled water, and the number of intracellular bacteria per ml whole blood was determined by quantitative plating on agar plates. Both groups were compared by Mann-Whitney U test. Results: After 15 or 30 min of co-incubation, blood phagocytes from patients with C. difficile enteritis showed a reduced density of phagocytosed or adherent bacteria in comparison to blood phagocytes from control patients (15 min: p = 0.046, 30 min: p = 0.005). The density of intracellular bacteria decreased less rapidly over time in the blood from C. difficile patients (median Δlog CFU/mL × h [25th/75th percentile] −0.893 [−1.893/−0.554] vs. −1.483 [−2.509/−1.028]; p = 0.02). In line with these results, the percentage of intracellularly killed bacteria was decreased in phagocytes from C. difficile-infected patients compared to controls (median intracellular killing rate 64.3% for blood phagocytes from C. difficile patients vs. 81.9% for blood phagocytes from control patients within 30 min of co-incubation, p = 0.048). Conclusion: Blood phagocytes from patients with C. difficile enteritis exhibited a reduced capacity to phagocytose and kill bacteria in comparison to blood phagocytes from age- and sex-matched control patients. Patients with C. difficile infection may have a higher disposition to develop infectious diseases than age- and sex-matched control patients. [ABSTRACT FROM AUTHOR]

Background: Systematic surveillance of Clostridioides difficile infection (CDI) in our institution showed a reduction in the incidence of healthcare associated CDI (HA-CDI) during COVID-19 pandemic. Aim: Our objective was to search for factors related to this reduction. Methods: We retrospectively studied the trend of the incidences of HA-CDI, Multidrug Resistant (MDR) organisms, total antibiotic and chlorine consumptions as well as the influence of the last two on the incidence of HA-CDI. Results: During COVID-19 pandemic, the HA-CDI incidence was reduced with respect to the previous years, although total antibiotic consumption was found to increase (p <.01). MDR organisms' incidence was found to increase (p <.01), as well as the chlorine consumption (p =.04) which was the only factor to be related to the decreased rates of HA-CDI (r = −0.786, p <.05). Discussion: In our institution, COVID-19 epidemic overlapped with the reduction in the HA-CDI's incidence. This could be due to faithful compliance with the contact precaution measures but then, we would expect the incidence of MDR organisms to decrease as well. Chlorine usage for environmental cleaning was generalized during pandemic. It was the only factor to be related to the decreased rates of HA-CDI, highlighting the importance of environmental cleaning as a measure for HA-CDI prevention. [ABSTRACT FROM AUTHOR]

Background: Fecal Microbiota Transplant (FMT) is an effective treatment for recurring Clostridioides Difficile Infections (rCDI). FMT administered via oral capsules (caFMT) offers several practical advantages to conventional liquid FMT. We began using caFMT in 2021 imported from an external institution. Based on similar production methods, we began our own caFMT production in 2022. We aimed to evaluate the quality of our caFMT. Study Design and Methods: We created a database of all FMT treatments (n = 180) provided by our institution. Quality of all FMT was evaluated by treatment success rates. We compared our caFMT to the imported caFMT. Results: Our caFMT yielded similar success rates compared to that of the imported caFMT, 65% (CI 95% 58–72%) and 72% (CI 95% 66–79%) respectively. FMT administered via colonoscopy had a significantly higher success rate, 79% (CI 95% 73–85%) than own our caFMT and other routes of administration. The combined success rate of treatments increased notably for all routes of administration when repeating FMT after prior failure. Discussion: The fact that our caFMT compared similarly to the imported caFMT was viewed as a success in terms of quality assurance. Our caFMT had a slightly lower success rates compared to data from other studies, but could be affected by several other factors than our FMT-production methods. A lower success rate of caFMT compared to FMT via colonoscopy is acceptable due to the practical advantages offed by caFMT. Our study serves as a practical example, proving that of the standardization of caFMT production is indeed viable. [ABSTRACT FROM AUTHOR]

Clostridioides difficile is a Gram-positive, spore-forming, rod-shaped, obligate anaerobe that is the leading cause of antibiotic-associated diarrhea. Type IV pili (T4P) are elongated appendages on the surface of C. difficile that are polymerized from many pilin proteins. T4P play an important role in C. difficile adherence and particularly in its persistence in the host intestine. Recent studies have shown that T4P promote C. difficile aggregation, surface motility, and biofilm formation, which may enhance its pathogenicity. Additionally, the second messenger cyclic diguanylate increases pilA1 transcript abundance, indirectly promoting T4P-mediated aggregation, surface motility, and biofilm formation of C. difficile. This review summarizes recent advances in C. difficile T4P research and the physiological activities of T4P in the context of C. difficile pathogenesis. [ABSTRACT FROM AUTHOR]

The objective of this study is to examine the comparative effectiveness of vancomycin and metronidazole in a confirmatory analysis of event-free survival (EFS) after initial infection in patients with Clostridioides difficile from a German multicentre cohort study. The IBIS multicentre cohort enrolled patients with an index episode of C. difficile infection between August 2017 and September 2020. The primary endpoint was EFS, defined as response to treatment with metronidazole or vancomycin within 10 days of initiation, absence of recurrence and death from any cause up to 90 days post-treatment. A Cox proportional hazards model with inverse probability of treatment weighting was used to investigate the comparative effectiveness of this outcome. Additionally, subgroup analyses were performed based on severe and non-severe infections. Of the 489 patients included, 118 (24%) received initial treatment with metronidazole and 371 (76%) with vancomycin. Of these, 78/118 (66.1%) and 247/371 (66.6%), respectively, responded to treatment within 10 days, neither developed a recurrence nor died within 90 days and thus achieved the outcome of EFS. In the subgroup of non-severe infections, 74/293 patients (25.3%) received metronidazole, and 219/293 (74.7%) received vancomycin. Of these, 33/74 (44.6%) metronidazole patients and 150/219 (68.5%) vancomycin patients survived event free. The Cox proportional hazards model revealed differences in EFS for the overall population and both subgroups (reference metronidazole: all severity levels: hazard ratio [HR] 0.46, [95% CI, 0.33 – 0.65]; non-severe: HR 0.39; [95% CI, 0.24 – 0.60]; severe: HR 0.52; [95% CI, 0.28 – 0.95]). Our analysis confirms current changes in guidelines, as it supports the superiority of vancomycin compared with metronidazole across all severity levels. [ABSTRACT FROM AUTHOR]

Clostridioides difficile strains of sequence type (ST) 37, primarily including PCR ribotype (RT) 017, are prevalent in mainland China. Our study aimed to compare the major virulence factors of an epidemic C. difficile isolate of ST37 type (Xy06) from China with the well-characterized C. difficile reference strains R20291 (RT027) and CD630E (ST54), as well as a Chinese ST54 strain (Xy07) isolated from the same hospital. The Xy06 genome was predicted to harbor two complete prophages and several transposon-like elements. Comparative analysis of PaLoc revealed a truncated tcdA gene, a functional tcdB gene, a functional tcdC gene, and well-conserved tcdR and tcdE genes. Phenotypic comparisons showed that Xy06 was a robust producer of TcdB, readily sporulated and germinated, and strongly bound to human gut epithelial cells. In a mouse model of C. difficile infection, Xy06 was more virulent than strains CD630E and Xy07 and was comparable to strain R20291 in virulence. Our data suggest the potential threat of the epidemic ST37 strains in China. [ABSTRACT FROM AUTHOR]

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

AbstractBackgroundObjectivesMethodsResultsConclusionsClostridioides difficile is a major burden for both healthcare systems and the patients. Faecal microbiota transplantation (FMT) is becoming more common as a treatment since it reduces the risk of recurrent Clostridioides difficile infection (rCDI).To evaluate how treatment with FMT is affecting the health-related quality of life (HRQoL) in patients with rCDI.A prospective observational cohort study was conducted where patients who were offered FMT as a treatment for rCDI were asked to fill in a questionnaire based on the Short Health Scale (SHS) and EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) about their HRQoL before and after treatment.Patients with rCDI had poor HRQoL, which improved following FMT.Since FMT cures, reduces the risk of new recurrences of CDI and improves the HRQoL of the patients, it should be offered as a treatment for patients with rCDI. Also, SHS is a useful and reliable instrument for measuring HRQoL in patients with rCDI. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is a chronic, relapsing condition wherein biologics have improved disease prognosis but introduced elevated infection susceptibility. Vedolizumab (VDZ) demonstrates unique safety advantages; however, a comprehensive systematic comparison regarding the risk of Clostridioides difficile infection (CDI) between vedolizumab and alternative medications remains absent. Method: Medline, Embase, Cochrane, and clinicaltrials.gov registry were comprehensively searched. Pooled estimates of CDI proportion, incidence, pooled risk ratio between ulcerative colitis (UC) and Crohn's disease (CD), vedolizumab and other medications were calculated. Data synthesis was completed in R using the package "meta". Results: Of the 338 studies initially identified, 30 met the inclusion/exclusion criteria. For CDI risk, the pooled proportion was 0.013 (95% CI 0.010–0.017), as well as the pooled proportion of serious CDI was 0.004 (95% CI 0.002–0.008). The comparative pooled risk ratios revealed: UC versus CD at 2.25 (95% CI 1.73–2.92), vedolizumab versus anti-TNF agents at 0.15 (95% CI 0.04–0.63) for UC and 1.29 (95% CI 0.41–4.04) for CD. Conclusion: The overall CDI risk in IBD patients exposed to vedolizumab was estimated to be 0.013. An increased risk of CDI was noted in UC patients receiving vedolizumab compared to those with CD. Vedolizumab potentially offers an advantage over anti-TNF agents for UC regarding CDI risk, but not for CD. Trial registration: The study was registered on the PROSPERO registry (CRD42023465986). [ABSTRACT FROM AUTHOR]

Background: Clostridioides difficile has been recognized as an emerging pathogen in both humans and animals. In this context, antimicrobial resistance plays a major role in driving the spread of this disease, often leading to therapeutic failure. Moreover, recent increases in community-acquired C. difficile infections have led to greater numbers of investigations into the animal origin of the disease. The aim of this study was to evaluate the genetic similarities between 23 environmental and animal isolates by using whole-genome sequencing and to determine antimicrobial resistance and virulence factor genes in toxigenic C. difficile strains to provide important data for the development of diagnostic methods or treatment guidelines. Results: The most common sequence type was ST11 (87%), followed by ST2 (9%) and ST19 (4%). In addition, 86.95% of the strains exhibited multidrug resistance, with antimicrobial resistance to mainly aminoglycosides, fluoroquinolones, tetracycline and B-lactams; nevertheless, one strain also carried other resistance genes that conferred resistance to lincosamide, macrolides, streptogramin a, streptogramin b, pleuromutilin, oxazolidinone and amphenicol. In addition, a wide range of virulence factor genes, such as those encoding adherence factors, exoenzymes and toxins, were found. However, we observed variations between toxinotypes, ribotypes and sequence types. Conclusions: The results of this study demonstrated significant genetic similarity between ST11 strains isolated from environmental sampling and from animal origin; these strains may represent a reservoir for community-acquired C. difficile infection, which is becoming a growing public health threat due to the development of multridug resistant (MDR) bacteria and the number of virulence factors detected. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota play important roles in several diseases like viral infections. In this systematic review, our objective was to assess the efficacy and safety of fecal microbiota transplantation (FMT) in treating various viral diseases. Methods: We conducted searches on databases including PubMed, Web of Science, Scopus, and Google Scholar until November 2023. Clinical trials reported outcomes related to safety of FMT or its efficacy in patients with viral diseases were included. We excluded other types of studies that enrolled healthy individuals or patients with other disorders and did not use FMT. The assessment of bias risk was conducted using the National Institutes of Health (NIH) study quality evaluation tool. Results: Eight studies with total 196 participants were included. Viral diseases were human immunodeficiency virus (HIV), hepatitis B, COVID-19 and Clostridioides difficile coinfection, and cytomegalovirus colitis. In hepatitis B cases, HBeAg clearance was significant in those received FMT (p<0.01), while it was not significant in another one (p = 0.19). A clinical response was noted in 37.5% of patients with cytomegalovirus colitis, with an equal percentage achieving clinical remission post-FMT. There was a significant reduction in Clostridioides difficile relapse rate in FMT group than controls in coinfection of Clostridioides difficile and COVID-19 (2.17% vs. 42.5%, p<0.05). In patients with HIV, partial engraftment of the donor microbiome and increases in alpha diversity were observed after FMT. No severe adverse events were reported. Most studies had fair or good qualities. Conclusions: Our findings revealed FMT as a promising, safe treatment for some viral diseases. It improved viral clearance, clinical outcomes, and inflammation. However, the varying responses and small sample sizes call for more trials on FMT in viral diseases. [ABSTRACT FROM AUTHOR]

Clostridioides difficile is a bacterial pathogen that has been implicated in severe gastrointestinal infections. C. difficile has intrinsic green autofluorescence and the level of this autofluorescence is known to be increased by growth time and oxygen. Currently, it is unclear if dietary compounds or metabolites from the gut microbiota are able to enhance C. difficile autofluorescence. Here, we aimed to determine potential factors that affect C. difficile autofluorescence. After screening a large repertoire of compounds, we identified several substances, like L-lysine and pantothenate, that led to an increased C. difficile autofluorescence. We also found that several members of the gut microbiota, such as Enterococcus faecalis, Klebsiella aerogenes and K. pneumoniae, can increase C. difficile autofluorescence through their secreted compounds. We further focused on the effect of K. pneumoniae on C. difficile autofluorescence and found that multiple enteric strains of K. pneumoniae could enhance C. difficile's autofluorescence. We used this enhanced autofluorescence to identify C. difficile in K. pneumoniae cocultures by flow cytometry. Our findings shed light on the relationship between C. difficile and other members of the gut microbiota, as well as different factors that can affect C. difficile autofluorescence. [ABSTRACT FROM AUTHOR]

Background Aim Methods Results Conclusion The incidence of Clostridioides difficile infection (CDI) in inflammatory bowel disease (IBD) is rising and associated with adverse outcomes. Optimal treatment for CDI in IBD remains unknown, with various organisations suggesting vancomycin as first‐line therapy.To compare treatment outcomes for metronidazole versus vancomycin in mild to moderate CDI in IBD.A retrospective analysis of IBD patients with CDI between January 2015 and December 2019 was conducted. Laboratory data and clinical outcomes were examined.Forty‐seven discrete episodes of CDI in 34 patients occurred during the study period. Fifty‐three per cent (18) had Crohn's disease, 44% (15) ulcerative colitis and 3% (1) IBD unclassified. Six per cent (3/47) of CDI cases were severe and excluded. In 68% (30/44) of mild to moderate CDI, metronidazole was prescribed, with treatment failure in 20% (6/30), CDI recurrence in 13% (4/30) and 20% (6/30) experiencing a further CDI episode. Comparatively, vancomycin was prescribed in 23% (10/44) without any treatment failures; however, 10% (1/10) had CDI recurrence and 40% (4/10) experienced another CDI episode. No statistically significant difference was noted between metronidazole and vancomycin therapy for treatment failure (P = 0.31), CDI recurrence (P = 1.0) or further CDI episodes (P = 0.23). Proton‐pump inhibitor therapy was the only risk factor associated with a higher rate of the composite outcome and remained significant on multivariate logistic regression (odds ratio 12.99 (95% confidence interval = 1.21–139.97), P = 0.03).Metronidazole compared to vancomycin for treatment of mild to moderate CDI in IBD is effective however may be associated with higher rates of treatment failure. [ABSTRACT FROM AUTHOR]

The Centers for Disease Control estimates antibiotic-associated pathogens result in 2.8 million infections and 38 000 deaths annually in the United States. This study applies species distribution modeling to elucidate the impact of environmental determinants of human infectious disease in an era of rapid global change. We modeled methicillin-resistant Staphylococcus aureus and Clostridioides difficile using 31 publicly accessible bioclimatic, health care, and sociodemographic variables. Ensemble models were created from 8 unique statistical and machine learning algorithms. Using International Classification of Diseases, 10th edition codes, we identified 305 528 diagnoses of methicillin-resistant S. aureus and 203 001 diagnoses of C. difficile presence. Three environmental factors—average maximum temperature, specific humidity, and agricultural land density—emerged as major predictors of increased methicillin-resistant S. aureus and C. difficile presence; variables representing health care availability were less important. Species distribution modeling may be a powerful tool for identifying areas at increased risk for disease presence and have important implications for disease surveillance systems. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokine levels and host genetic makeup are key determinants of Clostridioides difficile infection (CDI) outcomes. We previously reported that blocking the inflammatory cytokine macrophage migration inhibitory factor (MIF) ameliorates CDI. Here, we determined kinetics of MIF production and its association with a common genetic variant in leptin receptor (LEPR) using blood from patients with CDI. We found highest plasma MIF early after C difficile exposure and in individuals who express mutant/derived LEPR. Our data suggest that early-phase CDI provides a possible window of opportunity in which MIF targeting, potentially in combination with LEPR genotype, could have therapeutic utility. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionsPatients with Crohn’s disease (CD) and subsequent ocular manifestations may have worse outcomes when compared to matched patients with CD without ocular disease.In this retrospective cohort study, an aggregated electronic health records research network, TriNetX (Cambridge, MA, USA), was used to identify patients diagnosed with CD stratified by the presence or absence of ocular involvement with at least 1 year of follow-up. Propensity score matching (PSM) was performed to control for baseline demographics and medical comorbidities.Patients with CD with ocular disease showed a greater risk of undergoing bowel resections (RR: 2.06, 95% CI: 1.48–2.85, p < 0.001), developing other CD-related gastrointestinal complications (RR: 1.31, CI: 1.15–1.49, p < 0.001), or acquiring Clostridioides difficile infections (RR: 2.19, CI: 1.89–2.54, p < 0.001). Further, patients with CD with ocular sequelae had a greater risk of developing NASH (RR: 1.43, CI: 1.31–1.56, p < 0.001), CD-related nutrient deficiencies (RR: 1.38, CI: 1.29–1.49, p < 0.001), iron deficiency anemia (RR: 1.41, CI: 1.33–1.50, p < 0.001), CD-related dermatological disease (RR: 1.84, CI: 1.65–2.05, p < 0.001), osteoporosis (RR: 1.49, CI: 1.37–1.64, p < 0.001) and primary sclerosing cholangitis (RR: 1.63, CI: 1.11–2.38, p = 0.011). Among patients with CD with ocular involvement, there was an elevated risk of MI (RR: 1.36, CI: 1.14–1.63, p < 0.001), stroke (RR: 1.42, CI: 1.18–1.70, p < 0.001), VTE (RR: 1.37, CI: 1.22–1.54, p < 0.001), and sepsis (RR: 1.53, CI: 1.37–1.71, p < 0.001).Patients who have CD and subsequent ocular involvement have an increased risk of local intestinal complications, extraintestinal morbidity, and cardiovascular complications when compared to patients with CD without ocular involvement. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusions Detailed comparative assessment of procedure‐related factors associated with faecal microbiota transplantation (FMT) efficacy in Clostridioides difficile infection (CDI) is limited.We took advantage of the differences in procedures at the various French FMT centres to determine clinical and procedure‐related factors associated with FMT success in CDI.We performed a nationwide retrospective multicentre cohort study. All FMTs performed within The French Faecal Transplant Group for CDI from 2018 to 2022 were included. Clinical data were collected retrospectively from recipient medical files, characteristics of stool transplant preparations were prospectively collected by each Pharmacy involved. Univariate and multivariate analyses were performed using Fisher's test and multiple logistic regression.Six hundred fifty‐eight FMTs were performed for 617 patients in 17 centres. The overall efficacy of FMT was 84.3% (520/617), with 0.5% of severe adverse events possibly related to FMT (3/658). Forty‐seven patients were treated at the first recurrence of CDI with a similar success rate (85.1%). Severe chronic kidney disease (CKD; OR: 2.18, 95%CI [1.20–3.88]), non‐severe refractory CDI (OR: 15.35, [1.94–318.2]), the use of ≥ 80% glycerol (OR: 2.52, [1.11–5.67]), insufficient bowel cleansing (OR: 5.47, [1.57–20.03]) and partial FMT retention (OR: 9.97, [2.62–48.49]) were associated with CDI recurrence within 8 weeks.Conditions of transplant manufacturing, bowel cleansing, and a route of delivery tailored to the patient's characteristics are key factors in optimising FMT efficacy. FMT at first recurrence showed high success in real‐life practice, whereas it had lower efficacy in severe CDI and non‐severe refractory CDI. [ABSTRACT FROM AUTHOR]

Clostridioides difficile, a zoonotic pathogen causing enteric diseases in different animals and humans. A comprehensive study on the presence of toxin genes and antimicrobial resistance genes based on genome data of C. difficile in animals is scanty. In the present study, a total of 15 C. difficile isolates were recovered from dogs and isolates with toxin genes (D1, CD15 and CD26) along with two other non-toxigenic strains (CD28, CD32) were used for whole genome sequencing and comparative genomics. Sequence type-based clustering was noted in the whole genome phylogeny with 4 known multi-locus sequence typing (MLST) clades namely I, II, IV, and V and a cryptic clade. ST11 and ST54 were reported for the 2nd time worldwide in dogs. Out of 109 genomes used in the study, 29 genomes were predicted with all four toxin genes (toxA, toxB, cdtA, cdtB) while 22 did not have any of the toxin genes. ST11 of MLST clade V had the maximum number of 46 genomes predicted with at least one toxin gene. Among the genomes sequenced in this study, CD26 had a maximum of 5 AMR genes (aac(6′)-aph(2″), ant(6)-Ia, catP, erm(B)_18, and tet(M)_11) and CD15 was predicted with 2 AMR genes (aac(6′)-aph(2″), erm(B)_18). Tetracycline resistance genes were predicted most in the ST11 genome. Of the 22 non-toxigenic strains, 9 genomes (ST48 = 5, ST3 = 2, ST109 = 1, ST15 = 1) were predicted with a minimum of one AMR gene. Pangenome analysis indicated that the Bpan value is 0.12 showing that C. difficile has an open pangenome structure. This indicates that the organism can evolve by the addition of new genes. This study reports the circulation of clinically important ST11 and multidrug-resistant non-toxigenic strains among animals. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and safety of tofacitinib in patients with ulcerative colitis (UC) in clinical practice in Lebanon. Design: This was a retrospective cross-sectional study. The data were collected from hospital records. Patients with moderate to severe UC treated with tofacitinib between 2018 and 2021 were included. Patients' demographics, disease-specific characteristics, clinical assessment at three time points (8, 26, and 52 weeks), endoscopic evaluation at 24 weeks, and adverse events were collected. Results: A total of 60 UC patients with a mean duration of disease of 7.9 ± 4.7 years were enrolled. 61.7% of patients had extensive disease, and 58.3% had received ≥ 1 biologic prior to tofacitinib. Clinical remission was reported in 25, 34, and 31 patients (41.7%, 56.7%, and 56.4%) at 8, 26, and 52 weeks respectively. Endoscopic remission (endoscopic Mayo score 0 or 1) was observed in 58.3% of patients at 52 weeks. About one-third of patients (31.7%) stopped tofacitinib at one year, primarily for lack of efficacy or loss of response, with no significant difference between biologics-naïve and experienced patients (24% vs. 37.1% respectively). No serious adverse events or deaths were reported. Adverse events were reported in 3 patients (5.0%) - one C. difficile infection, one case of reversible lymphopenia, and one case of facial acne. No serious adverse events or deaths were noted. On multivariate analysis, biologic-naïve status and reduction or normalization of CRP were associated with clinical remission (OR = 10.87, 95% CI = 1.57, 100, and OR = 78.47, 95% CI = 2.09, 2940.32 respectively), while reduction or normalization of CRP was associated with endoscopic remission at 1 year (OR = 19.03, 95% CI = 1.64, 221.09). Conclusion: Tofacitinib was effective in the treatment of moderately severe ulcerative colitis in this real-world cohort in Lebanon. Further, the predictors associated with clinical and endoscopic remissions were found to be biologic-naïve status and reduction in CRP. Observed AEs were consistent with the known safety profile. One of the major limitations of this study is the smaller sample size and the retrospective nature of the study. Key Message: What is already known on this topic: – Although effectiveness of tofacitinib in ulcerative colitis has been established via real world evidence studies (RWDs), there have been no reports of RWD in West Asia or the Middle East and North Africa (MENA) region. What this study adds: – It was observed that biologic-naïve status of patients and reduction in C-reactive protein (CRP) levels were associated with clinical and endoscopic remission outcomes. Tofacitinib was effective in the treatment of moderately severe UC in the Lebanese real-world cohort and observed AEs were consistent with the known safety profile. How this study might affect research, practice, or policy: – This study provides insights to the physicians managing UC patients in the MENA region on the expected clinical journey for patients being treated with tofacitinib as well as the predictors of outcome. Future comparisons of this study with similar RWE studies in different geographical locations, will delineate the differences, if any, in the clinical course, based on demographical factors. [ABSTRACT FROM AUTHOR]

Clostridioides difficile infection (CDI) is an urgent public health threat with limited preventative options. In this work, we developed a messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccine targeting C. difficile toxins and virulence factors. This multivalent vaccine elicited robust and long-lived systemic and mucosal antigen-specific humoral and cellular immune responses across animal models, independent of changes to the intestinal microbiota. Vaccination protected mice from lethal CDI in both primary and recurrent infection models, and inclusion of non-toxin cellular and spore antigens improved decolonization of toxigenic C. difficile from the gastrointestinal tract. Our studies demonstrate mRNA-LNP vaccine technology as a promising platform for the development of novel C. difficile therapeutics with potential for limiting acute disease and promoting bacterial decolonization. [ABSTRACT FROM AUTHOR]

Background The 2021 update to the Infectious Diseases Society of America Clostridioides difficile infection (CDI) guidelines recommended fidaxomicin as the preferred treatment over vancomycin for patients with initial and recurrent CDI. Few studies have examined how treatment patterns and clinical outcomes of hospitalized CDI patients changed after the postguideline update or contemporary real-world outcomes of fidaxomicin vs vancomycin. Methods This retrospective, observational study used the PINC AI Healthcare Database on adult patients who received CDI treatment between 1/2020 and 6/2021 (pre period) and between 10/2021 and 9/2022 (post period). We examined treatment patterns of fidaxomicin, vancomycin, and metronidazole, as well as clinical and health care resource use outcomes of patients treated exclusively with fidaxomicin vs vancomycin, using nearest-neighbor propensity matching and hierarchical regression methods. As a sensitivity analysis, we repeated the fidaxomicin vs vancomycin comparisons among patients with recurrent and nonrecurrent index infections. Results A total of 45 049 patients with CDI from 779 US hospitals met initial inclusion criteria. Comparing the pre vs post periods, the proportion of patients treated with fidaxomicin increased from 5.9% to 13.7% (P <.001), vancomycin use decreased from 87.9% to 82.9% (P <.001), and metronidazole use decreased from 21.6% to 17.2% (P <.001). When comparing fidaxomicin vs vancomycin in the post period, fidaxomicin was associated with lower CDI recurrence (6.1% vs 10.2%; P <.001) and higher sustained clinical response (91.7% vs 87.8%; P <.001). Ninety-day postdischarge costs were not significantly different between groups. A sensitivity analyses showed similar findings. Conclusions Since the 2021 guideline update, fidaxomicin use has increased significantly but could be further utilized given its association with better clinical outcomes and no increase in postdischarge costs. [ABSTRACT FROM AUTHOR]

Controlled human infection models (CHIMs) are a critical tool for the understanding of infectious disease progression, characterising immune responses to infection and rapid assessment of vaccines or drug treatments. There is increasing interest in using CHIMs for vaccine development and an obvious need for widely available and fit‐for‐purpose challenge agents. Inno4Vac is a large European consortium working towards accelerating and de‐risking the development of new vaccines, including development of CHIMs for influenza, respiratory syncytial virus and Clostridium difficile. This report (in two parts) summarises a workshop held at the MHRA in 2021, focused on how to select CHIM candidate strains of influenza and respiratory syncytial virus (RSV) based on desirable virus characteristics and which immune assays would provide relevant information for assessing pre‐existing and post‐infection immune responses and defining correlates of protection. This manuscript (part 2) summarises presentations and discussions centred around RSV CHIMs and immune assays (an additional manuscript summarises influenza CHIM and immune assays: Inno4Vac workshop report Part 1: Controlled human influenza virus infection model (CHIVIM) strain selection and immune assays for CHIVIM studies, November 2021, MHRA, UK). [ABSTRACT FROM AUTHOR]

Clostridioides difficile is an intestinal pathogen of humans and animals. In community-associated infections, the environment is suggested to play a significant role in overall transmission routes. Although the prevalence of C. difficile in freshwater and soil has been widely studied, little is known about its presence in sediments. In this study, we tested 15 sediment samples collected from various freshwater sources. C. difficile was isolated from all sampled sites, yielding a total of 171 strains grouped into 26 ribotypes, with 001/072 and 014/020 being the most prevalent. Genome sequencing of 37 isolates from 17 PCR ribotypes confirmed the presence of highly related strains in the geographically distant and unlinked water samples. Eight divergent PCR ribotypes from clades C-II and C-III were found in six samples. In each sample, the unbound fraction (supernatant after sediment wash) and bound fraction (sonicated sediment sample) were subjected to enrichment. Sonication was only slightly better than washing in terms of sample positivity (14 positive samples with sonication and 11 with washing). However, sonication substantially increased the diversity of the PCR ribotypes obtained (23 in sonicated samples vs nine in washed samples). In conclusion, sediments are a rich source for investigating the diversity of environmental C. difficile, including isolates from divergent lineages. Selection of the isolation method can significantly impact the diversity of captured PCR ribotypes. IMPORTANCE Clostridioides difficile, a pathogenic bacterium that can cause intestinal infections in humans and animals, thrives in the gut but also disperses widely through spores found in the environment. Clinical and environmental strains often overlap with common PCR ribotypes, which are consistently isolated worldwide. Environmental studies have mostly focused on water and soil, but sediments have been very poorly studied. In this study, we investigated the presence of C. difficile in various freshwater sediments and evaluated the effectiveness of two different isolation approaches on positivity rates and strain diversity. C. difficile was found to be highly prevalent in sediments, with an isolation rate of 100%. Sonication proved to be more effective than simple washing for capturing a greater diversity of PCR ribotypes. Overall, this study underscores the widespread presence of C. difficile in freshwater sediments and emphasizes the importance of continued surveillance and monitoring to understand its ecology and transmission dynamics. [ABSTRACT FROM AUTHOR]

Among patients with hematopoietic stem cell transplants, infections, particularly multidrug‐resistant infections, pose a grave threat. In this setting, penicillin allergy labels are both common and harmful. Though the majority of patients who report penicillin allergy can actually tolerate penicillin, penicillin allergy labels are associated with use of alternative antibiotics, which are often more broad spectrum, less effective, and more toxic. In turn, they are associated with more severe infections, multidrug‐resistant infections, Clostridium difficile, and increased mortality. Evaluating penicillin allergy labels can immediately expand access to preferred therapeutic options, which are critical to care in patients with recent hematopoietic stem cell transplants. Point‐of‐care assessment and clinical decision tools now exist to aid the nonallergist in assessment of penicillin allergy. This can aid in expanding use of other beta‐lactam antibiotics and assist in risk‐stratifying patients to determine a testing strategy. In patients with low‐risk reaction histories, direct oral challenges can be employed to efficiently delabel patients across clinical care settings. We advocate for multidisciplinary efforts to evaluate patients with penicillin allergy labels prior to transplantation. [ABSTRACT FROM AUTHOR]

YabG is a sporulation‐specific protease that is conserved among sporulating bacteria. Clostridioides difficile YabG processes the cortex destined proteins preproSleC into proSleC and CspBA to CspB and CspA. YabG also affects synthesis of spore coat/exosporium proteins CotA and CdeM. In prior work that identified CspA as the co‐germinant receptor, mutations in yabG were found which altered the co‐germinants required to initiate spore germination. To understand how these mutations in the yabG locus contribute to C. difficile spore germination, we introduced these mutations into an isogenic background. Spores derived from C. difficile yabGC207A (a catalytically inactive allele), C. difficile yabGA46D, C. difficile yabGG37E, and C. difficile yabGP153L strains germinated in response to taurocholic acid alone. Recombinantly expressed and purified preproSleC incubated with E. coli lysate expressing wild type YabG resulted in the removal of the presequence from preproSleC. Interestingly, only YabGA46D showed any activity toward purified preproSleC. Mutation of the YabG processing site in preproSleC (R119A) led to YabG shifting its processing to R115 or R112. Finally, changes in yabG expression under the mutant promoters were analyzed using a SNAP‐tag and revealed expression differences at early and late stages of sporulation. Overall, our results support and expand upon the hypothesis that YabG is important for germination and spore assembly and, upon mutation of the processing site, can shift where it cleaves substrates. [ABSTRACT FROM AUTHOR]

To survive in the host, pathogenic bacteria need to be able to react to the unfavorable conditions that they encounter, like low pH, elevated temperatures, antimicrobial peptides and many more. These conditions may lead to unfolding of envelope proteins and this may be lethal. One of the mechanisms through which bacteria are able to survive these conditions is through the protease/foldase activity of the high temperature requirement A (HtrA) protein. The gut pathogen Clostridioides difficile encodes one HtrA homolog that is predicted to contain a membrane anchor and a single PDZ domain. The function of HtrA in C. difficile is hitherto unknown but previous work has shown that an insertional mutant of htrA displayed elevated toxin levels, less sporulation and decreased binding to target cells. Here, we show that HtrA is membrane associated and localized on the surface of C. difficile and characterize the requirements for proteolytic activity of recombinant soluble HtrA. In addition, we show that the level of HtrA in the bacteria heavily depends on its proteolytic activity. Finally, we show that proteolytic activity of HtrA is required for survival under acidic conditions. [ABSTRACT FROM AUTHOR]

Introduction: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. Objective, Design, and Patients: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. Methods: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. Results: TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6–13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6–19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. Conclusions: VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. Trial Registration: ClinicalTrials.gov identifier, NCT03183128 and NCT03183141. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance poses a significant threat to humanity, and the development of new antibiotics is urgently needed. Our research has focused on thiopeptide antibiotics such as micrococcin P2 (MP2) and derivatives thereof as new anti-infective agents. Thiopeptides are sulfur-rich, structurally complex substances that exhibit potent activity against Gram-positive pathogens and Mycobacteria species, including clinically resistant strains. The clinical development of thiopeptides has been hampered by the lack of efficient synthetic platforms to conduct detailed structure-activity relationship studies of these natural products. The present contribution touches upon efficient synthetic routes to MP2 that laid the groundwork for clinical translation. The medicinal chemistry campaign on MP2 has been guided by computational molecular dynamic simulations and parallel investigations to improve drug-like properties, such as enhancing the aqueous solubility and optimizing antibacterial activity. Such endeavors have enabled identification of promising lead compounds, AJ-037 and AJ-206, against Mycobacterium avium complex (MAC). Extensive in vitro studies revealed that these compounds exert potent activity against MAC species, a subspecies of non-tuberculous mycobacteria (NTM) that proliferate inside macrophages. Two additional pre-clinical candidates have been identified: AJ-024, for the treatment of Clostridioides difficile infections, and AJ-147, for methicillin-resistant Staphylococcus aureus impetigo. Both compounds compare quite favorably with current first-line treatments. In particular, the ability of AJ-147 to downregulate pro-inflammatory cytokines adds a valuable dimension to its clinical use. In light of above, these new thiopeptide derivatives are well-poised for further clinical development. [ABSTRACT FROM AUTHOR]

Clostridioides difficile toxin B (TcdB) is the key virulence factor accounting for C. difficile infection-associated symptoms. Effectively neutralizing different TcdB variants with a universal solution poses a significant challenge. Here we present the de novo design and characterization of pan-specific mini-protein binders against major TcdB subtypes. Our design successfully binds to the first receptor binding interface (RBI-1) of the varied TcdB subtypes, exhibiting affinities ranging from 20 pM to 10 nM. The cryo-electron microscopy (cryo-EM) structures of the mini protein binder in complex with TcdB1 and TcdB4 are consistent with the computational design models. The engineered and evolved variants of the mini-protein binder and chondroitin sulfate proteoglycan 4 (CSPG4), another natural receptor that binds to the second RBI (RBI-2) of TcdB, better neutralize major TcdB variants both in cells and in vivo, as demonstrated by the colon-loop assay using female mice. Our findings provide valuable starting points for the development of therapeutics targeting C. difficile infections (CDI). Xinchen Lv and colleagues design pan-specific protein mini-binders that neutralize Clostridioides difficile toxin B (TcdB) and solve TcdB-binder complex structures via cryo-electron microscopy. [ABSTRACT FROM AUTHOR]

Background: Clostridioides difficile is the most common cause of healthcare-associated diarrhea. Research suggests that treating C. difficile infections (CDI) with fidaxomicin (FDX) is more effective than vancomycin (VAN), with potential cost savings. The objective was to calculate the budget impact of FDX treatment compared to VAN from a German payer perspective. Research design and methods: The analysis used real-world data of patients discharged from University Hospital Cologne between Jan-01–2018 and Dec-31–2019. We identified recurrent and non-recurrent CDI cases and calculated direct treatment costs based on G-DRG flat rates. To calculate average costs per treatment and the budget impact, recurrence probabilities for VAN and FDX were taken from published evidence (28-day and 90-day scenarios). Results: Totally, 475 cases were analyzed, thereof 421 non-recurrent, causing mean costs of €32,901 per case (95% CI: 27.752–38.050). Thirty-two patients experienced a recurrence within 28 days, yielding mean costs of €10,952 (95% CI: 5.627–16.277) for their additional hospital stay. The resulting budget impact was €1,303 (95% CI: 670–1.937) in favor of FDX, ranging from €148.34 to €2,190.30 in scenario analyses. Conclusion: The analysis indicates FDX treatment can lead to cost savings compared to VAN. Future research should focus on specific patient groups, such as refractory CDI patients. [ABSTRACT FROM AUTHOR]

Clostridioides difficile is a major causative pathogen for antibiotic-associated diarrhea and C. difficile infections (CDIs) may lead to life-threatening diseases in clinical settings. Most of the risk factors for the incidence of CDIs, i.e., antibiotic use, treatment by proton pump inhibitors, old age, and hospitalization, are associated with dysbiosis of gut microbiota and associated metabolites and, consequently, treatment options for CDIs include normalizing the composition of the intestinal microbiome. In this review, with an introduction to the CDI and its global epidemiology, CDI-associated traits of the gut microbiome and its metabolites were reviewed, and microbiome-targeting treatment options were introduced, which was approved recently as a new drug by the United States Food and Drug Administration (U.S. FDA), rather than a medical practice. [ABSTRACT FROM AUTHOR]

Background and objective: Extending a consistent pharmacy antimicrobial stewardship weekend service was a newly implemented initiative. We sought to evaluate the impact of incorporating an Infectious Diseases (ID)-trained clinical pharmacist into an antimicrobial stewardship program (AMS) during weekends. Results: The number of documented interventions was 451 on 362 patients compared to 115 interventions on 108 patients during the pre-implementation period (p = 0.04), with interventions primarily targeting Watch antibiotics, as classified by the WHO AWaRe classification. A reduction in the LOS was observed, with a median of 16 days (8–34) during the post-implementation period compared to 27.5 days (10–56) during the pre-implementation period (p = 0.001). The median DOT increased during the post-implementation period to 8 (6–11), versus the increase to 7 (4–11) during the pre-implementation period (p ≤ 0.001). Finally, there was no significant difference observed in healthcare-associated CDI and infection-related readmission. Methods: This is a retrospective single-center, pre–post quasi-experimental study. Data including the documented pharmacist interventions were collected from the electronic medical record (EMR), the pre-implementation phase was in 2020, and post-implementation was in 2021. The primary outcome was to identify the number of AMS interventions through prospective audit and feedback review analysis. Secondary outcomes included antibiotic days of therapy (DOT), length of hospital stay (LOS), healthcare-associated Clostridioides difficile infection (CDI), and infection-related readmission. Conclusions: The pharmacist-driven weekend AMS is an opportunity for pharmacists to intervene and optimize patients' care plans. This initiative demonstrated significant increased AMS-related interventions, promoted judicious antimicrobial use, and contributed to a reduced length of hospital stay. Our findings need to be replicated in a larger prospective study. [ABSTRACT FROM AUTHOR]

Clostridioides difficile infection (CDI) is generally treated with vancomycin, metronidazole or fidaxomicin, although fecal microbiota transplantation (FMT) represents a promising therapeutic option for antibiotic-resistant recurrent C. difficile infections (rCDIs) in adults. In pediatric cystic fibrosis (CF) patients, CDIs are generally asymptomatic and respond to treatment. Here, we present the case of an 8-year-old female, initially diagnosed as "CFTR-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis" (CMRS/CFSPID), who then progressed to CF at 12 months. In the absence of CF-related symptoms, she presented multiple and disabling episodes of bloody diarrhoea with positive tests for C. difficile antigen and A/B toxin. After conventional treatments failed and several CDI relapses, FMT was proposed. Donor screening and GM donor–receiver matching identified her mother as a donor. Metataxonomy and targeted metabolomics provided, through a pre- and post-FMT time course, gut microbiota (GM) profiling to assess GM engraftment. At first, the GM map revealed severe dysbiosis, with a prevalence of Bacteroidetes and Proteobacteria (i.e., Klebsiella spp., Escherichia coli), a reduction in Firmicutes, a GM nearly entirely composed of Enterococcaceae (i.e., Enterococcus) and an almost complete depletion of Verrucomicrobia and Actinobacteria, mostly represented by Veillonella dispar. Post FMT, an increment in Bifidobacterium spp. and Collinsella spp. with a decrease in V. dispar restored intestinal eubiosis. Consistently, four weeks after FMT treatment, the child's gut symptoms cleared, without CDI recurrence. [ABSTRACT FROM AUTHOR]

(1) Background: We describe a model of primary mild-Clostridioides difficile infection (CDI) in a naïve host, including gut microbiota analysis, weight loss, mortality, length of colonization. This model was used in order to describe the kinetics of humoral (IgG, IgM) and mucosal (IgA) immune responses against toxins (TcdA/TcdB) and surface proteins (SlpA/FliC). (2) Methods: A total of 105 CFU vegetative forms of C. difficile 630Δerm were used for challenge by oral administration after dysbiosis, induced by a cocktail of antibiotics. Gut microbiota dysbiosis was confirmed and described by 16S rDNA sequencing. We sacrificed C57Bl/6 mice after different stages of infection (day 6, 2, 7, 14, 21, 28, and 56) to evaluate IgM, IgG against TcdA, TcdB, SlpA, FliC in blood samples, and IgA in the cecal contents collected. (3) Results: In our model, we observed a reproducible gut microbiota dysbiosis, allowing for C. difficile digestive colonization. CDI was objectivized by a mean weight loss of 13.1% and associated with a low mortality rate of 15.7% of mice. We observed an increase in IgM anti-toxins as early as D7 after challenge. IgG increased since D21, and IgA anti-toxins were secreted in cecal contents. Unexpectedly, neither anti-SlpA nor anti-FliC IgG or IgA were observed in our model. (4) Conclusions: In our model, we induced a gut microbiota dysbiosis, allowing a mild CDI to spontaneously resolve, with a digestive clearance observed since D14. After this primary CDI, we can study the development of specific immune responses in blood and cecal contents. [ABSTRACT FROM AUTHOR]

Background: Aerosols generated during toilet flushing are a potential source for transmission of viral and bacterial pathogens in bathrooms. However, manual decontamination of bathrooms after each use is not feasible. Methods: We tested the efficacy of a wall-mounted far ultraviolet-C (UV-C) light technology that only delivers far UV-C when people are not present for decontamination of surfaces and aerosolized viral particles in an unoccupied hospital bathroom. A quantitative disk carrier test method was used to test efficacy against organisms on steel disk carriers placed in 9 sites in the bathroom with an exposure time of 45 min and 2 h; Clostridioides difficile spores were also exposed for 24 h. Efficacy against aerosolized bacteriophage MS2 was tested with a 45-minute exposure. Results: The far UV-C technology reduced methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Candida auris, and bacteriophage MS2 on steel disk carriers by ≥ 1.2 log10 (range, 1.2 to 4.2 log10) at all test sites after 2 h of exposure. The technology reduced C. difficile spores by < 1 log10 after 2 h exposure, but 4 of 9 test locations had ≥ 2 log10 reductions after 24 h exposure. Aerosolized bacteriophage MS2 was reduced by 4 log10 plaque-forming units in 45 min. Conclusions: The far UV-C light technology could potentially be useful for automated decontamination of air and surfaces in bathrooms in healthcare and community settings. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Preventive management of tuberculosis in liver transplantation (LT) is challenging due to difficulties in detecting and treating latent tuberculosis infection (LTBI). The aim of this study was to analyze the safety and efficacy of a screening strategy for LTBI with the inclusion of moxifloxacin as treatment.We performed a retrospective single‐center study of all LTs performed between 2016 and 2019 with a minimum 4‐year follow‐up and a standardized protocol for the evaluation of LTBI.Pretransplant LTBI screening was performed in 191/218 (87.6%) patients, and LTBI was diagnosed in 27.2% of them. Treatment for LTBI was administered to 71.2% of the patients and included moxifloxacin in 75.6% of the cases. After a median follow‐up of 1628 days, no cases of active tuberculosis occurred among moxifloxacin‐treated patients. The incidence of Clostridioides difficile (0.46 vs. 0.38 episodes/1000 transplant‐days; p =  .8) and multidrug‐resistant gram‐negative bacilli infection (0 vs. 0.7 episodes per 1000 transplant‐days; p =  .08) were not significantly higher in comparison to patients who did not receive moxifloxacin.A preventive strategy based on systematic LTBI screening and moxifloxacin treatment before LT in positive cases appears safe and effective in preventing the development of tuberculosis in LT recipients. However, our findings are limited by a small sample size; thus, larger studies are required to validate our observations. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Chimeric antigen receptor (CAR) T‐cell therapy is an emerging therapeutic modality for relapsed and refractory hematological malignancies. Infectious complications following CAR T‐cell therapy are not well defined.This is a retrospective analysis of data on patients who received CAR T‐cell therapy between April 2018 and December 2022 at the Karmanos Cancer Center, Detroit. Patients’ data were collected up to their last known clinic or inpatient follow‐up visit. An infectious episode was defined as any microbiologically proven or clinically documented infection.Seventy‐six patients received therapy with FDA‐approved CAR T‐cell products. Thirty‐three patients (43.4%) had at least one infectious episode. There were 61 infectious episodes during a median follow‐up of 184 (96–340) days. Median duration for the onset of infection was 59 (22–209) days. Bacterial and viral infections occurred in 42.6% and 41% of the infectious episodes, respectively. COVID‐19 was the most common infectious complication (14.8%). Time‐to‐event analysis showed that most infections occurred within the first 100 days. Empirical antibiotic use during Cytokine Release Syndrome/Immune effector Cell‐Associated Neurotoxicity Syndrome (CRS/ICANS) in the absence of documented bacterial infection was reported in 85.7% of patients. Clostridioides difficile accounted for 11.5% of all infectious episodes. Five of six patients with C. difficile infection had CRS/ICANS and received antibiotics.COVID‐19 and C. difficile infection were the most common infections following CAR T‐cell therapy. Most infections occurred within the first 100 days. Empiric antibiotic use and C. difficile infection were common in patients with CRS/ICANS, in the absence of documented bacterial infection, thus providing an excellent opportunity for antimicrobial stewardship in this population. [ABSTRACT FROM AUTHOR]

Clostridioides difficile is a spore-forming pathogen and the most common cause of healthcare-associated diarrhea and colitis in the United States. Besides producing the main virulence factors, toxin A (TcdA) and toxin B (TcdB), many of the common clinical strains encode the C. difficile transferase (CDT) binary toxin. The role of CDT in the context of C. difficile infection (CDI) is poorly understood. Inflammation is a hallmark of CDI and multiple mechanisms of inflammasome activation have been reported for TcdA, TcdB, and the organism. Some studies have suggested that CDT contributes to this inflammation through a TLR2-dependent priming mechanism that leads to the suppression of protective eosinophils. Here, we show that CDT does not prime but instead activates the inflammasome in bone marrow-derived dendritic cells (BMDCs). In bone marrow-derived macrophages (BMDMs), the cell binding and pore-forming component of the toxin, CDTb, alone activates the inflammasome and is dependent on K+ efflux. The activation is not observed in the presence of CDTa and is not observed in BMDMs derived from Nlrp3-/- mice suggesting the involvement of the NLRP3 inflammasome. However, we did not observe evidence of CDT-dependent inflammasome priming or activation in vivo. Mice were infected with R20291 and an isogenic CRISPR/Cas9-generated R20291 ΔcdtB strain of C. difficile. While CDT contributes to increased weight loss and cecal edema at 2 days post infection, the relative levels of inflammasome-associated cytokines, IL-1β and IL-18, in the cecum and distal colon are unchanged. We also saw CDT-dependent weightloss in Nlrp3-/- mice, suggesting that the increased weightloss associated with the presence of CDT is not a result of NLRP3-dependent inflammasome activation. This study highlights the importance of studying gene deletions in the context of otherwise fully isogenic strains and the challenge of translating toxin-specific cellular responses into a physiological context, especially when multiple toxins are acting at the same time. Author summary: Clostridioides difficile is a pathogen causing life-threatening diarrhea. C. difficile transferase (CDT) toxin is present in many strains associated with severe disease but its role during C. difficile infection is unclear. In this study, we show that the pore forming subunit, CDTb, activates the inflammasome in myeloid-derived murine cells. While we found that CDT contributes to weight loss in a C. difficile mouse infection model, this was independent of the inflammasome function. This study highlights the importance of studying gene deletions in the context of otherwise fully isogenic strains and the challenge of translating findings in tissue culture models to animal infections. However, it does reveal an additive role for CDT in the tissue edema that occurs in the murine model of acute infection and is consistent with the idea that CDT contributes to the severity of CDI symptoms. [ABSTRACT FROM AUTHOR]

Background: Clostridioides difficile infection (CDI) is an infectious disease caused by the gram-positive, anaerobic bacterium C. difficile. The vulnerable populations for CDI include the elderly, immunocompromised individuals, and hospitalized patients, especially those undergoing antimicrobial therapy, which is a significant risk factor for this infection. Due to its complications and increased resistance to treatment, CDI often leads to longer hospital stays. This study aimed to determine the average length of hospital stay (LOS) of Polish patients with CDI and to identify factors affecting the LOS of infected patients. Methods: The study analyzed medical records of adult patients treated with CDI in one of the biggest clinical hospitals in Poland between 2016–2018. Information encompassed the patient's age, LOS results of selected laboratory tests, number of antibiotics used, nutritional status based on Nutritional Risk Screening (NRS 2002), year of hospitalization, presence of diarrhea on admission, systemic infections, additional conditions, and undergone therapies. The systematic collection of these variables forms the foundation for a comprehensive analysis of factors influencing the length of stay. Results: In the study period, 319 patients with CDI were hospitalized, with a median LOS of 24 days (min–max = 2–344 days). The average LOS was 4.74 days in 2016 (median = 28 days), 4.27 days in 2017 (median = 24 days), and 4.25 days in 2018 (median = 23 days). There was a weak negative correlation (Rho = -0.235, p < 0.001) between albumin level and LOS and a weak positive correlation between NRS and LOS (Rho = 0.219, p < 0.001). Patients admitted with diarrhea, a history of stroke or pneumonia, those taking certain antibiotics (penicillins, cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, colistin), and those using proton pump inhibitors, exhibited longer hospitalizations (all p < 0.001) or unfortunately died (p = 0.008). None of the individual predictors such as albumin level, Nutritional Risk Screen, pneumonia, stroke, and age showed a statistically significant relationship with the LOS (p > 0.05). However, the multivariate regression model explained a substantial portion of the variance in hospitalization length, with an R-squared value of 0.844. Conclusions: Hospitalization of a patient with CDI is long. Low albumin levels and increased risk of malnutrition were observed in longer hospitalized patients. Longer hospitalized patients had pneumonia, stroke, or surgery, and were admitted for a reason other than CDI. [ABSTRACT FROM AUTHOR]

Background: The nosocomial transmission of toxin-producing Clostridioides difficile is a significant concern in infection control. C. difficile, which resides in human intestines, poses a risk of transmission, especially when patients are in close contact with medical staff. Methods: To investigate the nosocomial transmission of C. difficile in a single center, we analyzed the genetic relationships of the bacteria. This was done using draft whole-genome sequencing (WGS) and examining single nucleotide polymorphisms (SNPs) in core-genome, alongside data regarding the patient’s hospital wards and room changes. Our retrospective analysis covered 38 strains, each isolated from a different patient, between April 2014 and January 2015. Results: We identified 38 strains that were divided into 11 sequence types (STs). ST81 was the most prevalent (n = 11), followed by ST183 (n = 10) and ST17 (n = 7). A cluster of strains that indicated suspected nosocomial transmission (SNT) was identified through SNP analysis. The draft WGS identified five clusters, with 16 of 38 strains belonging to these clusters. There were two clusters for ST81 (ST81-SNT-1 and ST81-SNT-2), two for ST183 (ST183-SNT-1 and ST183-SNT-2), and one for ST17 (ST17-SNT-1). ST183-SNT-1 was the largest SNT cluster, encompassing five patients who were associated with Wards A, B, and K. The most frequent room changer was a patient labeled Pt08, who changed rooms seven times in Ward B. Patients Pt36 and Pt10, who were also in Ward B, had multiple admissions and discharges during the study period. Conclusions: Additional culture tests and SNP analysis of C. difficile using draft WGS revealed silent transmission within the wards, particularly in cases involving frequent room changes and repeated admissions and discharges. Monitoring C. difficile transmission using WGS-based analysis could serve as a valuable marker in infection control management. [ABSTRACT FROM AUTHOR]

Clostridioides difficile, a cause of healthcare-associated infections, poses a significant global health threat. This multi-institutional retrospective study focuses on epidemic dynamics, emphasizing minor and toxin-negative clinical isolates through high-resolution genotyping. The genotype of the C. difficile clinical isolates during 2005 to 2022 was gathered from 14 hospitals across Japan (N = 982). The total number of unique genotypes was 294. Some genotypes were identified in every hospital (cross-regional genotypes), while others were unique to a specific hospital or those in close geographic proximity (region-specific genotypes). Notably, a hospital located in a sparsely populated prefecture exhibited the highest prevalence of region-specific genotypes. The isolation rate of cross-regional genotypes positively correlated with the human mobility flow. A 6-month interval analysis at a university hospital from 2019 to 2021 revealed a temporal transition of the genotype dominance. The frequent isolation of identical genotypes over a brief timeframe did not always align with the current criteria for defining nosocomial outbreaks. This study highlights the presence of diverse indigenous C. difficile strains in regional environments. The cross-regional strains may have a higher competency to spread in the human community. The longitudinal analysis underscores the need for further investigation into potential nosocomial spread. [ABSTRACT FROM AUTHOR]

Introduction: The greater predisposition to infections, as well as the possibility of a worse response to treatment, can lead to the excessive use of antimicrobials among cancer patients. C-reactive protein (CRP) has gained prominence as a tool for monitoring therapeutic responses and reducing the duration of antibiotic therapy; however, few studies have analyzed this protein in cancer patient populations. We hypothesize that cancer patients with a good response to antibiotic therapy show a faster decline in serum CRP levels, which would allow us to identify candidates for short-course treatments. Objective: To evaluate the behavior of serum CRP levels among adult cancer patients using antibiotic therapy, and its association with the duration of this treatment, therapeutic response, and clinical recurrence. Methods: This work consisted of a retrospective study with cancer patients admitted to a university hospital between September 2018 and December 2019. Adults (age ≥ 18 years) who underwent at least one course of antibiotic therapy were included. CRP behavior over the first 7 days of treatment was classified as: i) good response: when the CRP value on the fifth day of therapy reached 50% or less of the peak value detected in the first 48 h of treatment, and ii) poor response: Maintenance, within the same interval, of a CRP value > 50% of the peak value in the first 48 h. The duration of antibiotic therapy was categorized as up to seven full days or more. Outcomes were assessed by events that occurred during the 30 days of hospitalization or until hospital discharge. Primary outcome: Clinical recurrence of the index infection. Secondary outcomes: i) Death from any cause; ii) microbiological recurrence; iii) therapeutic response; iv) colitis associated with Clostridioides difficile; and v) isolation of multi-resistant bacteria, whether in clinical or surveillance samples. Results: The final analysis consisted of 212 patients, with a median age (IQ) of 59.2 (48 – 67) years old and a predominance of females (65%), who were hypertensive (35%), smokers (21%), and diabetics (17.8%). There was no difference in clinical recurrence between the two groups (8.1% vs. 12.2%; p = 0.364), with a lower 30-day mortality in the good CRP response group (32.2% vs. 14.5%; p = 0.002). Despite the tendency towards a lower occurrence of other secondary outcomes in the good response group, these differences were not statistically significant. In the poor CRP response group, outcomes like clinical recurrence, mortality, and therapeutic response were significantly worse, regardless of the duration of antibiotic treatment. Conclusion: In this study, cancer patients with a good CRP response during antibiotic therapy presented lower mortality and a higher proportion of satisfactory therapeutic responses. CRP can be a useful tool when combined with other clinical information in optimizing the duration of antimicrobial treatment in a hospitalized cancer population. [ABSTRACT FROM AUTHOR]

Purpose: Diverting Loop Ileostomy (DLI) with intraoperative colonic lavage has emerged as a potential alternative to Total Abdominal Colectomy (TAC) for treating Fulminant Clostridium Difficile Colitis (FCDC). This study aims to provide an updated review comparing DLI with TAC in managing FCDC. Methods: A systematic literature search was conducted using PubMed, Scopus, and Embase to identify retrospective and prospective studies comparing DLI with TAC for fulminant CDC treatment. A meta-analysis was performed to evaluate postoperative mortality rates and complications using R Studio version 4.4.1, calculating odds ratios (ORs) with 95% confidence intervals via the Mantel-Haenszel method. Heterogeneity was assessed using the Cochrane Q test and I2 statistics. Results: Our search yielded 228 relevant citations, of which 7 studies with a total of 7,048 patients were included. Of these, 1,728 underwent DLI. The mean age was 63.33 years in the DLI group and 65.74 years in the TAC group. Compared to TAC, DLI had significantly lower postoperative mortality (OR 0.75; 95% CI 0.62–0.90; P = 0.002; I2 = 34%). Trial sequential analysis for postoperative mortality rates showed the benefit of DLI with a sufficiently powered sample. The DLI group also had a significantly higher rate of ostomy reversal (OR 5.68; 95% CI 2.35–13.72; P < 0.001; I2 = 36%). Postoperative complications, such as thromboembolic events, surgical site infections, urinary tract infections, renal failure, and pneumonia, were not significantly different. Conclusion: DLI shows a lower postoperative mortality rate and higher ostomy reversal rate than TAC, suggesting it as a potential organ-preserving, minimally invasive alternative. Further high-quality studies and trials are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Biofilm formation and toxin production are some of the virulence factors of Clostridioides difficile (C. difficile), which causes hospital-acquired C. difficile infection (HA-CDI). This work investigated the prevalence and distribution of different strains recovered from HA-CDI patients hospitalized in 4 medical centres across Israel, and characterized strains' virulence factors and antibiotic susceptibility. One-hundred and eighty-eight faecal samples were collected. C. difficile 's toxins were detected by the CerTest Clostridium difficile GDH + Toxin A + B combo card test kit. Toxin loci PaLoc and PaCdt were detected by whole-genome sequencing (WGS). Multi-locus sequence typing (MLST) was performed to classify strains. Biofilm production was assessed by crystal violet. Antibiotic susceptibility was determined using Etest. Fidaxomicin susceptibility was tested via agar dilution. Sequence type (ST) 42 was the most (13.8%) common strain. All strains harboured the 2 toxins genes; 6.9% had the binary toxin. Most isolates were susceptible to metronidazole (98.9%) and vancomycin (99.5%). Eleven (5.85%) isolates were fidaxomicin-resistant. Biofilm production capacity was associated with ST (p < 0.001). In conclusion, a broad variety of C. difficile strains circulate in Israel's medical centres. Further studies are needed to explore the differences and their contribution to HA-CDI epidemiology. [ABSTRACT FROM AUTHOR]

Introduction: Antimicrobial therapy plays a crucial role in the management of CDI patients. However, the standard agent for treating CDIs is limited to oral fidaxomicin or vancomycin. For patients made nil by mouth, there is a clinically urgent and essential need to develop an intravenous antibiotic. Methods: For C. difficile with the lowest MIC of nemonoxacin and vancomycin, the inhibitory effects were tested using the kinetic time-kill assay and ex vivo coculture model. The effectiveness of nemonoxacin and vancomycin in inhibiting spore germination, the sporicidal activity, and the treatment of mice with CDIs were compared. Results: For clinical isolates and laboratory strains, lower MICs of nemonoxacin against C. difficile than levofloxacin and ciprofloxacin were observed, even in those harboring point mutations in the quinolone-resistance determining region. Although nemonoxacin failed to suppress spore outgrowth and germination in C. difficile, it exhibited an effective inhibitory effect against C. difficile in the kinetic time-kill assay and the ex vivo co-culture model. Mice receiving intraperitoneal nemonoxacin had less weight loss, higher cecum weight, a longer colon length, and lower expression of the tcdB gene, compared with untreated mice. Notably, there were no significant differences observed in weight loss, cecum weight, colon length, or tcdB gene expression between mice treated with vancomycin and those treated with any dose of nemonoxacin. Similarly, no significant differences were found between mice receiving combination therapy of intraperitoneal nemonoxacin plus oral vancomycin and those treated with intraperitoneal nemonoxacin or oral vancomycin alone. Discussion: The potential role of nemonoxacin, which can be administered parenterally, for treating CDIs was evidenced through the in vitro, ex vivo, and mouse models. [ABSTRACT FROM AUTHOR]

A group of bacterial proteases, the Pro‐Pro endopeptidases (PPEPs), possess the unique ability to hydrolyze proline‐proline bonds in proteins. Since a protease's function is largely determined by its substrate specificity, methods that can extensively characterize substrate specificity are valuable tools for protease research. Previously, we achieved an in‐depth characterization of PPEP prime‐side specificity. However, PPEP specificity is also determined by the non‐prime‐side residues in the substrate. To gain a more complete insight into the determinants of PPEP specificity, we characterized the non‐prime‐ and prime‐side specificity of various PPEPs using a combination of synthetic combinatorial peptide libraries and mass spectrometry. With this approach, we deepened our understanding of the P3‐P3′ specificities of PPEP‐1 and PPEP‐2, while identifying the endogenous substrate of PPEP‐2 as the most optimal substrate in our library data. Furthermore, by employing the library approach, we investigated the altered specificity of mutants of PPEP‐1 and PPEP‐2. Additionally, we characterized a novel PPEP from Anoxybacillus tepidamans, which we termed PPEP‐4. Based on structural comparisons, we hypothesized that PPEP‐4 displays a PPEP‐1‐like prime‐side specificity, which was substantiated by the experimental data. Intriguingly, another putative PPEP from Clostridioides difficile, CD1597, did not display Pro‐Pro endoproteolytic activity. Collectively, we characterized PPEP specificity in detail using our robust peptide library method and, together with additional structural information, provide more insight into the intricate mechanisms that govern protease specificity. [ABSTRACT FROM AUTHOR]

Background Recurrent Clostridioides difficile infection (CDI) is a critical clinical issue due to the increase in incidence and difficulty in treatment. We aimed to identify gut microbial and metabolic features associated with disease recurrence in a group of pediatric CDI patients. Methods A total of 84 children with primary CDI were prospectively enrolled in the study. Fecal samples collected at the initial diagnosis were subjected to 16S rRNA gene sequencing and targeted metabolomics analysis to profile the bacterial composition and metabolome. Results Twenty-six of 84 (31.0%) pediatric CDI patients experienced recurrence. The alpha diversity of the fecal microbiota was significantly lower in the recurrent group than in the nonrecurrent group, and the beta diversity was different from that of the nonrecurrent group. Taxonomic profiles revealed that the relative abundances of multiple bacterial taxa significantly differed between the recurrent and nonrecurrent groups. Linear discriminant analysis effect size analysis identified several bacterial genera that discriminated between recurrent and nonrecurrent groups, including Parabacteroides , Coprococcus , Dialister , and Clostridium. Recurrent bacteria presented lower abundances of several short-chain fatty acid (SCFA)–producing bacteria (Faecalibacterium , Butyricicoccus , Clostridium , Roseburia , and Ruminococcus), which were correlated with reduced fecal SCFA levels. In addition, several bile acids, including lithocholic acid (LCA), 12-ketoLCA, trihydroxycholestanoic acid, and deoxycholic acid, were decreased in recurrent patients. Conclusions Our study suggests that the differing gut microbiota profiles in pediatric CDI patients may contribute to disease recurrence by modulating SCFA concentrations and bile acid profiles. The gut microbiota and metabolite signatures may be used to predict disease recurrence in children with CDI. [ABSTRACT FROM AUTHOR]